Comprehensive Geriatric Oncology

Comprehensive Geriatric Oncology 2nd Edition Edited by

Lodovico Balducci MD Professor of Medicine and Program Leader Senior Adult Oncology Program H Lee Moffitt Cancer Center and Research Institute Tampa, FL 33612 USA Gary H Lyman MD MPH Professor of Medicine, Epidemiology and Biostatistics Medical Oncology and Hematology H Lee Moffitt Cancer Center and Research Institute Tampa, FL 33612 USA

William B Ershler MD Director, Institute for Advanced Studies in Aging and Geriatric Medicine 1819 Pennsylvania Avenue NW Washington, DC 20006 USA Martine Extermann MD Senior Adult Oncology Program H Lee Moffitt Cancer Center and Research Institute Tampa, FL 33612 USA

LONDON AND NEW YORK A MARTIN DUNITZ BOOK

© 2004 Taylor & Francis, an imprint of the Taylor & Francis Group First published in the United Kingdom in 2004 by Taylor & Francis, an imprint of the Taylor & Francis Group, 2 Park Square, Milton Park, Abingdon, Oxon OX14 4RN Tel: 01235 828600 Fax: 01235 829000 E-mail: [email protected] Website: http://www.dunitz.co.uk/ This edition published in the Taylor & Francis e-Library, 2006. To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to http://www.ebookstore.tandf.co.uk/. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. A CIP record for this book is available from the British Library. Library of Congress Cataloging-in-Publication Data Data available on application ISBN 0-203-49451-2 Master e-book ISBN

ISBN 0-203-59590-4 (Adobe e-Reader Format) ISBN 1 84184 296 6 (Print Edition) Distributed in North and South America by Taylor & Francis 2000 NW Corporate Blvd Boca Raton, FL 33431, USA Within Continental USA Tel: 800 272 7737; Fax: 800 374 3401 Outside Continental USA Tel: 561 994 0555; Fax: 561 361 6018 E-mail: [email protected] Distributed in the rest of the world by Thomson Publishing Services Cheriton House North Way Andover, Hampshire SP10 5BE, UK Tel: +44 (0)1264 332424 E-mail: [email protected] Composition by Scribe Design, Gillingham, Kent, UK

Contents List of contributors Preface to the second edition Preface to the first edition

ix xxvii xxx

Part 1— Overview 1. Aging and cancer BJ Kennedy 2. Essentials of clinical decision analysis: A new way to think about cancer and aging Gary H Lyman

2 18

Part 2— Epidemiology 3. Cancer mortality in the elderly, 1960–98: A worldwide approach Carlo La Vecchia, Franca Lucchini, Eva Negri, Fabio Levi 4. Cancer in older persons: Magnitude of the problem and efforts to advance the aging/cancer research interface Rosemary Yancik, Lynn AG Ries 5. Epidemiological research in aging: Perspectives and limitations Marion RS Bain, Jean C Harvey 6. Factors affecting the diagnosis and treatment of older persons with cancer James S Goodwin, Cynthia Osborne

51 63

78 94

Part 3— Biology of aging and cancer 7. Biology of aging and cancer William B Ershler 8. Age as a risk factor in multistage carcinogenesis Vladimir N Anisimov 9. Growth factors, oncogenes, and aging J Alberto Fernandez-Pol

109 123 170

10. Proliferative senescence and cancer Judith Campisi 11. Apoptosis, chemotherapy, and aging David E Fisher 12. Tumor-host interactions, aging, and tumor growth William B Ershler 13. Immunological changes of aging Edith A Burns, James S Goodwin 14. Biologic characteristics of primary breast cancer Maria Grazia Daidone, Rosella Silvestrini, Aurora Costa, Danila Coradini, Gabriele Martelli, Silvia Veneroni 15. Clinical evidence for change in tumor aggressiveness with age: A historical perspective Frederick F Holmes 16. Morbid anatomy of aging Giorgio Stanta 17. Natural history and epidemiology of monoclonal gammopathies Harvey Jay Cohen, Daniel Nikcevich

223 243 261 283 306

322

333 347

Part 4— The influence of aging on prevention, diagnosis and treatment of cancer 18. Physiology of aging: Relevance to symptoms, perceptions, and treatment tolerance Edmund H Duthie, Jr 19. Assessment of the older patient with cancer Lodovico Balducci, Martine Extermann 20. Frailty, cancer cachexia, and near death David Hamerman 21. Practical proposals for clinical protocols in elderly patients with cancer Martine Extermann, Lodovico Balducd 22. Under-representation of elderly patients in cancer clinical trials: Causes and remedial strategies Joseph M Unger, Laura F Hutchins, Kathie S Albain 23. Radiotherapy in the elderly: The achievements of the Geriatric Radiation Oncology Group (GROG) Patrizia Olmi, Giampiero Ausili Cefaro, Anna Marie Cerrotta 24. Quality of life considerations in the older cancer patient Patrida A Ganz 25. Social support and the elderly cancer patient Cleora S Roberts 26. Prognostic evaluation of the older cancer patient Lazzaro Repetto, Antonella Venturino, Walter Gianni

367

398 422 448 464

492

520 538 551

Part 5— Cancer prevention in the aged 27. Nutrition, cancer, and the aging process: A rationale for nutritional practice guidelines Nagi Kumar, Jeanne Hudson, Theresa Crocker, Diane Riccardi, Kathy Allen 28. Chemoprevention of cancer in the older person Lodovico Balducci, Claudia Beghe’ 29. Secondary prevention of cancer in the older person Claudia Beghe’, Lodovico Balducci 30. Barriers to cancer prevention in the older person Sarah A Fox, Richard G Roetzheim

571

618 645 665

Part 6— Management of cancer in the older person 31. Perspectives on training in geriatrics and oncology John M Bennett 32. Management of cancer in the older aged patient Lodovico Balducci, Charles E Cox, Harvey Greenberg, Gary H Lyman, Rafael Miguel, Richard Karl, Peter J Fabri 33. Surgical approaches to the older patient with cancer Peter J Fabri 34. Advances in geriatric surgery Peter J Fabri 35. Perioperative considerations in the geriatric oncology patient Rafael Miguel, Hector Vila 36. Hematopoiesis and aging Lynn C Mosdnski 37. Anemia and aging: Relevance to the management of cancer Lodovico Balducci, Cheryl L Hardy 38. Radiotherapy in the elderly Pierre Scalliet, Thierry Pignon 39. Cancer chemotherapy in the older patient Dario Cova, Lodovico Balducci 40. Hematopoietic stem cell transplantation in the older patient Karen K Fields, Benjamin Djulbegovic 41. Polypharmacy in the senior adult patient Mary E Corcoran, 42. Diagnosis and treatment of cancer in the elderly: Cost-effectiveness considerations Gary H Lyman, Nicole M Kuderer 43. Guidelines for the management of the older cancer patient Lodovico Balducci

685 688

702 715 731 753 782 801 818 864 890 905

933

Lodovico Balducci 44. Oncological emergencies in the elderly Lodovico Balducci, Claudia Beghe’

949

Part 7— Management of specific tumors in older persons 45. Treatment of acute myeloid leukemia in older patients Thomas Buchner 46. Chronic leukemias in the elderly Alexander SD Spiers 47. Hodgkin lymphoma in the elderly Paul Kaesberg 48. Non-Hodgkin lymphomas Bruce Peterson, Stuart Bloom 49. Advances in the treatment of multiple myeloma in the elderly patient Gabriela Ballester, Oscar Ballester, Claudia Corrado, David Vesole 50. Treatment of small cell lung cancer in the elderly Frances A Shepherd, Andrea Bezjak 51. Breast cancer in the older woman: An oncologic perspective Lodovico Balducci, Rebecca A Silliman, Nils Diaz 52. Breast cancer: A geriatric perspective Sarah B Blackman, Rebecca A Silliman, Lodovico Balducci 53. Colorectal cancer Barbara A Neilan 54. Head and neck oncology in the aging patient James N Endicott, Lodovico Balducci 55. Prostate cancer in the elderly Timothy D Moon 56. Transitional cell carcinoma of the bladder in the elderly Julio Pow-Sang, Jay Friedland, Albert Einstein 57. Brain tumors in the older person Alexandra Flowers 58. Gynecologic cancers in the elderly Tate Thigpen 59. Skin cancer in the aging patient Matthew J Reschly, Karen Laszlo Keller, Dan Smith, Neil A Fenske, L Frank Glass

980 995 1074 1094 1133 1150 1169 1244 1255 1267 1279 1312 1324 1363 1388

Part 8— Rehabilitation and supportive care 60. Management of infectious complications in the aged cancer patient John N Greene

1418

61. Symptom management in the older patient Robert Anderson, Walter B Forman 62. Oncological rehabilitation of the elderly Dario Dini, Alberto Gozza 63. Family caregiving issues for older cancer patients William E Haley, Allison M Burton, Laurie A LaMonde, Ronald S Schonwetter 64. Interdisciplinary teams in geriatric oncology Janine Overcash 863 Spirituality and medicine Mary Jane Marsh, Russell Meyer, Lodovico Balducci Index

1435 1467 1492

1509 1526

1532

List of contributors Kathie S Albain MD Professor of Medicine Loyala University Medical Center Cancer Center 2160 South First Avenue Maywood, IL 60153–5589 USA Kathy Allen RD Department of Nutrition H Lee Moffitt Cancer Center and Research Institute 12902 Magnolia Avenue Tampa, FL 33612 USA Robert P Anderson Oncology Pharmacist Veterans Affairs Medical Center Albuquerque, NM USA Vladimir N Anisimov PhD Chief, Laboratory of Experimental Tumors NN Petrov Research Institute of Oncology 68 Leningradskaya St Pesochny—2 St Petersburg Russia Marion RS Bain MB ChB Medical Director Information and Statistics Division National Health Service Scotland Trinity Park House, South Trinity Road Edinburgh EH5 3SQ UK Lodovico Balducci MD Professor of Oncology and Medicine Interdisciplinary Oncology Program

University of Florida College of Medicine and Professor of Medicine and Program Leader Senior Adult Oncology Program H Lee Moffitt Cancer Center and Research Institute 12902 Magnolia Avenue Tampa, FL 33612 USA Gabriela Ballester MD Fellow, Hematology Oncology Medical College of Georgia Augusta, GA 30912 USA Oscar Ballester Director, Stem Cell Transplant Program Medical College of Georgia Augusta, GA 30912 USA Claudia Beghe’ Associate Professor of Medicine University of Florida College of Medicine Tampa, FL and Medical Director Nursing Home Care Unit James A Haley Veterans Hospital Tampa, FL 33612 USA John M Bennett MD Professor of Medicine University of Rochester Cancer Center Rochester, NY 14642 USA Andrea Bezjak MD Department of Radiation Oncology Princess Margaret Hospital Toronto, Ontario M5G 2M9 Canada Sarah B Blackman MPH Health Care Compliance Specialist

University of Virginia 2270 Ivy Road Charlottesville, VA 22903 USA Stuart Bloom MD Medical Oncology, Hematology Hubert H Humphrey Cancer Center Robbinsdale, MN 55422–2900 USA Thomas Büchner MD Professor of Medicine University of Miinster Department of Medicine Hematology and Oncology D48129 Munster Germany Edith A Burns MD Assistant Professor of Medicine Section of Geriatrics Sinai Samaritan Medical Center Milwaukee, WI USA Allison M Burton BA Doctoral Candidate School of Aging Studies University of South Florida 4202 East Fowler Avenue Tampa, FL 33620 USA Judith Campisi PhD Senior Scientist Lawrence Berkeley National Laboratory 1 Cyclotron Road, 84–171 Berkeley, CA 94720 USA Giampiero Ausili Cefaro MD Chief, Radiotherapy Division Policlinico A Gemelli Universita Cattolica Sacro Cuore Largo A Gemelli, 8

Rome Italy Anna Marie Cerrotta MD Professor of Radiation Oncology Department of Radiotherapy National Cancer Institute Milano Italy Harvey Jay Cohen MD Professor of Medicine Chief of Geriatrics and Director, Center on Aging Duke University Medical Center Durham, NC 27710 USA and Director, FRECC, VAMC Durham, NC 27705 USA Danila Coradini PhD Experimental Oncology Department Unit 10—Determinants of Prognosis and Treatment Response Instituto Nazionale Tumori Via Venezian 1 20133 Milan Italy Mary E Corcoran CRPH Clinical Pharmacist H Lee Moffitt Cancer Center and Research Institute 12902 Magnolia Drive Tampa, FL 33612 USA Claudia Corrado MD Attending Physician National Academy of Medicine Buenos Aires Argentina Aurora Costa PhD Experimental Oncology Department Unit 10—Determinants of Prognosis and Treatment Response

Instituto Nazionale Tumori Via Venezian 1 20133 Milan Italy Dario Cova MD Chief, Oncology Service Pio Albergo Trivulzio Milano Italy Charles E Cox MD Professor H Lee Moffitt Cancer Center 12902 Magnolia Drive Tampa, FL 33612 USA Theresa Crocker MD, RD Department of Nutrition H Lee Moffitt Cancer Center and Research Institute 12902 Magnolia Avenue Tampa, FL 33612 USA Maria Grazia Daidone PhD Experimental Oncology Department Unit 10—Determinants of Prognosis and Treatment Response Instituto Nazionale Tumori Via Venezian 1 20133 Milan Italy Nils Diaz H Lee Moffitt Cancer Center and Research Institute 12902 Magnolia Avenue Tampa, FL 33612 USA Dario Dini MD Professor of Rehabilitative Medicine Istituto Nazionale per la Ricerca sul Cancro Genova Italy

Benjamin Djulbegovic MD Professor of Oncology and Medicine H Lee Moffitt Cancer Center and Research Institute University of South Florida Department of Interndisciplinary Oncology 12902 Magnolia Drive Tampa, FL 33612 USA Edmund H Duthie, Jr MD Professor of Medicine Chief, Division of Geriatrics and Gerontology Medical College of Wisconsin VA Medical Center Milwaukee Milwaukee, WI 53295 USA Albert B Einstein, Jr MD Executive Director Swedish Cancer Institute Swedish Health Services 1221 Madison Street #500 Seattie, WA 98104 USA James N Endicott MD Professor, Otolaryngology St Petersburg, FL USA William B Ershler MD Director, Institute for Advanced Studies in Aging and Geriatric Medicine Senior Investigator Clinical Research branch National Institute on Aging 1700 Wisconsin Avenue NW Washington, DC 20007 USA Martine Extermann MD Senior Adult Oncology Program H Lee Moffitt Cancer Center and Research Institute 12902 Magnolia Avenue Tampa, FL 33612 USA

Peter J Fabri MD Professor of Surgery Assistant Dean for Clinical Affairs University of South Florida, College of Medicine Tampa, FL 33620 USA Neil A Fenske MD Professor and Director Division of Dermatology and Cutaneous Surgery University of South Florida College of Medicine 12901 Bruce B Downs Boulevard Tampa, FL 33162 USA J Alberto Fernandez-Pol MD 437 Hunters Hill Drive Chesterfield, MO 63017 USA Karen K Fields Professor of Medicine and Oncology H Lee Moffitt Cancer Center and Research Institute University of South Florida 12902 Magnolia Avenue Tampa, FL 33612 USA David E Fisher MD Associate Professor Harvard Medical Center Dana-Farber Cancer Institute 44 Binney Street, Dana 630 Boston, MA 02115 USA Alexandra Flowers MD Coordinator, Neuro-Oncology Program Hartford Hospital 80 Seymour Street Hartford, CT 06102 USA Walter B Forman MD Professor, Department of Internal Medicine Division of Geriatrics

University of New Mexico Health Sciences Center Albuquerque, NM 87131 USA Sarah A Fox EdD MSPH Professor, Division of General Internal Medicine and Health Services Research Department of Medicine David Geffen School of Medicine University of California at Los Angeles 1100 Glendon Avenue, Suite 2010 Los Angeles, CA 90024-3524 USA Jay Friedland MD Assistant Professor of Radiation Oncology University of Pennsylvania Pennsylvania USA Patricia A Ganz MD Professor, Schools of Medicine and Public Health Division of Cancer Prevention and Control Research Jonsson Comprehensive Cancer Center University of California Los Angeles, CA 90095–6900 USA Walter Gianni U O Oncologia Istituto Nazionale di Riposo e Cura per Anziani (INRCA) Rome Italy L Frank Glass MD Associate Professor Division of Dermatology and Cutaneous Surgery University of South Florida College of Medicine 12901 Bruce B Downs Boulevard Tampa, FL 33162 USA James S Goodwin MD George and Cynthia Mitchell Distinguished Professor

The University of Texas Medical Branch Galveston, TX USA Alberto Gozza MD Associate Professor National Institute of Cancer Research Genova Italy Harvey Greenberg MD Associate Professor Department of Radiation Oncology H Lee Moffitt Cancer Center and Research Institute 12902 Magnolia Avenue Tampa, FL 33612 USA John N Greene MD Associate Professor Infection Control H Lee Moffitt Cancer Center and Research Institute 12902 Magnolia Avenue Tampa, FL 33612 USA William E Haley PhD Professor and Director School of Aging Studies University of South Florida 402 East Fowler Avenue Tampa, FL 33620 USA David Hamerman MD Distinguished University Professor and Director Resnick Gerontology Center Albert Einstein College of Medicine Montefiore Medical Center Bronx, NY 10467 USA Cheryl L Hardy MD Division of Hematology University of Mississippi School of Medicine 2500 N State Street

Jackson, MS USA Jean C Harvey BSc (Hons) Scottish Cancer Registry Information and Statistics Division National Health Service Scotland Trinity Park House, South Trinity Road Edinburgh EH5 3SQ UK Frederick F Holmes MD Edward Hasinger Distinguished Professor University of Kansas Medical Center School of Medicine, Department of Internal Medicine Division of General and Geriatric Medicine 3901 Rainbow Boulevard Kansas City, KA 66216-1234 USA Jeanne Hudson RD Department of Nutrition H Lee Moffitt Cancer Center and Research Institute 12902 Magnolia Avenue Tampa, FL 33612 USA Laura F Hutchins MD Professor of Medicine University of Arkansas for Medical Sciences 4301 W Markham Slot 508 Little Rock, AR 72205 USA Paul R Kaesberg MD Clinical Assistant Professor of Medicine Section of Medical Oncology University of Wisconsin School of Medicine c/o William S Middleton Veteran’s Administration Hospital 2500 Overlook Terrace Madison, WI 53705 USA

Richard Karl MD Chief of Surgery and Program Leader Gastrointestinal Tumor Program H Lee Moffitt Cancer Center and Research Institute 12902 Magnolia Avenue Tampa, FL 33612 USA Karen Laszlo Keller MD Resident Division of Dermatology and Cutaneous Surgery University of South Florida College of Medicine 12901 Bruce B Downs Boulevard Tampa, FL 33162 USA BJ Kennedy MD (deceased) Formerly Regents’ Professor of Medicine, Emeritus Masonic Professor of Oncology, Emeritus Division of Hematology, Oncology and Transplantation University of Minnesota Medical School Minneapolis, MN 55455 USA Nicole M Kuderer MD University of South Florida H Lee Moffitt Cancer Center and Research Institute 12902 Magnolia Avenue Tampa, FL 33612 USA Nagi Kumar PhD, RD, FADA Department of Nutrition H Lee Moffitt Cancer Center and Research Institute 12902 Magnolia Avenue Tampa, FL 33612 USA Carlo La Vecchia Instituto di Ricerche Farmacologiche ‘Mario Negri’ Via Eritrea 62 20157 Milan Italy Laurie A LaMonde PhD School of Aging Studies

University of South Florida 4202 East Fowler Avenue Tampa, FL 33620 USA Fabio Levi MD Registre Vaudois des tumeurs Institute Universitaire de Medecine Sociale et Preventive Centre Hospital Universitaire Vaudois 1011 Lausanne Switzerland Franca Lucchini Unite Epidemiologie du Cancer and Registeres Vaudois et Neuchatelois des tumours Institute Universitaire de Medecine Sociale et Preventive Centre Hospital Universitaire Vaudois 1011 Lausanne Switzerland Gary H Lyman MD MPH Director, Cancer Center of Albany Medical College 47 New Scotland Avenue Albany, NY 12208 and Professor of Medicine, Epidemiology and Biostatistics Medical Oncology and Hematology University of South Florida H Lee Moffitt Cancer Center and Research Institute 12902 Magnolia Avenue Tampa, FL 33612 USA Mary Jane Marsh RN Gastrointestinal Tumor Program H Lee Moffitt Cancer Center and Research Institute 12902 Magnolia Avenue Tampa, FL 33612 USA Gabriele Martelli MD Unit of Diagnostic Oncology and Outpatient Clinic Instituto Nazionale Tumori Via Venezian 1 20133 Milan Italy

Russell Meyer MDiv Tampa, FL USA Rafael Miguel MD University of South Florida, College of Medicine H Lee Moffitt Cancer Center and Research Institute 12902 Magnolia Avenue Tampa, FL 33612 USA Timothy D Moon MD Department of Surgery Division of Urology University of Wisconsin Madison, WI 53792 USA Lynn C Moscinski MD Professor, Department of Pathology University of South Florida, College of Medicine H Lee Moffitt Cancer Center and Research Institute 12902 Magnolia Avenue Tampa, FL 33612 USA Eva Negri Instituto di Ricerche Farmacologiche ‘Mario Negri’ Via Eritrea 62 20157 Milan Italy Barbara A Neilan Regional Hematology and Oncology, PA 4701 Ogletown Stanton Road Suite 2100 Newark, DE 19713 USA Daniel Nikcevich MD Division of Hematology/Oncology and Center on Aging Duke University Medical Center Durham, NC 27710 USA

Patrizia Olmi Radiotherapy Division Policlinico A Gemelli Universita Cattolica Sacro Cuore Largo A Gemelli, 8 Rome Italy Cynthia Osborne MD Simmons Comprehensive Cancer Center University of Texas Dallas, TX USA Janine Overcash PhD Assistant Professor University of South Florida College of Nursing Tampa, FL USA Bruce Peterson MD Division of Oncology University of Minnesota School of Medicine 420 Delaware Street SE Minneapolis, MN USA Thierry Pignon MD Department of Radiotherapy Hopital de la Timone Marseille France Julio Pow-Sang MD Associate Professor Department of Surgery H Lee Moffitt Cancer Center and Research Institute 12902 Magnolia Avenue Tampa, FL 33612 USA Lazarro Repetto MD U O Oncologia Istituto Nazionale di Riposo e Cura per Anziani (INRCA) Roma Italy

Matthew J Reschly MD Resident Division of Dermatology and Cutaneous Surgery University of South Florida College of Medicine 12901 Bruce B Downs Boulevard Tampa, FL 33162 USA Diane Riccardi MPH RD Department of Nutrition H Lee Moffitt Cancer Center and Research Institute 12902 Magnolia Avenue Tampa, FL 33612 USA Lynn AG Ries MS Cancer Statistics Branch Surveillance Program Division of Cancer Prevention and Control National Cancer Institute Bethesda, MD USA Cleora S Roberts Research Social Worker H Lee Moffitt Cancer Center and Research Institute 12902 Magnolia Drive Tampa, FL 33612 USA Richard Roetzheim MD MSPH Professor, Department of Family Medicine University of South Florida 12901 Bruce B Downs Blvd, MDC 13 Tampa, FL 33612 USA Pierre Scalliet MD Radiation Oncology Cliniques Universitaries St Luc Ave Hippocrate 10 Brussels Belgium Ronald S Schonwetter MD Professor and Director Division of Geriatric Medicine

Department of Internal Medicine University of South Florida College of Medicine and Chief Medical Officer LifePath Hospice and Palliative Care. Inc. Tampa FL 33612 USA Frances A Shepherd MD Scott Taylor Chair in Lung Cancer Research Princess Margaret Hospital Professor of Medicine University of Toronto Toronto, Ontario M5G 2M9 Canada Rebecca A Silliman MD PhD Professor of Medicine and Public Health Chief, Geriatrics Section Boston University School of Medicine Boston, MA 2118 USA Rosella Silvestrini PhD Experimental Oncology Department Unit 10—Determinants of Prognosis and Treatment Response Instituto Nazionale Tumori Via Venezian 1 20133 Milan Italy Dan Smith MD Resident Division of Dermatology and Cutaneous Surgery University of South Florida College of Medicine 12901 Bruce B Downs Boulevard Tampa, FL 33162 USA Alexander SD Spiers MD PhD FRCPE Professor of Medicine Quarry Wood End Gibraltar Lane Cookham

Maidenhead SL6 9TR UK formerly Director, Leukemia and Lymphoma Center H Lee Moffitt Cancer Center and Research Institute University of South Florida Tampa, FL 33612 USA Giorgio Stanta MD International Center for Genetic Engineering and Biotechnology Are Science Park Trieste Italy Tate Thigpen MD Professor of Medicine Director, Division of Oncology Department of Medicine University of Mississippi School of Medicine 2500 North State Street Jackson, MI USA Joseph M Unger MS Biostatistician Southwest Oncology Group Statistical Center Fred Hutchinson Cancer Research Center 1100 Fairview Avenue N PO Box 19024 Seattle, WA 98109-1024 USA Silvia Veneroni PhD Experimental Oncology Department Unit 10—Determinants of Prognosis and Treatment Response Instituto Nazionale Tumori Via Venezian 1 20133 Milan Italy Antonella Venturino U O Oncologia Medica USL 1 Imperiese

Ospedale di Sanremo (IM) Italy David Vesole MD Associate Professor University of Arkansas for Medical Sciences Little Rock, AR USA Hector Vila MD Assistant Professor and Chief of Anesthesiology H Lee Moffitt Cancer Center and Research Institute Department of Interdisciplinary Oncology University of South Florida Tampa, FL 33612 USA Rosemary Yancik PhD Chief, Cancer and Aging Section, Geriatrics Program National Institutes of Health National Institute on Aging Bethesda, MD USA

Preface to the second edition The past decade has seen a spate of interest in issues related to cancer in the older person. More and more, the older cancer patient has become representative of the majority of cancer patients and the focus of both research and clinical activities. Some recent milestones in geriatric oncology include the formation of an International Society of Geriatric Oncology (SIOG), the proliferation of training programs in geriatric oncology in major academic centers in the USA, the publication of a curriculum in geriatric oncology by the American Society of Clinical Oncology (ASCO), the institution of task forces in geriatric oncology within the ASCO, the American Association for Cancer Research (AACR), and the European Organization for the Research and Treatment of Cancer (EORTC), the establishment of aging-related committees within the major cooperative groups, the foundation of a Geriatric Oncology Consortium (GOC), and the proliferation of research projects and scientific papers related to cancer and aging. Perhaps the final seal of approval given to this emerging discipline has been the combined NCI/NIA conference held in Bethesda in 2001, involving the directors of all comprehensive cancer centers in the USA. This conference spawned a number of RFPs, both for the Institution of Geriatric Oncology Programs within the Cancer Centers and for individual research projects in cancer and aging, as testimony of the scientific community’s commitment to the pursuance of these issues. As a result of these initiatives, a number of important principles have been established. First, the complex biologic relationship of aging and cancer has been highlighted, with the recognition that some molecular and environmental changes of aging may favor and others may oppose the development of cancer. Second, some interactions of aging and cancer growth have been elucidated, together with the mechanisms that render some tumors more aggressive and others more indolent in the older person. Third, the risks and benefits of cancer treatment in older individuals have been better defined, with the recognition that older individuals tolerate emergency procedures less well than the younger ones, and are more subjected to some complications of chemotherapy, such as myelosuppression, mucositis, and neurotoxicity. Fourth, the instruments for a more uniform evaluation of the older person have been developed: the Comprehensive Geriatric Assessment is still the mainstay of any intervention, providing a nosologic classification of age, an estimate of life-expectancy and tolerance of treatment, and an outline of reversible conditions that may complicate cancer treatment. New screening instruments are being developed to make the geriatric assessment cost-and time-effective and user-friendly, and these have been complemented by new tests of physical performance as well as by laboratory tests. The discovery that circulating levels of interleukin-6 and D-dimer predict functional decline and mortality in an otherwise healthy elderly population may represent a turning point in the assessment of aging. Fifth, knowledge of the field has developed enough to formulate the first guidelines for the management of cancer in the older person. These exciting developments could be

summarized by saying that oncology has kept pace with demographic trends and has become attuned to study and serve the most likely cancer patient of the future, namely the older person. The previous edition of this book has certainly contributed to this surge of interest and activity. One could say that the major role of the previous edition has been to awaken academic, professional, and public awareness to the size of the problem and to the need for more investigations, and to ensure that older individuals benefit fully from recent advances in cancer prevention and cancer treatment. In doing so, it has been necessary to dispel the myth that older individuals are too frail or too short-lived to deserve preventive and therapeutic interventions, and to outline the principles of clinical trials in the elderly, to identify potential subjects of bench-to-bedside translation in the biologic interactions of cancer and age, and to review sparse data regarding cancer prevention and cancer treatment. These goals have largely been accomplished. To remain effective and meaningful, the book needs to adjust its directions to the changing clinical landscape. This new edition of Comprehensive Geriatric Oncology still offers an exhaustive review of the biology of cancer and aging, of the epidemiologic trends in the country and in the world, and of the clinical trials that concern cancer prevention and cancer treatment in the elderly. In addition, this new edition addresses issues of healthcare delivery, including cost and evaluation of utility and outcome, suggests new research approaches to older cancer patients, explores newly emerging problems such as anemia in the elderly and especially in elderly cancer patients, reviews existing guidelines for the prevention and treatment of cancer in the elderly, and studies the effectiveness of training programs in geriatric oncology. In the editors’ plans, Comprehensive Geriatric Oncology will still represent the major reference work for basic, population, and clinical scientists interested in the issue and for practitioners ministering to older cancer patients. In addition, the editors would like to make the book a frame of reference for the ongoing dialogue in the field of geriatric oncology. We do realize that we are no longer the only voice in the field; we hope to become the source that shapes the dialogue, the note to which different notes are attuned. As before, the measure of our accomplishment will be the recognition of our readership. This book is multivocal, as it includes authors from different countries and different continents. This aspect of Comprehensive Geriatric Oncology reflects the universality of the problem and of the interest in the problem, at least in the Western world. At the same time, this worldwide representation is aimed to accommodate different attitudes toward and different interpretations of aging, with the deeply held conviction that different cultures may each teach unique lessons in the approach to the older person and the older patient. The combination of different experiences may indicate the safest and speediest route in sailing uncharted waters. We would like to thank, in addition to the contributors to the books, the scientists and clinicians worldwide who have shared their experience with us during encounters in real and cyberspace, the other healthcare professionals—mainly nurses, social workers, pharmacists, and dieticians—who have worked with us as a team, and above all the patients who have provided the most vital lessons to the development of geriatric oncology. While it is impossible to name everybody, we feel we have to address very special thanks to Rosemary Yancik, PhD, of the National Institute on Aging, who has been the uncontested founder of the field and has remained the most acknowledged

leader, for continuous leadership and inspiration. We also wish to acknowledge the loss of two giants of oncology, who have been among the pioneers of geriatric oncology: BJ Kennedy MD and Paul Carbone MD. Both of them identified the field of cancer and aging as a prime area of intervention and used their world-renowned academic pulpit to spread the word and support our effort. Lodovico Balducci Gary H Lyman William B Ershler Martine Extermann

Preface to the first edition Management of cancer in the older-aged person is an increasingly common problem. The issues of geriatric oncology are as complicated and elusive as the definition of aging/a highly individualized process involving changes in physical, cognitive, emotional, social and economic domains. In epidemiological studies the changes of aging have been well recognized as restricted physiologic reserve, higher prevalence of comorbidity, diminished and delayed processing of new information, enhanced susceptibility to depression, limited social support, de-creased financial resources, and confinement. However, the occurrence, the severity of the interactions, and the overall impact of these changes in the individual person are not predictable from one’s chronologic age. Despite the inability to establish certain chronologic boundaries of senescence, that has handicapped the study of the interactions of aging and disease, in 1992 we endeavored to publish the first treatise of geriatric oncology. Our effort was inspired and supported by the conviction that cancer in older persons may be considered a different disease from cancer in the younger persons, that the biology of the aged tumor host influenced the growth of cancer, that the management of cancer in the older person deserved an individualized approach in terms of prevention and treatment, and that medical decisions involving the older person with cancer involved the knowledge and the awareness of the multidimensional changes of age. This view/which was then a minority view, has been largely vindicated by recent molecular and epidemiologic discoveries, and by recent approaches to cancer treatment. Just to quote a few examples, age is today a well recognized negative prognostic factor for large cell lymphoma and for ovarian cancer, the prevalence of multidrug resistance in leukemic myeloblasts in persons aged 60 and over was found to be as high as 57% (versus 17% in younger patients), and a number of treatment protocols aimed at older persons with special forms of cancer, such as non-Hodgkin’s lymphoma and breast cancer, have been developed. In the introduction to a previous publication we stated that the characteristics of aging are influenced by evolving cultural and environmental factors. Accordingly, we proposed to lay the foundation for a continuing discourse on aging and cancer. We believe the time is ripe for reframing and restating our original propositions in the light of the information accumulated during the last five years. Unquestionably, the issues of cancer and aging have elicited more interest during the past five years than ever before: for example, all major cooperative oncology groups both in the USA and in Europe have included committees devoted to the issues of aging, three international conferences devoted to cancer and age, with multinational support, have been held at biennial intervals in Argentina, Italy and the USA; the National Institute on Aging has issued a RFA for the study of breast cancer in the older woman, and the number of scientific articles, communications, and reviews concerning management of cancer in the older person have increased dramatically. At the same time, the spectacular advances in molecular biology have shed unexpected light on the interactions of aging

and cancer. The flourishing of these diverse activities has yielded a host of new information that will deeply affect the approach to the older person with cancer. Our previous publication highlighted a number of areas where interactions of aging and cancer appeared likely. This book addresses the major areas of cancer biology, cancer prevention and cancer treatment in the light of newly acquired knowledge. Among the major additions to our new book we would like to underline an international epidemiological perspective, an analysis of age-related molecular and immunologic changes, a review of the physiology of aging, an ‘in depth’ analysis of chemoprevention, a guide to the assessment of life-expectancy, comorbidity, and quality of life, new advances in the use of anesthesia in the older person with cancer, and an examination of gastrointestinal and thoracic malignancies in older individuals. In addition, the issues of surgery/ chemotherapy, radiotherapy and nutrition, as well as the chapters related to screening, decision analysis, supportive management, nursing issues, breast cancer, lymphomas and multiple myeloma, have been expanded to accommodate new knowledge and new problems. The aim of this book is threefold. First and foremost, we wish to assist the practitioner in delivering the best possible cancer care to older patients. For this purpose, we provide an extensive review of current information on the effects of age on tolerance of antineoplastic treatments, such as surgery, radiation therapy, cytotoxic chemotherapy, hormonal and biologic therapy and we explore the role of novel interventions, such as bone marrow transplantation, administration of hemopoietic growth factors and endoscopic surgery. We also take a close look at the management of common malignancies in the elderly and we examine the influence of age on treatment choice. A painstaking analysis of major clinical trials is included, whenever possible, to identify data pertinent to older patients. Frequently, when cancer occurs in the very old, supportive care is the most appropriate form of management. Accordingly, we study supportive care of the older-aged person with cancer, focusing on symptom management, rehabilitation, quality of life assessment, and support structures. Information on patients, disease, and treatment has been prefaced by a chapter devoted to decision analysis. We feel that decision analysis represents a valuable clinical tool to plan the most favorable course of action in complex clinical situations, such as those involving elderly cancer patients. The clinical aspects of these situations present the practitioner with complex and often competing forces. Familiarity with decision analysis may guide the practitioner toward the management strategy associated with optimal outcome and may aid health policy decisions in the cost effective utilization of limited resources. Second, we wish to promote cancer prevention in the older-aged person. The incidence of most malignancies increases with age and, therefore, the elderly represent an ideal target for both secondary and tertiary prevention of cancer. Secondary prevention involves reversal of late carcinogenic stages, while tertiary prevention is achievable through screening asymptomatic persons for early cancer. For this reason we will illustrate the biological basis of increased cancer risk with aging, we entertain pharmacologic interventions that may lessen the risk of cancer and we review the results of clinical trials exploring early detection of common cancers in older persons. The data on cervical cancer may represent the first direct demonstration of the life-saving effect of screening in older persons. As in the case of cancer management, decision analysis may

direct the institution of the safest and most cost-effective preventative strategy in individual situations. Third, we wish to highlight emerging issues of geriatric oncology and present a research agenda for geriatric cancer in the older person. We believe that care delivery to the older-aged person with cancer is an area of major controversy and that this issue should be studied directly in the community where the elderly patient receives care. For this purpose, practitioners of oncology and of geriatrics should be ready to participate in community-based clinical trials that will embrace the data provided in this or similar volumes in the future. This book is directed primarily at the practicing oncologist. For this reason, the general principles of cancer treatment and the standard management of specific diseases were streamlined. We hope, however, that the book may also appeal to general surgeons, geriatricians and health professionals who provide primary care to elderly patients. It is possible that biologists may find in this book a rapid and exhaustive review of molecular and cellular interactions of aging and cancer, behavioral and social scientists may find a comprehensive outline of emotional and social problems of the older cancer patients, and clinical epidemiologists and health care planners may find important information related to the incidence of cancer in older patients and cancer care delivery to the older patients around the world. We hope to entice practitioners of various specialities and scientists of different disciplines to reflect on the multidimensional nature of aging and to work together to enhance our understanding of this important subject. The future of this book depends upon the feedback we receive from our interested readership. We do not know of any other clinical area which depends on the contribution of different disciplines and on the input from clinical practice to a higher degree than geriatric oncology. Lodovico Balducci Gary H Lyman William B Ershler

PART I Overview

1 Aging and cancer BJ Kennedy Introduction Aging is a normal process of our lifespan, not a disease. The US population is aging and older persons are living longer. Their future involves significant medical, public health, economic, social, and ethical issues.1 With aging, the incidence of cancer increases, and our expanding older population makes the prevalence of cancer more apparent. Recent reviews of geriatric oncology have characterized the problem in terms of the volume of patients and the diagnosis and treatment of the older person with cancer.1–7 To meet this challenge, there will be more emphasis on physician education in geriatrics, an increase in basic and clinical research on cancer in older persons, and an adjustment in physicians’ methods of care of older persons with cancer. Attitudes towards aging are undergoing a major change. Aging has been perceived as the end of life, with older persons having little potential for growth. Such perceived negative characteristics include cognitive impairment, decreased quality of life, poor prognosis, limited life-expectancy, and decreased social worth. As a result, efforts for maintenance of health of older persons have been impaired. To reverse this negative perception, elimination of the terms ‘senior citizens’, ‘golden age’, ‘elderly’, ‘frail old’, ‘older-old’ has been encouraged. The preferred term is ‘older persons’, which specifies no numerical age limit to the aging process and places more emphasis on the physiologic status of the patient. America is growing older.8,9 The US population over the age of 65 has increased 10fold since 1900. Today, 34.7 million Americans—one in every eight—are over 65 (12.5% of the total US population), compared with only one of every 15 persons in 1930 (Figure 1.1). It is projected that in 2020, one in every five Americans will be over 65.10 In 2010, the first wave of ‘baby boomers’—the 76 million babies born between 1946 and 1965—will reach 65 (Table 1.1). The predicted prolonged longevity and augmented size of this group will trigger a massive increase in the number of persons over 65 (Table 1.2).

Aging and cancer

3

Figure 1.1 Population (in millions) of ages 65 and over from 1960 to 2050. Source: US Bureau of the Census.

Table 1.1 Year and age of baby boomers born between 1945 and 196510 Year

Age

1975

10–30

1990

25–45

2010

45–65

2030

65–85

Comprehensive Geriatric Oncology

4

Table 1.2 Projected number of persons over age 65 in the USA Year

Millions

% of population

1990

31

12.5

2020

53

16.4

2030

70

20.1

Figure 1.2 Population 85 years and over: 1900– 2050 (in millions). Source: US Bureau of the Census, decennial censuses for specified years and population projections of the United States by age, sex, race, and Hispanic origin: 1993 to 2050. Current Population Reports, Series P-25, No. 1104. Washington,

Aging and cancer

5

DC: US Government Printing Office, 1993. Data for 1990 from 1990 Census of Population and Housing, CPH-L-74, modified and actual age, sex, race, and Hispanic origin data. The average length of life continues to increase. Life-expectancy in the USA has increased by 25 years since the start of the 20th century (Table 1.3). Life-expectancy for White women born today is 85 years while for White men born today it is 77 years.9 More impressive is the number of years remaining for older persons (Table 1.4). The maximum lifespan has been projected to be about 120 years. The number of older persons is increasing dramatically. Survival to the age of 80 and beyond has increased in many developed countries.11 Those aged 85 and over are the most rapidly growing group, having represented 2.2% of the population in 1980, and projected to represent 6% in 2010 and 18.9% in 2050 (Figure 1.2). Currently, 21% of all deaths occur in people over 85 years. There were 36000 persons over age 100 in 1990, and this is currently expected to double. Fifty percent of these live in nursing homes.

Table 1.3 Average life-expectancy9 Year (AD)

Length of life (years)

100

22

Middle Ages

33

1776

35

1850

42

1900

47

1950

68

1990

75

2050

85

Table 1.4 Remaining years of White female lifeexpectancy9 Current age

Years remaining

65

19.2

75

11.2

85

6.3

Comprehensive Geriatric Oncology

6

Figure 1.3 Percentage of persons aged 65 expected to survive to age 90:1940– 2050. Source: 1940–1980 from National Center for Health Statistics, decennial life tables; 2000 and 2050 from unpublished life tables consistent with population projections of the United States, by age, sex, race, and Hispanic origin: 1993 to 2050. Current Population Reports, Series P-25, No. 1104. Washington, DC: US Government Printing Office, 1993.

Aging and cancer

7

Figure 1.4 Number of men per 100 women by age: 1994. Source: US Bureau of the Census, data consistent with US population estimates by age, sex, race, and Hispanic origin: 1990 to 1993. Population Paper Listing-8 (PPL-8). Washington, DC: US Government Printing Office, 1994. Surviving to age 65 is more common nowadays. The Census Bureau projections imply that by 2050, over 40% of persons aged 65 years can expect to live to at least age 90 (Figure 1.3). Moreover, women are outliving men. The trend in sex ratio illustrates the greater survivorship probabilities of women (Figure 1.4). Progress against infectious diseases during the past 50 and more years has made it possible for people to live longer. Yet, because of fatty diets, cigarette smoking, and sedentary lifestyle, coronary heart disease was the number one killer. In the past 20 years, however, the death rate from coronary heart disease has plunged 48% because of the adoption of healthier lifestyles. With new drugs and treatment strategies, the coronary heart disease death rate is predicted to plummet still further this decade. With the decrease in coronary heart disease and vascular diseases, people are living longer, which has resulted in a new era of degenerative diseases, including Alzheimer’s disease and cancer. Cancer is a disease primarily of older persons (Figure 1.5).12 Over 60% of all cases of cancer are diagnosed after age 65—an age group that constitutes only 12.5% of the current US population. By 2030, 70% of patients with cancer will be over 65. More than 67% of cancer deaths occur in this older group. The risk of persons over 65 years of age developing cancer is 10 times that of those under 65. Up to the age of 50, the incidence of cancer is higher in women. After age 60, there is a remarkable increase in cancer

Comprehensive Geriatric Oncology

8

incidence among men. The growth of the older population, especially those over 75, implies that there will be marked increases in the number of incident cancers diagnosed during the next several decades.13 Concomitantly, death rates from cancer in older persons will continue to increase, but perhaps at a slower rate. There are multiple reasons for the greater incidence of cancer in older persons. They have less resistance and longer exposure to carcinogens, a decline in immune competence, alterations of antitumor defenses, decreased DNA repair, defects in tumor suppressor genes, and differences in biologic behavior, including such factors as angiogenesis. Because of the increased incidence and prevalence of cancer in older persons, as well as their higher mortality rate from cancer, it has been implied that no progress has been made in the fight against cancer. The data suggest otherwise (Table 1.5). The higher rates of cure of acute leukemia in children, testicular cancer in men, and Hodgkin lymphoma are responsible for a 23% decrease in cancer mortality in persons under 55 years. However, there has been a 17% increase in cancer mortality in those over 55 years.14

Figure 1.5 Average annual cancer incidence rates by age category: 1992– 1996 (logarithmic scale).12

Aging and cancer

9

Table 1.5 US cancer mortality per 10000014 Year

Age <55

>55

1968

43

775

1985

35

905

−23%

+17%

% change

Physiology of aging The normal process of aging is associated with a progressive age-related reduction in function of many organs, including losses such as renal, pulmonary, immune, cardiac, hematologic, hepatic, muscle, sight, hearing, osseous, and brain functions. Physiologic functions of various organ systems at age 70 may be 50% of those observed at age 30. The volume of the liver decreases and blood flow to the liver decreases about 1% per year with age. A decrease in hepatic clearance and metabolism of drugs by the liver is also apparent. The most consistent physiologic change with aging is a decline in renal function. With a concomitant decrease in muscle mass, the serum creatinine level remains normal, making the creatinine clearance a more reliable indicator of renal function. It has been clearly shown that nephrotoxicity of cisplatin does not worsen with advancing age. Advancing age is associated with a decline in immune competence, as suggested by the higher incidence of cancer in older persons and their greater susceptibility to infections. The diminished immune functions are reflected by lymphocyte response to stimulation, delayed-type sensitivity, and antibody responses. With the involution of the thymus, T-cell deficiency may be a factor. Furthermore, interleukin-2 synthesis decreases with age. Mice with restricted caloric intake have a longer lifespan than those fed ad libitum. This prolonged lifespan is credited to the preservation of immune function. The consequences of these changes with age, added to comorbid diseases, have profound effects on tolerance to treatments of cancer, including surgery, radiotherapy, and chemotherapy. Although such changes should be taken into consideration when treating older patients for cancer, chronologic age alone should not be used as a guide to cancer prevention or therapy. It is the physiologic performance of the patient that is of prime importance.

Table 1.6 Estimated leading sites for cancer incidence: 2001, all ages15 Site Prostate

No. of cases 198100

Comprehensive Geriatric Oncology

10

Breast

193700

Lung

169500

Colorectal

135400

Non-Hodgkin lymphoma

63600

Table 1.7 Leading sites for cancer mortality in persons over 60 years of age: 199815 Age 60–79

Age >80

Male

Female

Male

Lung Prostate

Lung Breast

Colorectal Pancreas Non-Hodgkin lymphoma

Female

Ovary

Prostate

Colorectal

Colorectal

Breast

Bladder

Pancreas

Pancreas

Non-Hodgkin

lymphoma

Specific neoplasms The leading sites for the incidence of cancer for all ages (Table 1.6) differ from the leading sites for cancer mortality in older persons (Table 1.7). Most elderly patients benefit from thoughtful consideration of specific, comprehensive management plans to cure, control, or palliate a cancer. Advanced age is not a contraindication to major surgery, providing that comorbid diseases will not influence the potential mortality. Radiotherapy may be an excellent alternative. Chemotherapy is well tolerated when used with appropriate caution. Breast Breast cancer is the most common cancer in women. The incidence increases with age, with approximately 48% of all cases occurring in women older than 65. Older women are less likely to perform self-examination of the breast, have an annual breast examination, or have an annual mammogram. In fact, about two-thirds of women over age 65 in the USA do not have regular mammograms, despite payment by Medicare.16 A greater proportion of older persons has estrogen receptor-positive tumors than the younger population, reflecting a biologic difference of this cancer with age. The tumors are more likely to be well differentiated, have lower proliferative rates, and have more favorable histologic types. The approach to definitive therapy in early stages of the disease is comparable to that in the younger population. In the context of adjuvant therapies for disseminated disease in older persons, the chronologic and physiologic differences result

Aging and cancer

11

in altered hormonal or chemotherapy approaches compared with younger patients. The limited data on treatment efficacy in older women with breast cancer and selection bias in clinical trials have resulted in substantial variations in treatments.17 Treatment of the older patient is often influenced by factors other than the medical condition. Lung cancer Lung cancer is the leading cause of death from cancer in both sexes over age 75. There is a threefold greater risk for lung cancer in men over 65. Lung cancer is probably not a direct result of the aging process, but reflects the period of time necessary for tumor induction due to long-term tobacco use. After age 70, the age-specific incidence of lung cancer decreases, which may reflect a decline in smoking habits as people approach age 50. Of course, those who developed lung cancer earlier have already died. There also is a biologic difference in lung cancer in older persons. There is more squamous cell cancer in patients over 70 (71%) than in those under 50 (58%), which may reflect the less advanced stage of the disease in older patients. Although older persons may have a greater risk of early death after thoracotomy, the likelihood of long-term survival following surgery is not diminished by age alone. Hence, the risk of surgery is well worth the benefit in selected patients. Older patients fare just as well as younger ones with radiotherapy or palliative chemotherapy. Colorectal cancer Colorectal cancer is the third most common malignancy in the USA, and age is a leading risk factor. Over 90% of cases occur in those over 50, and the survival rates decrease with age. Unfortunately, the diagnosis of colorectal cancer is made in the late phase of the disease, because the elderly are less likely to receive routine health examinations. Stage for stage, surgery or chemotherapy should be employed as in younger persons. Adjuvant chemotherapy for stage III cancers is well tolerated.18 Prostate cancer Prostate cancer is the most common tumor in American men, and a major cause of death from cancer—second only to lung. After the age of 80 years, 50% of all men may have stage Al cancer (not clinically apparent). However, when initially diagnosed, nearly 70% of patients will have advanced disease. The introduction of the prostate-specific antigen (PSA) blood test has resulted in a greater number of patients diagnosed in the earlier phase of the disease. Introduction of free PSA may result in fewer ultrasounds and biopsies. Because prostate cancer is a relatively understudied disease among elderly men, data are lacking on the preferred method of management, especially in those over 75. The factors of symptoms, signs of obstructions, PSA level, tumor size, and histologic grade influence the decision-making process. Prostatectomy, radiotherapy, hormonal therapies, and watchful waiting are alternatives to be considered.

Comprehensive Geriatric Oncology

12

Pancreatic cancer The incidence of pancreatic cancer is increasing worldwide, and it ranks fourth as a cause of cancer deaths. Because of the aggressiveness of this cancer and its low curability rate, the mortality figures are similar for both sexes. Palliative surgery, radiotherapy for localized disease, and/or chemotherapy are selectively employed. Melanoma The incidence and mortality rate of melanoma are increasing at a faster rate than for any other cancer, except for lung cancer in women, as is the mortality rate.19 With increasing age, there is an increasing incidence of melanoma. Prolonged sun exposure is a factor. Survival can be substantial for these older patients, providing that constraints are not placed on the provision of curative treatment. Cervical cancer Cervical cancer incidence and mortality worldwide are second only to those of breast cancer, and in some countries this disease is the major cause of death in women of reproductive age.20 This disparity is due to a lack of screening programs, in part due to rural and socioeconomic factors. Cervical cancer in women over 65 accounts for 25% of new cases and 41% of deaths from this disease. Increasing age is associated with increased stage at time of presentation, yet in regions where the older women have been aggressively screened, their death rates have declined. Less than 50% of women over 65 years of age have been screened for cervical cancer (Table 1.8). Use of surgery, radiotherapy, or chemotherapy should not be restricted on the basis of age alone.

Table 1.8 Pap screening for cervical cancer Age

% tested

18–39

81

40–59

67

>60

52

Source: US Centers for Disease Control.

Leukemia Chronic lymphocytic leukemia (CLL) is one of the principal hematologic neoplastic diseases of older persons, and its incidence may be greater than reported, since its indolent nature may result in its failure to be registered in tumor registries. Treatment is usually initiated when specific signs or symptoms occur. Chemotherapy in persons over 70 is implied to be of benefit.

Aging and cancer

13

Nearly 60% of patients with acute myeloid leukemia (AML) are older than 60. Treatment in this age group has improved. As each decade has passed, the complete remission rate for those surviving treatment has increased.1 The duration of remission and the survival time of older responders to therapy are comparable to those of younger patients, although the older patient is at a greater risk during induction therapy because of uncontrolled infections during the neutropenic phase. Increasing age is associated with a lower complete response rate, slower neutrophil recovery, and longer hospitalizations than younger adults.21 A common feature of AML in the elderly is myelodysplasia, for which several new drugs are being investigated. For the older patient with AML and good functional status, induction chemotherapy is preferred. Since the use of hematopoietic growth factors in AML has been associated with reduced infection, shortened hospitalization, and improved survival, it has been recommended that hematopoietic growth factors be used routinely in persons aged 70 and over during moderately toxic chemotherapy.22 Nevertheless, for many patients, palliative intervention remains an appropriate option. Hodgkin lymphoma Hodgkin lymphoma has a bimodal age incidence curve, peaking in the late 20s then declining to age 45, after which the incidence increases steadily with age. Age is a major prognostic factor influencing treatment response, duration of response, and survival. In advanced disease, the response rate to chemotherapies was lower in patients over 60 compared with younger persons. In a national pattern-of-care study, as the age of the patient at diagnosis increased, the survival decreased.23 Analysis revealed that both age and stage, independent of each other, are significant prognostic factors for Hodgkin lymphoma. There may be biologic differences in patients at advancing age, resulting in a poorer prognosis. Non-Hodgkin lymphoma The incidence of non-Hodgkin lymphoma (NHL) has dramatically increased over the past decade, and is expected to continue to rise. The disease presentation is the same in younger and older persons. Stage III and IV lymphocytic NHL have an indolent course and are responsive to chemotherapy, yet do not attain complete remissions. Incomplete remission may not require maintenance chemotherapy. A few elderly patients may never require treatment.24 Patients older than 65 have had greater treatment-related toxicity, lower complete response rates, and decreased survival when compared with younger patients. Overall survival is affected by comorbid conditions.25 Treatment considerations An age bias in the management of cancer has been recognized in a number of studies.1 Attitudes toward aging, rather than scientific facts, have affected decisions by physicians. Chronologic age is associated with perceived negative characteristics, including poor prognosis, cognitive impairment, decreased quality of life, limited life expectancy, and

Comprehensive Geriatric Oncology

14

decreased social worth. Older patients are discriminated against based on chronologic age. Greater age has been associated with less screening for cancer, less staging of diagnosed cancer, less aggressive therapy, or no treatment at all. Fewer older women have had a Pap test for cancer. Women over 80 have had fewer mammographic screenings for breast cancer, and staging has been less vigorous. Because of older patients’ impaired physiologic reserve and a fear of excessive operative mortality in older patients with cancer, some physicians have been reluctant to recommend curative major surgical procedures and to favor more conservative treatment, thereby losing the potential curability of cancer by surgery. Study of the outcomes of surgery in patients of 90 and older revealed that these extremely old patients fared quite well, and survival at 5 years was comparable to that expected. During the 10-year period of study from 1975 through 1985, operative rates increased in this age group,26 and continue to increase. Advanced age is not a contraindication to major surgery, providing that the presence of comorbid diseases will not influence the potential mortality. Radiotherapy or chemotherapy is often less aggressive as well, and, for some patients, no treatment is administered. The lack of progress against cancer in older patients may be due to failure to apply standard therapy as fully for them as for younger people. The decision on management of cancer in older persons should be based upon the individual needs of a patient and not upon chronologic age alone. Clinical trials Patients over 65–70 are generally under-represented in cancer treatment trials. Data on cooperative group phase III studies have shown a declining entry in the past 5 years of patients over 65. Age restriction is not a valid eligibil-ity criterion for US National Cancer Institute trials. Possible explanations have been suggested.27,28 These include: (i) the presence of comorbidity; (ii) a research focus on aggressive therapy, the toxicity of which is unacceptable to the elderly; (iii) fewer trials being available aimed at older patients; (iv) exclusion of older persons based on criteria for eligibility in a trial; (v) limited expectations for long-term benefit by providers, relatives, and patients; (vi) lack of financial social, and logistic support for participation in trials; and (vii) failure to refer patients to centers where trials are available. Because of the importance of research on the interaction between chronologic age and effectiveness of therapy, older patients should be allowed and encouraged to enroll in clinical trials. The apparent discrimination in not treating older patients as aggressively as younger patients, and in excluding older patients from research trials, is not justified. Costs The rapid growth in the older population and their increased utilization of medical care is a major determinant of increasing healthcare costs in the USA. Medicare expenditures for healthcare services continue to expand, despite efforts to the contrary. Some of the expanding costs are due to the growing fraction of Medicare providers in specialty fields,

Aging and cancer

15

the expansion of technologies that are useful to patients, services that became available for conditions that were untreatable 30 years ago, and the ever-enlarging older population. Currently, there are four working Americans supporting each retiree. In the future, there will be only two per retiree, and there will be fewer sons and daughters to support and care for older persons. As more people live long enough to develop cancer, chronic illnesses, disability, and dependence, more relatives in their 50s and 60s will be facing the concern and expense of caring for them. The government will not be able to meet the cost. Hence, plans need to be developed that allow people to save for their own retirement healthcare needs. As the demand for long-term care facilities increases, longterm care will become the most important healthcare issue. In the next several decades, geriatric and cancer care will become a significant medical, public health, economic, and social challenge. Manpower In the evolution of the subspecialty of medical oncology, the initial definition of the subjects of relevance of this subspecialty included gerontology.29 It was perceived that cancer in the aging population would be a major health problem. The number of certified medical oncologists has grown at an awesome rate since 1973, and is now well over 8100. Yet a surplus of medical oncologists is not anticipated. The need for oncology manpower will surpass that for cardiology. Because of the increased number of visits for their therapy, an expanded need for more oncologists must be anticipated to meet the requirements for care of patients with cancer in the early part of the 21st century.30,31 It is reasonable to assume that primary care physicians will be more responsible for teaching cancer prevention, emphasizing early cancer detection, and administering some of the standard therapies. Moreover, since many cancers are now cured, the overall healthcare of the patient becomes increasingly important as that patient continues to grow older. Conclusions The US population is growing older. Physicians need to be more familiar with the medical needs of older patients and their greater chance of developing cancer. The importance of geriatric oncology was recognized a quarter of a century ago when the subjects of relevance in medical oncology training were specified. Primary care physicians and oncologists need to be prepared for the impending increase in the number of older persons with cancer. References 1. Kennedy BJ. Aging and cancer. J Clin Oncol 1988; 6:1903–11. 2. Proceedings of National Conference on Cancer and the Older Person. Cancer 1994; 74: No. 7. 3. Yancik R, Havlik RJ, Wesley LON et al. Cancer and comorbidity in older patients: a descriptive profile. Ann Epidemiol 1996; 6:399–412. 4. Cohen HJ. Biology of aging as related to cancer. Cancer 1994; 74: 2092–100.

Comprehensive Geriatric Oncology

16

5. Balducci L, Hardy CL, Lyman GC. Hematopoietic reserve in the older cancer patient; clinical and economic considerations. Cancer Control 2000; 7:539–47. 6. Goodwin JS, Samet JM, Hunt WC. Determinants of survival in older cancer patients. J Natl Cancer Inst 1996; 88:1031–8. 7. Muss HB, Cohen HJ, Lichtman SM. Clinical research in the older cancer patient. Hematol Oncol Clin North Am 2000; 14:283–91. 8. Spencer G. Projections of the population of the United States, by age, sex, and race: 1988–2080. Current Population Reports, Series P-25, No. 1018. Washington, DC: US Government Printing Office, 1989. 9. US Census Bureau, 1999 Survey. Washington, DC: US Census Bureau, 2000. 10. Tauber CM. Sixty-five plus in America. Revised edition. Current Population Reports, Special Studies. Washington, DC: US Government Printing Office, 1993:23–178 RV. 11. Manton KG, Vaupel JW. Survival after the age of 80 in the United States, Sweden, France, England, and Japan. N Engl J Med 1995; 333: 1232–5. 12. Bushhouse S, Punyko J, Soler J, Cords J. The occurrence of cancer in Minnesota, 1988–1996: incidence, mortality, trends. Minneapolis: Minnesota Cancer Surveillance System, Minnesota Department of Health, August 1999. 13. Polenak AP. Projected number of cancers diagnosed in the US elderly population, 1990 through 2030. Am J Publ Health, 1994; 84:1313–16. 14. Division of Chronic Disease Control. Years of potential life lost due to cancer—United States, 1968–1985. JAMA 1989; 261:209. 15. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001. CA Cancer J Clin 2001; 51:15–36. 16. Trontell AE, Franey EW. Use of mammography services by women aged ≥65 years enrolled in Medicare—United States, 1991–1993. JAMA 1995; 274:1420. 17. Silliman RA, Balducci L, Goodwin JS et al. Breast cancer care in old age: what we know, don’t know, and do. J Natl Cancer Inst 1993; 85:190–9. 18. Sargent D, Goldberg R, MacDonald J et al. Adjuvant chemotherapy for colon cancer (cc) is beneficial without significant increased toxicity in elderly patients: results from a 3351 pt. metaanalysis. Proc Am Soc Clin Oncol 2000; 19:241a (Abst 933). 19. Cohen HJ, Cox E, Manton K, Woodbury M. Malignant melanoma in the elderly. J Clin Oncol 1987; 5:100–6. 20. Boffeta P, Parkin DM. Cancer in developing countries. CA Cancer J Clin 1994; 44:81–90. 21. Schiffer CA, Mclntyre OR. Age related changes in adults with acute leukemia. In: The Underlying Molecular, Cellular. and Immunological Factors in Cancer and Aging (Yang SS, Warner HR, eds). New York: Plenum Press, 1993:215–29. 22. Balducci L, Yates J. General guidelines for the management of older patients with cancer. NCCN Proceedings. Oncology 2000; 14:221–7. 23. Kennedy BJ, Fremgren AM, Menck HR. National Cancer Data Base report on Hodgkin’s disease, 1985–1989 and 1990–1994. Cancer 1998; 83:1041–7. 24. Rosenberg SA. Non-Hodgkin’s lymphoma—selection of treatment on the basis of histologic type. N Engl J Med 1979; 301:924–8. 25. Lichtman SM. Lymphoma in the older patient. Semin Oncol 1995; 22(Suppl 1): 25–8. 26. Hosking MP, Warner MA, Lobdell CM et al. Outcomes of surgery in patients 90 years of age and older. JAMA 1989; 261:1909–15. 27. Trimble EL, Carter CL, Cain D et al. Representation of older patients in cancer treatment trials. Cancer 1994; 74:2209–14. 28. Hutchins LF, Unger JM, Crowley JJ et al. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 1999; 341:2061–7. 29. Kennedy BJ, Calabresi P, Carbone P et al. Training program in medial oncology. Ann Intern Med 1973; 78:127–30. 30. Kennedy BJ. The origin and evolution of Medical Oncology. Lancet 1999; 354(Suppl): 41.

Aging and cancer

17

31. Kennedy BJ. Aging and cancer. Oncology 2000; 14:1731–40.

2 Essentials of clinical decision analysis: A new way to think about cancer and aging Gary H Lyman Introduction Clinical medicine is fundamentally an effort to make decisions in the setting of what is often considerable uncertainty based on a set of facts and a set of rules that we apply to these facts.1 Medical knowledge may be derived from personal experience as well as systematic research. Our knowledge base represents an enormous collection of facts as well as opinion gathered over years of formal education, training, and experience in both preclinical and clinical settings. On the other hand, our understanding of how to gather information and evaluate it in order to arrive at correct decisions is obtained in a much less direct manner, largely through observation of experienced clinicians and trial and error. It is only in recent years that the discipline of decision analysis has been extended to clinical medicine from other disciplines.2,3 The factual foundation of our clinical knowledge is based upon objective evidence derived from both published and unpublished research. Such evidence will vary substantially over time and from one setting to another, while the rules of reasoning that we use to make decisions based on this information are fundamentally the same regardless of the setting. However, clinical reasoning skills vary greatly from clinician to clinician, and for a physician they vary from subject to subject.4–6 The focus of this chapter is on the application of these methods and the unique features of cancer in the elderly that should be considered in making clinical decisions. In our search for the truth, clinicians often utilize both deductive and inductive reasoning, but, as we shall see, both approaches have their limitations, often leading us to move back and forth between them. Deductive reasoning bases conclusions on the application of a set of rules to a set of presumed true premises. Deduction concludes what would likely be observed if a certain reality exists. For example, hypothesis testing infers the likelihood of certain results under certain conditions being true, such as the null hypothesis of not real treatment difference. Such reasoning assumes a certain falsepositive rate (an alpha or type I error) or false-negative rate (a beta or type II error) and therefore should be considered error-based. While such reasoning is very objective, it cannot be used to expand our understanding and is certainly less useful to clinicians. Inductive reasoning bases conclusions on repeated observation and inferring reality on the basis of these observations, and therefore can be considered evidence-based. Repeated observation is less objective, but can be used to generate new hypotheses. Induction in the form of clinical prediction infers the likelihood of reality based on the data or evidence observed. Neither form of reasoning represents a direct approach to

A new way to think about cancer and aging

19

knowledge or truth. In science and medicine, we often combine these two forms of reasoning to approach the real world. We start off by asking a question or generating a hypothesis, and then generating data by observation or experimentation. Such observations or data analysis allows us to generate new hypotheses, which require further observation and analysis. Even this approach fails to provide any reliable path to definitive answers to our questions about the world, including medical science. Essentials of clinical decision making Decision making in any clinical or public health situation is based on a structuring of the problem, knowledge of the performance of diagnostic tests and therapeutic modalities, and a reasonable understanding of the likelihood and value of various outcomes based on experience or the literature.7,8 The question or decision choice to be made must be explicitly defined. Probabilities and outcomes may be variably derived either from personal judgment based on education and experience or systematic research or from evidence generally derived from the medical literature. In the tradition of evidence-based medicine, the probabilities and outcomes utilized, including clinical, quality of life, and economic measures while considering experience and clinical judgment, should be based on the best evidence available. The randomized controlled trial (RCT) or meta-analyses of RCTs are generally considered among the greatest scientific advances of the 20th century, and results from such trials or reviews represent the best source of evidence when available. Decision making in the elderly patient with cancer requires a specific understanding of the epidemiology and natural history of the disease, as well as the diagnostic, therapeutic, and supportive care strategies available.9 The value of establishing the diagnosis and/or treating elderly patients with cancer may differ from that in younger patients because of such factors as the greater prevalence of cancer and the limited life-expectancy of older patients. The value of early diagnosis of certain cancers as well as the responsiveness to systemic therapy may also differ greatly among cancers afflicting the elderly. Probabilities In the testing situation (screening, diagnostic testing, etc.), the probabilities of interest are the various test performance characteristics as well as the prevalence of the condition in the population under investigation. The major objective of cancer screening and diagnostic testing is to separate those with cancer from those without cancer. Ideally, positive test results should be seen only in those with disease (true positive) and negative test results should be seen only in those without disease (true negative). However, clinical testing is almost always associated with a certain number of false-positive results in those without disease and false-negative results in those with disease. The performance of screening and diagnostic tests is assessed on the basis of several measures (see Appendix 2.2).10–14 The sensitivity of a test is the probability of a positive test result in those with the disease. The specificity of a test is the probability of a negative test result in those without the disease. Of greater interest to clinicians, generally, are the measures of predictive value. The predictive value positive is the probability of the disease in

Comprehensive Geriatric Oncology

20

someone with a positive test. Alternatively, the predictive value negative is the probability of being without disease if the test is negative. The predictive value of a test depends not only on the sensitivity and specificity of the test but also on the prevalence of the disease in those being tested. Prevalence represents the probability of disease in the population at a given time. Since the incidence and prevalence of cancer increase dramatically with increasing age, the positive predictive value of a screening or diagnostic test generally increases with increasing age. With increasing disease prevalence, there will be a decreasing proportion of false-positive results, potentially increasing the diagnostic yield per unit cost.15–17 We have observed that physicians frequently overestimate post-test probabilities, particularly when disease prevalence is low in the population.16,17 We believe that healthcare professionals should receive formal training in the proper evaluation of test information.17

Figure 2.1 Graphic representation of the three dimensions of health outcomes: clinical (survival and response), psychological (quality of life and symptoms/toxicity), and economic (costs and charges). Combined measures of outcome include quality-adjusted life-years (QALYs) or the quality-adjusted time without symptoms of disease or toxicity of treatment (Q-TWIST) for the clinical and psychological dimensions, cost-effectiveness (cost per life-year gained) for the clinical

A new way to think about cancer and aging

21

and economic dimensions, and costutility (cost per QALY gained) for the clinical, psychological, and economic dimensions. Outcome measures Patient outcomes may be measured in a variety of ways: clinical, quality of life and economic. Perhaps the greatest strength of outcomes analysis is the ability to combine into summary measures clinical, quality of life, and cost outcomes (Figure 2.1). Such combined measures provide powerful and elegant methods for comprehensive comparisons reflecting the impact of cancer and cancer interventions. Clinical outcomes may assess both management benefit and harm.18 Clinical outcomes measured in controlled clinical trials generally refer to treatment efficacy in terms of survival, time to recurrence, or disease-free survival. Outcome measures applied to the population of diseased individuals define treatment effectiveness. Both direct and indirect measures are available. Commonly utilized direct clinical measures of outcome are survival, disease-free survival, and life-expectancy. A survival function represents the cumulative proportion alive or alive and free of disease (disease-free survival) over time. Survival is directly related to the risk of dying over each unit of time (mortality rate). The survival of a group of individuals may be summarized by various measures such as the median (50th percentile) or the proportion alive at certain time points such as 1 or 5 years. Life-expectancy represents the average number of years of life remaining at any given age. In seriously ill patients, including elderly cancer patients, life is relatively short and the mortality rate is approximately constant. When the mortality rate is approximately constant, the relationship between survival and time is described by a declining exponential function. Such an approximation is sufficiently close for almost all decision-making applications. Under the assumption of a declining exponential approximation for life-expectancy (DEALE), life-expectancy is the inverse of the mortality rate. In addition, the total mortality rate may be considered the sum of the agespecific mortality rate and the mortality rates for any disease(s) (see Appendix 2.4). In some clinical settings, the mortality rate may vary over time. In this situation, other models are utilized to estimate life-expectancy. When a patient is likely to experience several different health states over time, a Markov model may be utilized. If the transition probabilities of moving from one health state to another over time are known, lifeexpectancy can be estimated. The Markov model assumes that the transition probability to a new health state is determined by the current health state and not previous states. Quality-of-life considerations can be incorporated by formally assessing patient preferences or utilities for various outcomes and adjusting years of life-expectancy in the form of quality-adjusted life-years (QALYs). A variety of methods are available to adjust clinical outcome measures for the impact on quality of life. Patient willingness to pay to achieve effectiveness or to avoid toxicity can be incorporated into a cost-benefit analysis. Utility analysis attempts to adjust the outcome value based on patient perception of quality of life in different outcome states. After ranking possible outcomes and assigning values of 0 and 1 to those with the lowest and highest quality of life, the intermediate outcomes can be assigned values by means of a standard reference gamble or a time

Comprehensive Geriatric Oncology

22

trade-off equating the amount of time in good health to a specified period of time in the disease state. Each of these methods of adjustment has limitations in implementation and interpretation. However, they do begin to address a dimension of management outcome that has not been adequately considered in the past. Costs are generally measured in monetary units such as dollars. Common direct measures of economic impact include costs, charges, and cost-to-charge ratios. Costs represent the product of a measure of activity or resource utilization times the unit costs or cost per unit of activity. Indirect measures of outcome effectiveness include treatment response, duration of response, and time to disease recurrence. Measures of indirect cost include lost income from illness or premature death as well as other costs not directly related to the services provided. Marginal costs as well as marginal effectiveness refer to the differences in these measures between two strategies. In a cost-benefit analysis, benefits must be converted into the common monetary unit. In a cost-effectiveness analysis, the cost for each unit of added effectiveness over time is calculated; this may allow the comparison of different strategies with the same effectiveness measures.

Table 2.1 Clinical decision making: clinical decision models Elements •

The model structure

•

The probabilities

•

Outcome measures (cost and effectiveness)

Strengths •

Evaluation of various choices

•

Threshold and sensitivity analysis

•

Cost-effectiveness and cost-utility analyses

Decision analysis A useful decision model requires three elements (Table 2.1): (i) a structure in the form of a decision tree leading forward from two or more choices at a decision node (represented by a square); (ii) a set of probabilities for each branch in the model leading from a chance node (represented by a circle); and (iii) a value for each possible pathway through the model leading up to a terminal node (represented by an arrow). With each branch that follows a chance event, a probability or probability variable is assigned a baseline value. The baseline value may be derived from the literature or represent personal judgment. Probabilities must be between 0 and 1 and must add up to 1 for the branches of a given chance node. Outcome measures can be formatted in a variety of ways, and often involve either a negative value such as cost or a positive value such as effectiveness. The generation and evaluation of a clinical decision model has a number of important strengths (Table 2.1).

A new way to think about cancer and aging

23

The strategy utilized in decision analysis involves determining the decision choice associated with the greatest expected value.7–12 This can be expressed as the greatest expected effectiveness or the least expected cost or cost-effectiveness. Figure 2.2 illustrates a hypothetical decision model or tree for two therapeutic alternatives with uncertainty about the diagnosis of disease. In Figure 2.2(a), the outcome for each treatment/disease pathway is represented as a utility. The benefit of treatment by convention is represented by the difference among treated and untreated individuals with the disease, while the harm or risk of treatment is the difference among treated and untreated individuals without the disease. Similar relations between benefit and risk are illustrated when considering quality of life adjustment (Figure 2.2b) and economic considerations (Figure 2.2c). Once baseline probabilities and outcome values have been assigned, each node can be evaluated by multiplying the outcome value by the probability of each branch and adding the products of the branches from each node together. The expected value therefore represents a weighted sum of the expected values of all possible paths, where the weights are given by the probabilities of the various chance events. The resulting expected value is then utilized as the outcome value for the immediately preceding branch. In this fashion, the model is ‘folded back’, achieving an expected outcome value for each decision choice. The choice associated with the greatest expected value should represent the desired choice for reasonable decision makers. There are times when decisions involve immediate versus delayed effects or costs where decision makers may reasonable differ as to the optimal choice. Confidence limits on the expected value can be estimated if the distribution of the individual probabilities and outcome values are known. Utilizing a Monte Carlo technique, the distribution of expected values can be estimated by sampling the known distributions in the model as the model is evaluated repeatedly.

Comprehensive Geriatric Oncology

p, probability of disease; UNN, utility for no treatment and no disease;

24

A new way to think about cancer and aging

25

UTN, utility for treatment and no disease; UTD, utility for treatment and disease; UND, utility for no treatment and disease; LE, life-expectancy; LYRX, life-years with treatment; LYC, life-years in control (without treatment); QRX, quality adjustment with treatment; QC, quality adjustment in control (without treatment); QALY, quality-adjusted life-years; QLYG, quality-adjusted life-years gained; QLYL, quality-adjusted life-years lost; CRX, cost associated with treatment; CC, cost associated with control (no treatment).

Figure 2.2 Schematic decision trees for clinical decision making based on utility analysis: model based on choice between treatment and no treatment despite uncertainty concerning diagnosis. The threshold probability of disease (Pthreshold), represents the prevalence of disease at which the expected utility associated with treatment equals that associated with no treatment. This can be found by equating the expected outcomes with and without treatment and then solving for P. (a) Utilities (U) are based on patient preferences for different health states for each pathway through the tree. Benefit is defined as the net positive utility between treatment or no treatment in patients with the disease, while risk represents the net negative utility between treatment or no treatment in individuals without disease. (b) Utilities are based on quality-adjusted life-expectancies associated with different health states and treatment groups. Benefit is defined as the quality-adjusted life-

Comprehensive Geriatric Oncology

26

years (QALYs) gained with treatment in those with disease, while risk represents the QALYs lost owing to treatment in individuals without disease. (c) Utilities are based on costs and benefits associated with different health states for each pathway through the tree. Benefit is defined as the gain in life-years with treatment among those with disease, while risk represents the marginal cost associated with treatment in those without disease. One of the most powerful features of decision modeling is the ability to conduct a sensitivity analysis. In a simple (one-way) sensitivity analysis, the baseline value of a variable is varied over the range of possible values. As the value of a variable is varied, the expected outcome value of each choice varies, giving a functional relationship or curve relating the variable and the associated outcome value from the model. The value of the variable at which the curves associated with two choices intersect represents the threshold where the outcome values for two strategies are equal. The threshold is the value of any variable for which the expected values of any two choices are equal. The threshold probability can be calculated by equating the expected values and solving the resulting equation, and is equal to the proportion of the total difference in utilities with treatment observed in patients without disease or the ratio of risk to risk plus benefit (Figure 2.2a). The outcomes can be expressed in more familiar terms such as survival or life-expectancy. However, to solve the equation in order to estimate a threshold, the risk or cost must be expressed in similar terms of reduced life-expectancy or survival. This is most readily accomplished by incorporating utilities in the form of QALYs and considering both the impact of disease and treatment on quality of life (Figure 2.2b). Solving this equation, the threshold represents the proportion of the total change in lifeyears (or QALYs) among both patients with disease and those without disease (benefit plus cost) represented by the loss in life-years or QALYs among those without disease (cost). The threshold is represented as the proportion surviving. Above and below the threshold, one or the other choice is favored on the basis of having the greatest expected value. The values of two variables may be varied simultaneously, generating a threshold function. Obviously, any combination of values of the two variables that do not lie on the threshold curve will result in expected values favoring one strategy or the other. Likewise, the values of three variables may be varied simultaneously, yielding a family of threshold curves. In theory, any number of variables may be varied simultaneously, although such an analysis is limited by the ability to conceptualize and graphically depict such relationships.

A new way to think about cancer and aging

27

The application of decision-analytic techniques to clinical medicine in general and the management of the elderly cancer patient in particular have many potential benefits. These strategies force the clinician to explicitly state the question being asked, the data and assumptions to be utilized, and how these will be analyzed to formulate a decision. Different clinicians utilizing the same data and the same logic should arrive at the same conclusion. The ability to assess the effect of variations in the assumptions on the optimal choice in a sensitivity analysis is a major strength of this approach. These techniques should be most helpful clinically in the most complex cases with the greatest degree of uncertainty. Decision analysis should also be a useful aid to teaching students and resident physicians how to utilize clinical data even relatively early in their clinical experience. Decision analysis may also facilitate research into the process of clinical reasoning. Finally, these techniques may be applied to health outcomes and health policy research and facilitate the development of reasonable clinical practice guidelines for management of the elderly cancer patient. Aging and cancer Increasing age represents the single most important risk factor for cancer. As shown in Figure 2.3, the number of cancer deaths in the USA peaks between the ages of 65 and 75 and then decreases owing to competing risks for mortality in the declining population at risk. Cancer incidence and mortality rates, however, continue to increase throughout life, at least up to age 80–85 (Figure 2.4). As shown in Table 2.2, cancer mortality rates

Figure 2.3 Graphic display of cancer incidence rates and the number of new cases for the US population by 5-year

Comprehensive Geriatric Oncology

28

age group for the period 1973–98. The cancer incidence rate per 100000 individuals per year is displayed as a line graph while the numbers of new cases (×100) are represented by the vertical bars.

Figure 2.4 Graphic display of cancer mortality and cancer incidence rates for the US population by 5-year age group for the period 1973–98. The cancer mortality rate in deaths per 100000 per year is displayed as solid diamonds. The cancer incidence rate in cases per 100000 per year is displayed as solid squares. The differences in cancer incidence rates and cancer mortality rates by 5-year age group are displayed as vertical bars.

A new way to think about cancer and aging

29

Table 2.2 Cancer mortality rates (deaths per 100000 individuals per year)19 Age group

Total

Males

Females

0–4

2.7

2.9

2.5

5–9

2.7

3.0

2.4

10–14

2.7

3.0

2.3

15–19

3.8

4.4

3.1

20–24

5.4

6.5)

4.4

25–29

8.5

8.9

8.0

30–34

14.9

14.0

15.7

35–39

27.4

23.9

30.8

40–44

52.3

48.1

56.4

45–19

100.4

98.3

102.3

50–54

186.2

195.9

176.9

55–59

315.7

353.7

280.6

60–64

506.9

600.0

424.0

65–69

731.1

904.8

586.0

70–74

1001.2

1273.6

791.0

75–79

1231.0

1612.8

965.5

80–85

1518.9

2113.3

1177.1

85+

1776.0

2680.9

1412.0

increase with age more dramatically for males than for females, with a nearly twofold difference in those over the age of 85.19 Cancer incidence and mortality rates have increased considerably over the past several decades in the USA.20,21 Although age-adjusted cancer mortality rates have also increased, most of this increase is attributable to increasing cancer mortality in individuals over the age of 65. Age-specific cancer mortality rates have actually decreased substantially in younger age groups over the past two decades, while they have increased in those 65 and over (Table 2.3). Most of the increase in cancer mortality rates in those 65 and over has been due to lung cancer, with lesser contributions from genitourinary cancer and the hematologic malignancies.

Comprehensive Geriatric Oncology

30

Table 2.3 Changes in cancer mortality rates (1950– 98)19 Age group

Mortality rates/100 000/year 1950

1975

Percentage change 1950–98

1998

0–4

11.1

5.2

2.3

−77.5

5–14

6.6

4.7

2.6

−59.6

15–24

8.5

6.6

4.5

−48.2

25–34

19.8

14.6

10.9

−43.6

35–44

64.2

53.9

38.9

−38.4

45–54

175.2

179.2

134.2

−22.6

55–64

394.0

423.2

385.9

−0.7

65–74

700.0

769.8

830.2

19.4

75–84

1160.9

1156.0

1320.3

14.7

85+

1450.7

1437.9

1751.4

21.5

158.1

162.3

161.5

3.1

All ages

The increase in cancer mortality rates among the elderly appears to be related, at least in part, to increasing cancer incidence rates. For some types of cancer, old age represents a poor prognostic factor. This observation most likely relates to the biology of the disease, delays in diagnosis resulting in more advanced stage of disease at presentation, complicating comorbid conditions, and poor tolerance of or poor compliance with potentially effective treatment programs. Older patients are often treated less aggressively based on chronologic age without consideration of functional status and comorbid conditions.22 Elderly patients with cancer appear to do nearly as well as younger patients after adjusting for the type of cancer, tumor stage, comorbid conditions, and treatment.2,23 The outcome of certain malignancies actually appears to favor the elderly, perhaps because of biologic differences in tumor behavior. Table 2.4 illustrates the incidence, mortality, and relative survival of the 10 leading sites of invasive cancer among the elderly. The specialized needs of the elderly cancer patient suggest that attention should be directed toward a better understanding of clinical decision making in this population. Full attention to quality of life and cost, in addition to measures of survival or longevity, is of paramount importance in the elderly cancer patient.3,24 In addition, a better understanding is needed of those factors that influence a clinician’s decisions when caring for elderly cancer patients.25 Optimal decision making in the elderly requires knowledge of the life-expectancy associated with different age groups. Figure 2.5 reveals the relationship between

A new way to think about cancer and aging

31

Table 2.4 Cancer incidence, mortality, and survival rates for the 10 leading sites of invasive cancer in those aged 65 and over for the period 1973–9819 Incidencea All sites (invasive)

Mortalitya

5-year relative survival (%)

2151

1068

58.2

Colon/rectum

288

119

61

Lung

349

314

13

Prostate (males)

966

217

97

Breast

262

70.5

87

Bladder

112

26

77

Lymphomas

79

44

47

Pancreas

59

57

3

Uterus (females)

97

22

79

Stomach

44

27

21

Leukemia

52

39

34

a

Per 100000 population per year, age-adjusted to the 1970 US standard population.

Figure 2.5 Graphic display of US population and life-expectancy by 5-year age group. The age-specific US population (×106)

Comprehensive Geriatric Oncology

32

for the year 2000 is displayed as shaded vertical bars. Life-expectancy in years for the US population from birth and for 5-year age-specific groups is displayed as solid squares. increasing age and decreasing life-expectancy.19 It is important to note that although lifeexpectancy from birth has increased dramatically since the turn of the 20th century, there has been little increase in the life-expectancy of those aged 65 and over or of the total lifespan (Table 2.5).26 Decision making in the elderly must consider both the increase in cancer mortality and the decrease in life-expectancy with increasing age. Figure 2.6 illustrates this complex relationship by displaying the age-specific loss in life-expectancy due to cancer with age. Clearly, the greatest impact of cancer on years of productive life is in the range of 50–80 years of age. The relative importance of prolonging survival and the acceptability of certain types of discomfort or costs

Table 2.5 Life-expectancy (years)19 From birth

From age 65

Year

Males

Females

Males

Females

1900

46

48

11

12

1910

48

52

11

12

1920

54

55

12

13

1930

58

62

12

13

1940

61

65

12

14

1950

66

71

13

15

1960

67

73

13

16

1970

67

75

13

17

1980

70

78

14

18

1990

72

79

15

19

1999

74

79

16

19

A new way to think about cancer and aging

33

Figure 2.6 Graphic display of the annual loss in age-specific lifeexpectancy from cancer (years (×103) for the US population for the year 2000 by 5-year age groups. Also illustrated by darker bars is the proportion of life-expectancy lost from cancer among those aged 65 and over. vary among individuals. Physicians must be aware that such factors as age, race, sex, and socioeconomic status may influence treatment decisions in a subtle and often unrecognized manner. Where feasible, the patient’s values should be incorporated into any decision analysis that is performed.27–29 Appropriate adjustment of survival by the anticipated impact on quality of life is particularly important in decision making in the elderly. This chapter illustrates the usefulness of decision analysis in improving our understanding of those factors important in medical and public health decisions in the elderly. Clinical decision models can be utilized to evaluate virtually any clinical scenario, including screening, prevention, treatment, and supportive care. In screening and prevention strategies, it is assumed that the intervention has the potential to reduce the occurrence or risk of disease, while in treatment and supportive care strategies, it is assumed that it has the potential to reduce the consequences of disease or its treatment. Such decision models can be utilized to evaluate not only complex clinical problems and guide choices but also the impacts of quality of life and cost.30 If differences in clinical or quality-adjusted clinical outcomes are possible, a cost-effectiveness or cost-utility analysis is most commonly employed to evaluate the economic impact of a disease and its treatment. When no difference in clinical or adjusted outcome is anticipated, a costminimization analysis may be the most valuable approach to economic analyses to

Comprehensive Geriatric Oncology

34

identify the strategy associated with the lowest costs. The issues related to clinical decision making in elderly patients with cancer will be illustrated with regard to both cancer screening and treatment.

Figure 2.7 Decision tree for a hypothetical cancer screening test. The decision node is illustrated as a rectangle leading to the choice whether or not to screen a population or individual. Patients may or may not have cancer, which is unknown at the time of the decision whether or not to screen. Screening can accurately reflect those with or without disease or may provide false-negative or falsepositive results. The outcomes of interest include both estimated cost and life-expectancy, each of which varies with the pathway through the tree. Cancer screening The ideal test for screening for disease at any age would have perfect sensitivity and specificity and would detect disease early with no cost or toxicity. In addition, when considering screening tests, the disease being sought should be treatable when diagnosed early and yet cause morbidity or even mortality if not detected early. In reality, clinical

A new way to think about cancer and aging

35

tests have less than perfect sensitivity and specificity. Tests are often costly, and may be associated with significant morbidity and mortality due either to the testing procedure or to the evaluation of individuals with positive test results. A diagnostic test or treatment associated with only a modest probability of enhancing the beneficial outcome may be justified if it is associated with little or no harmful effect or cost. In contrast, a procedure associated with frequent morbidity or mortality is only justified if it is associated with a high probability of improved patient survival. The impact of any screening test or strategy must ultimately be evaluated in the population to be screened. However, to illustrate issues related to aging and cancer screening, a hypothetical screening test for cancer is presented (Figure 2.7). It is assumed that this test is capable of detecting a cancer earlier than in those not screened. It is also assumed that earlier detection for this cancer can improve survival. The impact of age on the value of this screening test will be assessed with regard to both cost and effectiveness.

Figure 2.8 Graphic displays of sensitivity analyses of life-expectancy for screened and unscreened populations for hypothetical cancer screening test. In (a), life-expectancy in years is displayed on the vertical axis and cancer prevalence with increasing age on the horizontal axis. Changes in life-expectancy for the screened population are displayed as a solid line, whereas those for the unscreened population are shown as a dashed line. The impact of screening on life-expectancy is seen to increase with increasing disease prevalence and age. In (b), marginal cost-effectiveness in cost in dollars per year of lifeexpectancy extended is displayed on

Comprehensive Geriatric Oncology

36

the vertical axis and cancer prevalence with increasing age on the horizontal axis. The cost for each life-year extended is seen to decrease with increasing disease prevalence and age. When considering a malignancy for which there is effective treatment when diagnosed early, screening is associated with the greatest expected value for most reasonable assumptions. However, since disease prevalence and thus the positive predictive value increase while life-expectancy decreases with advancing age, the net effectiveness of screening in the elderly is a complex function. The annual incidence of cancer in the general US population over the age of 65 is approximately 2%. Cancer prevalence at any given time in an unscreened population is considerably greater than its incidence because of the accumulation of cases in proportion to the average duration between screen-detected disease and non-screened diagnosed disease. In addition, cancer prevalence varies considerably between the various cancers considered for screening. As shown in Figure 2.8(a), life-expectancy decreases with increasing disease prevalence and therefore increasing age in both screened and unscreened populations. The fall in life-expectancy with increasing cancer prevalence, however, is less rapid in the screened population than in the unscreened population. Therefore, the comparative effectiveness of such screening is greater with increasing age and increasing disease prevalence. Figure 2.8(b) demonstrates that the cost-effectiveness (i.e. cost per life-year gained) of screening improves with increasing disease prevalence and age. Table 2.6 illustrates the effect of age on the cost-effectiveness of screening for a hypothetical malignancy. In this example, it is assumed that the 5-year survival of patients diagnosed routinely at the time of symptom onset is 50%, whereas the survival of those detected by screening while asymptomatic is 90%. Under these assumptions, the optimal effectiveness and cost-effectiveness of screening are observed in individuals 65– 75 years of age. This observation is the result of the increasing positive predictive

Table 2.6 Age and screening test performance Age group Life-expectancy (years) Prevalencea Years gainedb Cost per year ($)c 25–35

50

0.004

540

36919

35–45

41

0.0014

1670

11978

45–55

32

0.0053

5240

3783

55–65

24

0.0132

10290

1899

65–75

16

0.0248

13010

1471

75–85

10

0.0372

11350

1647

85+

6

0.0480

7380

2481

a

Based on a preclinical duration of disease of 24 months.

A new way to think about cancer and aging

37

b

Per 100000 individuals screened. Based on a cost of screening of $100 and a cost of diagnosis of $1000.

c

value associated with increasing disease prevalence but a corresponding fall in lifeexpectancy with increasing age. The effectiveness and cost-effectiveness of cancer screening increase as the magnitude of the absolute difference in survival between unscreened and screened individuals increases. Test sensitivity and specificity have noticeably less impact on the calculated expected value. Although cost estimates affect the measured cost-effectiveness, they do not alter the basic relationships and conclusions of the model. Therefore, screening for a malignancy in which early intervention is beneficial can be effectively and costeffectively applied in the elderly. Cancer treatment For cancer treatment decisions, the diagnosis must already be established. Therefore, disease prevalence is no longer an issue in cost-effectiveness analysis. Alternatively, issues related to cost and quality of life often take on even greater importance than with screening. A variety of factors must be considered, including the type, stage, and grade of tumor, the patient’s functional status, the presence of any complicating medical conditions, and a number of psychological and socioeconomic factors. The clinician should consider the age-specific life-expectancy of the individual before committing the patient to treatment associated with considerable morbidity. The types of malignancies that afflict the elderly appear in general to be less responsive to systemic therapy than the malignancies found in younger individuals. Alternatively, many malignancies found in elderly patients are most effectively treated by surgical resection when early diagnosis is possible. When palliation with little impact on longevity is the most likely outcome, the limited life-expectancy of the elderly and quality of life issues may favor no treatment. When highly treatable and potentially curable disorders are involved, the greatest expected value will almost always favor the decision to treat regardless of age. However, since both treatment response and toxicity correlate directly with treatment intensity, the clinician is often faced with very difficult clinician decisions.31 These points can be illustrated by reference to a hypothetical treatment program for advanced cancer shown in Figure 2.9. In this example, we assume that responding patients with a certain malignancy experience a doubling in median survival, although with some risk (5%) of early mortality. Outcome is assessed in terms of both treatment cost and effectiveness. Marginal cost-effectiveness is shown in Figure 2.10 for both unadjusted effectiveness measured in terms of life-expectancy and for quality-adjusted life-expectancy where both non-response and treatment are each associated with a 25% reduction in the quality of life. Often, a utility analysis with formal assessment of patient preferences is required for objective and valid adjustment. The average quality-adjusted

Comprehensive Geriatric Oncology

38

Figure 2.9 Decision tree for a hypothetical cancer treatment program. The decision node is illustrated as a rectangle leading to the choice whether or not to treat a population or individual. All patients are assumed to actually have cancer. Whether patients will survive or respond to treatment is unknown at the time of treatment. The outcomes of interest include both estimated cost and life-expectancy, each of which varies with the pathway through the tree. life-expectancy and cost-effectiveness associated with treatment increase as the treatment mortality decreases, the response rate increases, or the impact of treatment on median survival increases (Figure 2.10a). Treatment appears to become reasonably cost-effective above response rates of 30%. Based on initial conditions for individuals over age 65, including a median survival of 1 year untreated, a 5% risk of treatment mortality, and a 50% decrease in the hazard for mortality among responders, the threshold response rate favoring treatment without quality adjustment is 6%. With quality adjustment for both non-response and treatment toxicity as outlined above, a threshold response rate of 22% is estimated above which treatment provides greater quality-adjusted life-expectancy than no treatment. Looking alternatively at the hazard ratio threshold, the ratio below which treatment is favored is 0.84 without quality adjustment and 0.60 with quality adjustment. The impact of the hazard ratio associated with treatment response on cost-effectiveness is

A new way to think about cancer and aging

39

illustrated in Figure 2.10(b) for unadjusted conditions as well as with quality-of-life adjustment. Treatment appears to become reasonably cost-effective when the hazard ratio is 0.50 or less. The estimated patient mortality rate includes the disease-specific mortality rate as well as the age-specific mortality rate. Therefore, the response threshold for treatment increases with increasing age owing to a decrease in age-specific life-expectancy. Under the hypothetical conditions illustrated here, treatment of an individual aged 85 or more is favored only when a response rate more than 31% is likely. Likewise, the unadjusted and adjusted hazard ratio thresholds for individuals age 85 and over decrease to 0.81 and 0.49, respectively. As illustrated in Figure 2.10(c), the cost-effectiveness of cancer treatment under these conditions increases with decreased age-specific life-expectancy, rising dramatically after age 75, particularly when quality of life is considered. Clearly, the conditions under which treatment is favored in this treatment model become more restrictive with increasing age. While the treatment response threshold increases with increasing age, treatment may still be favored in responsive malignancies under a wide variety of assumptions. It should be mentioned that available supportive care measures appears to be valuable in elderly patients receiving cancer treatment. In fact, the benefit from such measures appears to be as great as, if not greater than, when applied to younger patients.32 The risk and severity of neutropenic complications, including febrile neutropenia, are greater among the elderly.33,34 The use of hematopoietic growth factors is a good example of the value of supportive measures in elderly patients receiving systemic chemotherapy for moderately aggressive but responsive malignancies. The colony-stimulating factors such as granulocyte colony-stimulating factor (G-CSF) have been shown to reduce the severity and duration of neutropenia as well as the incidence of febrile neutropenia and documented infections associated with various systemic cancer chemotherapy regimens for a variety of malignancies.35 The effectiveness of the colony-stimulating factors has been studied in elderly patients with lymphomas and acute leukemia and has been found to be at least as effective as in younger patients. In a recent meta-analysis of eight trials of elderly patients with non-Hodgkin lymphoma (NHL) receiving CHOP-like regimens, the summary risks of severe neutropenia and febrile neutropenia are 66% and 25%, respectively, across these trials.36 In a series of 577 patients with intermediate-grade NHL, older patients experienced significantly more febrile neutropenia.37 In addition, older patients received significantly fewer courses of CHOP and, in a multivariate analysis, received significantly lower dose intensity than younger patients. A recent study of nearly 80000 episodes of febrile neutropenia at 115 academic medical centers demonstrated that patients 65 years of age

Comprehensive Geriatric Oncology

40

Figure 2.10 Graphic displays of two-way sensitivity analyses for a hypothetical cancer treatment program with and without quality of life adjustment. In each plot, cost-effectiveness with treatment is shown on the vertical axis.

A new way to think about cancer and aging

41

In (a), the response rate as the proportion responding is displayed on the horizontal axis. The cost per lifeyear extended with treatment is seen to decrease with increasing rate of response to the treatment. The impact of treatment on cost-effectiveness when the impact on quality of life is considered is seen to be less, and only at higher response rates than when unadjusted life-expectancy alone is considered. Treatment appears to become reasonably cost-effective above a response rate of 30%. In (b), the hazard ratio for mortality between treated and untreated patients is displayed on the horizontal axis. The cost per life-year extended with treatment is seen to decrease with decreasing hazard ratio as an indicator of increasing treatment effect. The impact of treatment on costeffectiveness when the impact on quality of life is considered is seen to be less, and only at lower hazard ratios than when unadjusted life-expectancy alone is considered. Treatment appears to become cost-effective when associated with a hazard ratio of 0.50 or less. In (c), the age-specific lifeexpectancy associated with increasing age groups is displayed on the horizontal axis. The cost per life-year extended with treatment is seen to increase with decreasing age-specific life-expectancy associated with increasing age. The impact of treatment on cost-effectiveness when the impact on quality of life is

Comprehensive Geriatric Oncology

42

considered is less, and is lost at a younger age than when unadjusted life-expectancy alone is considered. or older who develop febrile neutropenia experience nearly twice the risk of death of younger patients.38 The meta-analysis of three RCTs of older patients receiving CHOPlike chemotherapy without and with G-CSF support demonstrated risks of 82% and 50%, respectively, for grade IV neutropenia and 40% and 25%, respectively, for febrile neutropenia.36 Thus, G-CSF appears to be as effective in the elderly as in younger patients. In fact, the National Comprehensive Cancer Network (NCCN) Guidelines Advisory Panel for the management of older individuals has recommended routine primary prophylaxis with G-CSF in patients aged 70 and more receiving chemotherapy intensity-equivalent to CHOP. They have also recommended that hemoglobin levels in such patients be kept at or above 12g/dl, utilizing recombinant erythropoietin if necessary.39 Discussion Managing the elderly cancer patient involves decisions based on a wide variety of factors aimed at providing the patient with the optimal duration and quality of life.40 Careful attention to the entire patient situation, familiarity with advances in cancer diagnosis and treatment, and an understanding of the rational use of clinical data and measured outcomes should assist physicians in making the appropriate clinical decision for each patient. The risk of most cancers increases progressively with increasing age. Based on the observed natural history of many cancers affecting the elderly and the availability of effective treatment modalities when tumors are localized, early and accurate detection appears to offer the best opportunity for improving cancer survival in the elderly. Several available cancer screening strategies have been shown to be cost-effective when applied to an elderly population. Current recommendations for cancer screening among individuals aged 50 and more are presented in Table 2.7. Similarly, increasing attention is being focused on methods of cancer prevention. The application of such methods, often associated with lower levels of toxicity than active treatment, to a higher-risk subgroup such as the elderly offers tremendous opportunities. Tamoxifen chemotherapy among others may represent the beginning of a very promising method of cancer control in the susceptible elderly population. The value of available treatment strategies in treating elderly patients with malignancy is perhaps less clear, and depends greatly upon the type of cancer involved and the treatment strategy utilized, with its associated toxicity. Malignancies affecting the elderly are often considered less responsive to treatment than those more commonly seen in younger patients. In addition, elderly patients with their more frequent comorbidities appear to represent a more vulnerable population for the adverse consequences of cancer treatment. However, several studies have demonstrated that elderly patients selected on the basis of underlying risk factors tolerate definitive cancer treatment, including surgery, radiation therapy, and chemotherapy.23,24

A new way to think about cancer and aging

43

The only potential for cure in most elderly patients with malignancy is provided by early and complete surgical removal. The clinician must recognize, however, that major surgery is associated with greater risk in the elderly than in younger patients, largely due to the increased frequency of comorbid medical disorders.41 The greater operative risk among the elderly is most problematic when palliation is the goal, rather than when curative resection is undertaken.42 Several malignancies may be cured or controlled effectively by the application of radiation therapy. This is often effective in relieving tumor symptoms related to compression and obstruction in patients with advanced disease. The therapeutic ratio of normal tissue tolerance to tumor lethal dose falls with increasing age.43 Systemic chemotherapy is capable of prolonging the survival of patients with a variety of advanced malignancies, with cure being possible in such disorders as lymphomas, breast cancer, and small cell lung cancer. The magnitude and duration of treatment response often depend directly on treatment intensity. The greater the impact of treatment on prolonging patient survival, the greater is the toxicity that is generally considered acceptable. On the other hand, the more that quality of life is compromised by treatment, the less important mere prolongation of survival becomes. When chemotherapy is administered with the intention of prolonging survival, dose reduction may significantly compromise disease control.44 The toxicity of chemotherapy in the elderly may be increased by the associated physiologic and pathologic changes that occur with aging.

Table 2.7 Recommendations for cancer screening over the age of 5047 Cancer

Procedure

Recommended frequency

Cervix

Papanicolaou test

Yearly until 3 consecutive negative tests, then every 3 years

Breast

Self-examination

Monthly

Physical examination

Yearly

Mammography

Yearly

Colon/rectum Digital rectal examination

Yearly

Fecal occult blood test

Yearly

Sigmoidoscopy

Every 3–5 years

Digital rectal examination

Yearly

Prostate-specific antigen

Yearly

Uterus

Endometrial sample

Once at menopause

Ovary

Pelvic examination

Yearly

Multiple

General physical examination

Yearly

Prostate

chemotherapy on proliferating normal elements, such as hematopoietic stem cells, appear to occur more frequently or severely among the elderly owing to age-related decreases in

Comprehensive Geriatric Oncology

44

The acute toxic effects of hematopoietic stem cell reserves. These effects may also be increased in patients exposed to previous treatment and in those with reduced functional and nutritional status that limits tolerable treatment intensity. It should be remembered that hormonal manipulation may produce tumor regression with acceptable toxicity in a variety of malignancies, including breast, prostate, and uterine cancers.45 Elderly cancer patients should be considered potential subjects for approved clinical trials, with the exception of those with serious complicating medical conditions and those incapable of informed consent. Elderly patients eligible for prospective multi-institutional clinical trials have been found to experience no increase in the frequency or severity of chemotherapy toxicity.46 In addition, elderly patients in these studies did not differ in important risk factors or compliance with treatment dosage and had equivalent response rates to younger patients. Although the tumor response and toxicity associated with systemic treatment depend more on physiologic factors than on actual age, experimental drugs should generally be avoided in the very elderly. The malignancies afflicting the elderly are less likely to be those that respond to new treatment modalities. In addition, unusual and potentially life-threatening toxicities must be anticipated in this group. If experimental treatment is undertaken, it should be performed as a part of a well-designed, controlled clinical trial with fully informed consent. When aggressive treatment approaches are not a reasonable consideration, much may still be offered to the aged cancer patient, including the control of pain and other symptoms of the underlying malignancy. Aggressive psychosocial support is essential in managing the elderly cancer patient. Owing to the limitations on life-expectancy and frequent comorbid conditions in the elderly, quality of life must be a primary concern of the treating clinician. Decisions to limit treatment in the elderly cancer patient with untreatable or refractory disease must also eventually be considered. Decision analysis provides both a framework for thinking about healthcare in the elderly and a fertile area for methodologic and healthcare outcomes research. Decision analysis is particularly suited to assessing the usefulness of prevention and earlydetection strategies in complex settings with mixed outcomes, as exemplified in the elderly. Such an approach is particularly valuable in situations where a decision based on simple survival is incomplete or unsatisfactory. In healthcare planning for the elderly, any useful medical and public health strategy must consider performance outcome in terms of both benefits and risks, including costs. Decision analysis is ideally suited for assessing the value of new therapeutic strategies, as well as technologies aimed at reducing disease and treatment-related toxicity. Finally, it provides a usefiil framework for continuous objective evaluation of rapidly evolving clinical strategies in an era of increasing health awareness and cost containment. The application of decision analytical methods to healthcare in the elderly should not only improve our understanding of this rapidly expanding field but also result in improved quality of care and quality of life for the elderly patient with cancer. References 1. Kahneman D, Slovic P, Tversky A. Judgement under Uncertainty: Heuristics and Biases. Cambridge: Cambridge University Press, 1982. 2. Pauker SG, Kassirer JP. Decision analysis. N Engl J Med 1987; 316: 250–8.

A new way to think about cancer and aging

45

3. Kassirer JP, Moskowitz AJ, Lau J, Pauker SG. Decision analysis: a progress report. Ann Intern Med 1987; 106:275–91. 4. Albert DA, Munson R, Resnik MD. Reasoning in Medicine: An Introduction to Clinical Inference. Baltimore: John Hopkins University Press, 1988. 5. Sox HC, Blatt MA, Higgins MC, Maston KI. Medical Decision Making. Boston: Butterworth, 1988. 6. Kassirer JP, Gorry GA. Clinical problem solving: a behavioral analysis. Ann Intern Med 1978; 89:245–55. 7. Weinstein MC, Fineberg HV. Clinical Decision Analysis. Philadelphia: WB Saunders, 1980. 8. Kong A, Barnett GO, Mosteller F, Youtz C. How medical professionals evaluate expressions of probability. N Engl J Med 1986; 315: 740–4. 9. Balducci L, Lyman GH. Cancer in the elderly. Epidemiologic and clinical implications. Clin Geriatr Med 1997; 13:1–14. 10. Wasson JH, Sox HC, Goldman L, Neff RK. Clinical prediction rules: applications and methodological standards. N Engl J Med 1985; 313: 793–799. 11. Schwartz S, Griffin T. Medical Thinking: The Psychology of Medical Judgement and Dedsion Making. New York: Springer-Verlag, 1986. 12. Schwartz WB, Gorry GA, Kassirer JP, Essig A. A decision analysis and clinical judgment. Am J Med 55:459–72. 13. Mushlin AI. Diagnostic tests in breast cancer: clinical strategies based on diagnostic probabilities. Ann Intern Med 1985; 103:79–85. 14. Rembold CM, Watson D. Posttest probability calculation by weights: a simple form of Bayes theorem. Ann Intern Med 1988; 108:115–20. 15. Sox HC. Probability theory in the use of diagnostic tests: an introduction to critical study of the literature. Ann Intern Med 1986; 104: 60–6. 16. Griner PF, Mayewski RJ, Mushllin AI, Greenland P. Selection and interpretation of diagnostic tests and procedures: principles and applications. Ann Intern Med 1981; 94:553–600. 17. Health and Public Policy Committee. American College of Physicians. The use of diagnostic tests for screening and evaluating breast lesions. Ann Intern Med 1985; 103:147–51. 18. Djulbegovic B, Cantor A, Lyman GH, Ruckdeschel JC. Understanding treatment benefits and harms. Evidence-Based Oncol 2000; 1: 66–8. 19. Vital Statistics of the United States 1950–2000. Washington, DC: US Government Printing Office, 2001. 20. Cancer in Florida, 1981–1983. Tallahassee, FL: Health Program Office, Epidemiology Program, Department of Health and Rehabilitative Services, 1986. 21. SEER Cancer Statistics Review 1973–1998. Washington, DC: US Government Printing Office, 2000. 22. Greenfield S, Blanco DM, Elashoff RM, Gaaz PA. Patterns of care related to age of breast cancer patients. JAMA 1987; 251:2766–70. 23. Peterson BA, Kennedy BJ. Aging and cancer management. Part 1: Clinical observations. Cancer 1979; 29:322–32. 24. Butler RN, Gastel B. Aging and cancer management: research perspectives. Cancer 1979; 29:322–32. 25. Beghe’ C, Balducci L. Geriatric oncology: perspectives from decision analysis. A review. Arch Gerontol Geriatr 1990; 10:141–62. 26. Miller BA, Ries LAG, Hankey BF et al (eds). SEER Cancer Statistics Review 1973–1990. Bethesda, MA: National Cancer Institute, NIH Publication 93–2789, 1993. 27. Brody DS. The patient’s role in clinical decision making. Ann Intern Med 1980; 93:718–22. 28. Lo B, Jonsen AR. Clinical decisions to limit treatment. Ann Intern Med 1980; 93:764–8. 29. Beck Jr, Kassirer JP, Parker SG. A convenient approximation of life expectancy (the DEALE). 1. Validation of the method. Am J Med 1982; 72:883–8.

Comprehensive Geriatric Oncology

46

30. Lyman GH, Kuderer N, Balducci L. Cancer care in the elderly: cost and quality of life considerations. Cancer Control 1998; 5:347–54. 31. Extermann M, Balducci L, Lyman GH. What threshold for adjuvant therapy in older breast cancer patients? J Clin Oncol 2000; 18: 1709–17. 32. Balducci L, Hardy CL, Lyman GH. Hematopoietic growth factors in the older cancer patient. Curr Opin Hematol 2001; 8:170–87. 33. Lyman GH, Lyman C, Ogboola Y. Risk models for the prediction of chemotherapy-induced neutropenia. Neutropenia Oncol 2001; 1:2–7. 34. Intragumtornchai T, Sutheesophon J, Sutcharitchan P et al. Leuk Lymphoma 2000; 37:351–30. 35. Lyman GH, Kuderer NM, Djulbegovic B. Prophylactic granulocyte colony-stimulating factor in patients receiving dose intensive cancer chemotherapy: a meta-analysis. Am J Med 2002; 112:406–11 36. Lyman GH, Balducci L, Agboola Y. Use of hematopoietic growth factors in the older cancer patient. Oncol Spectrum 2001; 2:414–21. 37. Morrison VA, Picozzi V, Scott S et al. Clin Lymphoma 2001; 2:47–56. 38. Lyman GH, Kuderer NM, Agboola O et al. Blood 2001; 98:432a. 39. Balducci L, Lyman GH. Patients aged >70 are at high risk for neutropenic infection and should receive hemopoietic growth factors when treated with moderately toxic chemotherapy. J Clin Oncol 2001; 19:1583–5. 40. Balducci L, Lyman GH, Fabri PJ. Management of cancer in the aged. Comp Therap 1996; 22:88–93. 41. Sherman S, Suidot CE. The feasibility of thoracotomy for lung cancer in the elderly. JAMA 1987; 258:927–30. 42. Lewis AAM, Khoury GA. Resection for colorectal cancer in the very old: Are the risks too high? BMJ 1988; 296:459–61. 43. Samet J, Hunt WC, Key C et al. Choice of cancer therapy varies with age of patient. JAMA 1986; 225:3385–90. 44. Frei E III, Canellos GP. Dose: a critical factor in cancer chemotherapy. Am J Med 1980; 69:585–94. 45. Extermann M, Balducci L, Lyman GH. Optimal duration of adjuvant tamoxifen treatment in elderly breast cancer patients: influence of age, comorbidities and various effectiveness hypotheses on life expectancy and cost. Breast Dis, 1996; 9:327–39. 46. Begg CB, Cohen JL, Ellerton J. Are the elderly predisposed to toxicity from cancer chemotherapy? Cancer Clin Trials 1980; 3:369–74. 47. Smith RA, Mettlin CJ, Davis KJ, Eyre H. American Cancer Society guidelines for the early detection of cancer. CA Cancer J Clin 2000; 50:34–9. 48. Lyman GH, Kuderer NM. Diagnosis and treatment of cancer in the elderly: cost-effectiveness considerations. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:510–24.

Appendix 2.1: Glossary Probability A number between 0 and 1 representing the likelihood of an event. Odds The ratio of the probability that an event occurs divided by the probability that the event does not occur. Conditional probability The probability of an event given the occurrence of another event. Prior probability The pretest probability of an event or the prevalence.

A new way to think about cancer and aging

47

Posterior probability The conditional probability of an event given that another event or a specific test outcome has occurred. True-positive rate The probability of a positive test result in diseased individuals (sensitivity). False-positive rate The probability of a positive test result in those without disease. True-negative rate The probability of a negative test result in those without disease (specificity). False-negative rate The probability of a negative test result in those without disease. Predictive value positive The probability of disease in those with a positive test result. Predictive value negative The probability of no disease in those with negative test results. Sensitivity analysis A study of changes in outcome measures with changes in probabilities, value outcomes, or decision assumptions. Life-expectancy The average life remaining for individuals of a given age. Expected value The average outcome value over possible outcome paths, with the value of each path being weighted by the probability of the path. Cost-effectiveness The cost for each unit of outcome value gained, such as years of additional life-expectancy. Appendix 2.2: Test performance The following summarizes test performance characteristics useful in decision analysis based on probability theory. Here P(X) is defined as the probability of an event X. P(X|Y) represents the conditional probability of event X given that event Y has occurred. The odds of X is defined as P(X)/[1−P(X)]. Sensitivity=P(positive test|disease) Specificity=P(negative test|no disease) Predictive value positive=P(disease|positive test) Predictive value negative=P(disease|negative test)

Comprehensive Geriatric Oncology

48

Appendix 2.3: Expressions for Bayes’ Theorem •

•

• ln(post-test odds)=ln(pretest odds)+ln(LR) where ln indicates the natural logarithm

S=S0 e−mt

Appendix 2.4: Declining exponential approximation for lifeexpectancy (DEALE)

where S0=number of patients alive at time 0 S=number of patients alive at time t e=base of natural logarithms m=mortality rate:

See also Appendix 42.1 in Chapter 42 of this volume.48

A new way to think about cancer and aging

49

PART 2 Epidemiology

3 Cancer mortality in the elderly, 1960–98: A worldwide approach Carlo La Vecchia, Franca Lucchini, Eva Negri, Fabio Levi Introduction Between the 1950s and the early 1990s, there was a general tendency towards rising cancer mortality, and towards leveling of differences in certified cancer mortality in the elderly population in various areas of the world.1,2 These trends were interpreted by some authors as indicators of an ongoing generalized cancer epidemic.3,4 However, there were substantial limitations and uncertainties in the reliability and validity of cancer death certification and their trends in the elderly, and changes in certified mortality for several sites may well reflect improved ascertainment, increased use of screening and diagnostic techniques in the elderly, and, in greater generality, changes in medical practice. Still, there was no widespread and generalized rise in cancer mortality in the elderly, with the major exception of lung and other tobacco-related neoplasms. Some decline in overall cancer mortality from the late 1970s onwards has been reported from the USA5–7 and Western Europe.8–10 However, trends in the elderly population up to the early 1990s tended systematically to be less favorable.2–4,11 This may be due to a different cohort pattern of cancer mortality across various generations and hence age groups,12 to more substantial changes in diagnosis and certification accuracy in the elderly,2,13 to a lower impact of earlier diagnosis and improved treatment in the elderly,14,15 or to contributions from various factors. Given also their particular health relevance, it is therefore important that recent trends in cancer mortality in the elderly be monitored. Along this line, we considered mortality from six major cancer sites plus total cancer mortality at age 65–84 in Europe, the USA, and Japan up to 1998. Materials and methods Official death certification numbers for 22 European countries (the 15 countries of the European Union, EU, plus 7 others), excluding Albania and a few countries with a population of less than 1 million (i.e. Andorra and Liechtenstein), the USA, and Japan were derived from the World Health Organization (WHO) database. During the calendar period considered (1960–1998), three different Revisions of the International Classification of Diseases (ICD) were used.16–18 Classification of cancer deaths were thus recoded, for all the calendar periods, according to the 9th Revision (ICD-9).17 To improve

Comprehensive Geriatric Oncology

52

comparability of data throughout different countries and calendar periods, we have pooled together all intestinal sites, including the rectum. Estimates of the resident population, generally based on official censuses, were obtained from the same WHO databank. From the matrices of certified deaths and resident populations, age-specific rates for each 5-year age group considered (65–69 to 80–84) and calendar period were computed. Age-standardized rates were based on the World Standard Population.19 Results Figure 3.1 gives trends in age-standardized mortality at age 65–84 from all cancers and selected cancer sites in the EU, other European countries, the USA, and Japan over the period 1960–97. Most of the following comments, however, refer to the trends observed over the last decade, i.e. between 1985–89 and 1995–98. After earlier rises, total cancer mortality at age 65–84 has been declining in the EU (from 1457/100000 in 1985–89 to 1378/100000 males in 1995–98, −5.5%; from 712 to 690/100000 females, −4.5%), in US males (from 1266 to 1237/100000, −2.3%), but not females (from 732 to 764/100000, +4.5%), and in Japanese females (from 557 to 526/100000, −5.6%), but not males (from 1218 to 1295/100000, +6.3%). Cancer mortality in the elderly rose for both sexes in Eastern Europe, from 1294 to 1359/100000 for males, +5.1%; from 669 to 688/100000 for females, +2.7%. Gastric cancer mortality steadily declined in all the areas considered, and the fall over the last decade was proportionally larger in the EU (about 30% in both sexes) as compared with eastern Europe (−23%), the US (−20% in males and −17% in females), or Japan (−19% in males and −31% in females). Rates in Japan, moreover, were six to eight times higher than in the USA, and were intermediate in Europe. Colorectal cancer rates in the elderly, after earlier rises, declined over the last decade in both sexes in the EU (−11% for males and −20% for females), and the USA (−16% for males and −18% for females), but rose in Eastern Europe (+16% in males and +4% in females), and in Japan, mostly in males (+23% for males and +4% for females). In 1995– 98, intestinal cancer rates for Japanese males (135/100000) were higher than in the USA (124/100000), while the rate in the EU was 152/100000, and that in Eastern Europe was 175/100000. After substantial rises between 1960 and 1985, lung cancer rates at age 65–84 for the first time declined over the last decade by 8.5% in males in the EU, and by 0.9% while they rose from 80 to 90/100000 in Eastern Europe, and from 19 to 24/100000 in Japan.

Cancer mortality in the elderly, 1960-98

53

Figure 3.1 Trends in age-standardized (at age 65–84, World Standard) death certification rates per 100000 population from selected cancers or groups of cancers in the EU, selected Eastern European countries (E Europe), the USA, and Japan: 1960– 97.

Comprehensive Geriatric Oncology

54

in the USA. Rates were still upwards in Eastern European (+6%) and Japanese (+12%) males and in females in all areas (+16% in the EU, +24% in Eastern Europe, +36% in the USA, but only +1.2% in Japan). While in elderly men the differences in lung cancer rates across broad geographic areas were relatively limited, in women an approximately threefold difference was still evident between the rates of 67–77/100000 in Japan and Europe, and the rates of 212/100000 in the USA. Again after earlier rises in most areas, breast cancer mortality in women aged 65–84 declined by 8% in the USA and by 3% in the EU, to reach 106/100000 in both areas, Prostate cancer mortality in males aged 65–84 declined by 4% in the EU and 6% in the USA, to reach the same value of 149/100000 for both areas. In Eastern Europe, prostate cancer mortality rose from 113 to 127/100000

Cancer mortality in the elderly, 1960-98

55

(+13%). In Japan, prostate cancer mortality over the last decade rose by 33%, from 36 to 48/100000. Mortality from myeloma at age 65–84 steadily rose by 10–20% in both sexes in all geographic areas considered over the last decade, continuing a long-term and substantial upward trend, which had already been evident since the early 1960s. Tables 3.1 (for males) and 3.2 (for females) give mortality rates from total cancer mortality and selected cancer sites in different European countries, besides the EU, the USA, and Japan. Declines (though to a different degree) were observed in France, Germany, Italy, and the UK for total cancer mortality in both sexes, whereas rates were upwards in most of Eastern Europe, and showed no consistent pattern in Southern Europe. Lung cancer trends were appreciably different across countries in elderly males,

Comprehensive Geriatric Oncology

56

with a 25% fall in the UK, but not in other major European countries, and were generally upwards (though to a different degree) for elderly females. A substantial decline in breast cancer mortality (−14%) was observed in the UK, where rates were originally higher, but not in other major European countries. Prostate cancer rates were downwards in France and Italy, but upwards in most other countries. Mortality from myeloma was consistently upwards in most European countries, except the UK, Finland, the Netherlands, and Norway. The Russian Federation had the highest total cancer mortality (1532/100000) in elderly males, and some of the highest rates for most sites, except breast and prostate. Over the last decade, cancer mortality rates increased in elderly Russians by 7.4% in males and 5.5% in females.

Discussion The main finding of this updated analysis of cancer mortality in the elderly is the observation of a change of trends for males in the USA and for both sexes in the EU, with the consequent end of a long-term rise and the beginning of a measurable fall in males. Some decline in total cancer mortality was observed also for females in Japan. This is an innovative observation, since declines in total cancer mortality have been registered in young20,21 and middle age, as well as in overall age-standardized rates,5–10 but rates in the elderly had been rising for longer, and have been described as a particular unfavorable indicator of cancer mortality.3,4,11 In all geographic areas considered, a component of the fall has been the steady decline in gastric cancer.22 However, in the EU, and mostly the USA, gastric cancer rates were already low in the 1980s, and consequently this was a relatively minor component of the global trends.

Cancer mortality in the elderly, 1960-98

57

Of major relevance are the changing trends in lung and other tobacco-related neoplasms—in both sexes and various geographic areas. Thus, lung cancer mortality rates in elderly males have started leveling off in the EU (and substantially in the UK23) and in the USA.3 This reflects the decreased smoking prevalence in subsequent generations of elderly males,24,25 and the increased rates of stopping smoking, mostly for males in the USA and Northern Europe. Lung cancer rates, in contrast, have increased by 36% in US females, reaching a rate of over 210/100000, i.e. twice that of breast cancer. The rise was 16% in the EU, with a rate of 77/100000. These unfavorable trends reflect the increased prevalence of smoking in elderly women in the USA6 and, to a lesser degree, Europe. Within Europe, female rates in Denmark, Iceland, and the UK approached 200/100000, too.26 An 8% fall in breast cancer mortality for elderly women was registered in the USA, and a 3% fall in the EU. These favorable trends reflect advancements in screening, early diagnosis, and treatment of breast cancer,27–30 although the falls are smaller than the 15– 20% reported for younger women (aged 50–70),31 thus raising the question of modifying diagnostic and treatment approaches to breast cancer in elderly women. A similar line of reasoning applies to prostate cancer in the EU and USA.32,33 In any case, the first observation of favorable changes in trends in mortality from these common cancers in the elderly is extremely encouraging. Mortality from breast and prostate cancer in the elderly was still rising in Japan, but absolute rates remained comparatively low.34

Table 3.1 Trends in age-standardized (65–84 years, World Standard) death certification rates per 100000 men from five major cancers plus total mortality in various countries between 1985–89 and 1995–98 (unless otherwise mentioned in parentheses) Stomach Country

Intestines % 1985– change 89

lung

1995– 98

% 1985– change 89

Prostate 1995– 98

% 1985– change 89

Myeloma

1995– 98

% 1985– change 89

Total all sites

1985– 89

1995– 98

1995– 98

% 1985– change 89

1995– 98

% change

Austria

162.1

103.9

−35.9

195.5

178.6

−8.6

353.8

321.2

−9.2

165.9

157.3

−5.2

13.2

17.0

28.8

Bulgaria

163.0

117.9

−27.7

119.0

140.5

18.1

219.4

211.8

−3.5

81.0

91.6

13.1

2.8

2.1

−25.0

1373.0

1263.8

−8.0

870.7

884.4

Czech Republic

170.7

111.6

−34.6

305.5

292.8

−4.2

520.9

468.1

−10.1

162.9

166.9

2.5

15.2

18.9

1.6

24.3

1749.2

1674.8

−4.3

Denmark (95–96)

70.1

49.5

−29.4

202.4

198.9

−1.7

464.8

440.4

−5.2

182.7

209.1

14.4

21.7

26.3

21.2

1500.9

1516.5

1.0

Finland (95–96)

124.2

78.9

−36.5

113.0

101.1

−10.5

457.3

385.9

−15.6

162.7

181.1

11.3

25.6

20.5

−19.9

1330.0

1234.0

−7.2

France (95–97)

81.9

56.2

−31.4

187.5

143.6

−23.4

323.6

326.6

0.9

170.1

142.3

−16.3

17.2

17.7

2.9

1479.2

1370.2

−7.4

Germany

137.7

95.2

−30.9

187.9

175.9

−6.4

387.4

368.0

−5.0

158.5

155.9

−1.6

16.4

19.6

19.5

Greece (95–97)

78.4

66.5

−15.2

72.4

71.5

−1.2

381.6

392.3

2.8

81.8

96.5

18.0

10.4

12.1

16.3

1420.1

1345.3

−5.3

1128.7

1160.0

2.8

Hungary

204.4

156.6

−23.4

229.6

293.3

27.7

460.6

543.3

16.0

164.5

177.5

7.9

11.2

15.6

39.3

1636.8

1835.1

12.1

Ireland (95–96)

117.2

84.5

−27.9

209.4

188.9

−9.8

424.7

389.3

−8.3

176.0

197.3

12.1

27.1

27.0

−0.4

1434.2

1427.4

−0.5

Comprehensive Geriatric Oncology

58

Italy (95– 96)

163.0

113.0

−30.7

160.6

137.3

−14.5

439.2

441.0

0.4

121.2

107.2

−11.6

16.2

18.1

11.7

1498.5

1437.9

−4.0

Nether lands (95– 97)

119.9

81.8

−31.8

175.1

161.5

−7.8

678.1

548.4

−19.1

168.8

177.4

5.1

25.2

25.4

0.8

1679.9

1535.9

−8.6

Norway (95–96)

104.0

76.8

−26.2

169.1

168.6

−0.3

251.2

278.6

10.9

218.7

229.9

5.1

31.7

28.8

−9.1

1230.2

1251.6

1.7

Poland (95–96)

205.2

151.9

−26.0

115.2

143.4

24.5

435.5

508.9

16.9

102.3

120.8

18.1

1380.5

1511.6

9.5

Portugal

197.1

159.8

−18.9

143.7

156.3

8.8

178.2

217.3

21.9

137.5

172.7

25.6

1035.4

1171.9

13.2

Romania

143.5

123.7

−13.8

72.6

96.0

32.2

175.9

226.5

28.8

76.8

91.2

18.8

792.8

917.7

15.8

Russian Federation (95–97)

309.2

247.9

−19.8

135.5

153.1

13.2

445.3

457.3

2.7

66.1

78.0

18.0

1426.5

1531.6

7.4

Spain (95–97)

123.8

95.3

−23.0

119.7

139.1

16.2

328.6

365.6

11.2

131.5

131.5

0.0

13.4

17.2

28.4

1258.1

1306.7

3.9

Sweden (95–96)

84.7

55.8

−34.1

131.4

123.4

−6.1

199.2

191.8

−3.7

199.4

221.1

10.9

22.1

23.2

5.0

1082.3

1051.6

−2.8

Switzer land (90– 94)

88.3

73.6

−16.6

167.4

154.8

−7.5

384.3

358.2

−6.8

217.4

220.7

1.5

21.7

24.8

14.3

1434.8

1365.2

−4.9

United Kingdom (95–97)

122.2

80.5

−34.1

178.6

151.7

−15.1

550.8

414.5

−24.7

160.6

161.5

0.6

21.8

21.1

−3.2

1536.5

1375.3

−10.5

European Union (95–97)

126.9

90.1

−29.0

170.5

151.7

−11.0

423.8

387.6

−8.5

155.1

149.5

−3.6

17.8

19.6

10.1

1457.2

1377.5

−5.5

USA (95– 97)

40.6

32.7

−19.5

147.8

123.9

−16.2

440.6

436.7

−0.9

158.4

148.9

−6.0

21.8

23.9

9.6

1265.6

1236.7

−2.3

304.5

245.9

−19.2

109.6

135.1

23.3

273.4

305.2

11.6

36.3

48.1

32.5

10.2

12.5

22.5

1218.0

1294.7

6.3

Japan (95–97)

9.7

15.8

62.9

Table 3.2 Trends in age-standardized (65–84 years, World Standard) death certification rates per 100000 women from five major cancers plus total mortality in various countries between 1985–89 and 1995–98 (unless otherwise mentioned in parentheses) Stomach Country

Intestines

1995– 1995– 89 98

% 1985– change 89

lung

1995– % 1985– 98 change 89

Breast 1995– 98

% 1985– change 89

Myeloma 1995– 98

% 1985– change 89

Total all sites

1995– 98

% 1985– change 89

1995– 98

% change

Austria

91.4

61.2

−33.0

119.1

98.3

−17.5

60.6

70.5

16.3

117.0

106.5

−9.0

11.1

14.7

32.4

762.7

687.0

−9.9

Bulgaria

91.3

62.9

−31.1

76.3

84.1

10.2

42.6

41.9

−1.6

66.9

71.3

6.6

1.5

1.7

13.3

497.1

492.9

−0.8

Czech Republic

81.4

52.8

−35.1

167.8

140.9

−16.0

54.9

78.4

42.8

115.3

116.6

1.1

11.7

12.9

10.3

871.9

851.5

−2.3

Denmark (95–96)

32.4

21.4

−34.0

140.9

131.0

−7.0

137.3

197.9

44.1

139.5

151.5

8.6

14.7

16.5

12.2

906.3

980.4

8.2

Finland (95–96)

63.3

40.4

−36.2

78.0

67.6

−13.3

50.2

54.5

8.6

84.8

79.1

−6.7

17.4

19.3

10.9

654.1

611.6

−6.5

France (95– 97)

32.0

20.1

−37.2

101.1

74.6

−26.2

32.4

41.0

26.5

99.0

98.9

−0.1

12.2

12.3

0.8

602.7

567.2

−5.9

Cancer mortality in the elderly, 1960-98

59

Germany

66.0

45.9

−30.5

135.9

113.3

−16.6

50.3

66.8

32.8

109.5

110.3

0.7

11.0

13.8

25.5

767.4

722.5

−5.9

Greece (95–97)

43.0

34.4

−20.0

59.7

48.7

−18.4

48.5

51.1

5.4

69.3

83.5

20.5

7.9

8.8

11.4

521.7

535.4

2.6

Hungary

86.0

65.8

−23.5

151.3

154.9

2.4

80.3

113.7

41.6

111.7

122.5

9.7

9.3

11.9

28.0

855.3

900.7

5.3

Ireland (95–96)

52.5

37.9

−27.8

128.4

103.1

−19.7

144.0

160.4

11.4

122.8

129.7

5.6

18.4

16.8

−8.7

839.3

853.5

1.7

Italy (95– 96)

74.3

54.9

−26.1

102.4

75.5

−26.3

52.7

60.8

15.4

100.2

100.0

−0.2

11.7

13.0

11.1

682.3

646.2

−5.3

Netherlands (95–97)

44.0

30.3

−31.1

119.3

103.3

−13.7

50.7

89.3

76.1

136.1

133.4

−2.0

16.2

17.0

4.9

724.1

729.9

0.8

Norway (95–96)

43.9

32.8

−25.3

110.9

113.5

2.3

57.5

95.6

66.3

99.7

98.8

−0.9

19.0

18.4

−3.2

667.8

709.7

6.3

Poland (95–96)

74.3

56.9

−23.4

79.6

92.3

16.0

57.2

71.8

25.5

70.3

77.8

10.7

674.7

706.2

4.7

Portugal

95.2

71.4

−25.0

91.5

79.8

−12.8

26.6

28.5

7.1

71.9

81.9

13.9

531.6

544.9

2.5

Romania

7.3

11.9

63.0

60.7

51.4

−15.3

53.6

61.8

15.3

35.7

45.2

26.6

59.9

70.9

18.4

460.3

497.9

8.2

Russian Federation (95–97)

141.8

108.4

−23.6

87.2

94.9

8.8

52.3

49.3

−5.7

50.0

67.7

35.4

605.7

639.3

5.5

Spain (95– 97)

58.8

40.0

−32.0

78.3

74.9

−4.3

25.5

25.7

0.8

71.7

77.3

7.8

9.8

12.8

30.6

540.9

522.0

−3.5

Sweden (95–96)

37.6

26.4

−29.8

89.0

83.5

−6.2

60.0

82.9

38.2

93.1

89.0

−4.4

15.7

17.2

9.6

673.5

685.9

1.8

Switzerland (90–94)

37.3

30.1

−19.3

94.2

85.0

−9.8

45.8

53.9

17.7

138.0

131.1

−5.0

15.4

15.7

1.9

695.0

669.4

−3.7

United Kingdom (95–97)

48.7

31.7

−34.9

117.1

91.7

−21.7

158.1

180.7

14.3

144.0

123.4

−14.3

14.9

14.5

−2.7

850.9

835.7

−1.8

European Union (95– 97)

57.0

39.2

−31.2

112.0

89.9

−19.7

66.5

77.4

16.4

109.6

106.0

−3.3

12.3

13.9

13.0

712.2

680.0

−4.5

USA (95– 97)

17.7

14.7

−16.9

98.6

80.7

−18.2

155.1

211.6

36.4

115.7

106.2

−8.2

14.9

16.5

10.7

731.8

764.1

4.4

Japan (95– 97)

118.3

81.3

−31.3

67.9

70.4

3.7

66.3

67.1

1.2

19.0

24.4

28.4

7.2

8.5

18.1

557.2

525.9

−5.6

It is more difficult to explain the leveling trends and the declines in colorectal cancer mortality, particularly for elderly women. These too may be due, at least in part, to earlier diagnosis, but a more favorable pattern of risk factor exposure (including diet and perhaps hormones for women)35,36 has probably also played some role. Mortality from myeloma, in contrast, has been steadily rising in most countries considered, with the sole exception of some Northern European countries. Diagnostic improvements and changes in classification still partly or largely account for these trends, but it is also possible that some real increases have occurred in the incidence and mortality for myelomas,37 as well as for lymphomas,38 which have also increased in most areas—in the absence, however, of obvious explanations, and of consistent patterns. Liver and brain cancers are other sites for which the incidence has been rising in the elderly, but the WHO database was inadequate to understand and evaluate their trends in various countries.13,39–41

Comprehensive Geriatric Oncology

60

In greater generality, it is important to stress the limitations and uncertainties of cancer death certification for the elderly and their trends over time. Although the exact influence of changed certification accuracy on trends in cancer rates is undefined, almost certainly this has implied some systematic upward trends over time, following generalized improvements in diagnosis and certification of selected cancers, including particularly prostate cancer and myeloma.2,13,39 Within Europe, a substantial variation in mortality from several major cancer sites was still observed in the elderly, although for other neoplasms (such as breast or prostate) tendencies towards leveling of trends were also apparent.42 Most trends remain unfavorable for elderly populations of both sexes in Eastern Europe, reflecting both rising trends in underlying incidence—due to unfavorable patterns in smoking, the characteristics of diet and other risk factor exposure, and to systematic delays in the adoption of improved diagnosis and treatment approaches.43 Thus, while stomach cancer rates remain high in these areas of the continent, lung cancer rates in males have reached some of the highest rates observed (over 500/100000 in Hungary and Poland), and trends for breast or prostate cancer rates were still upwards. Comprehensive intervention for cancer control among the elderly in all areas of the world, but particularly in Eastern Europe, is therefore a public health priority.44–47 Acknowledgements This study was made possible by a core grant from the Swiss League Against Cancer. Support was also received from the Italian Association for Cancer Research. References 1. La Vecchia C, Levi F, Lucchini F, Negri E. International perspectives of cancer and aging. In: Comprehensive Geriatric Oncology, 1st edn (Balducci L, Lyman GH, Erschler WB, eds). Amsterdam: Harwood Academic Publishers, 1998:19–93. 2. Levi F, La Vecchia C, Lucchini F, Negri E. Worldwide trends in cancer mortality in the elderly, 1955–1992. Eur J Cancer 1996; 32A: 652–72. 3. Hoel DG, Davis DL, Miller AB et al. Trends in cancer mortality in 15 industrialized countries, 1969–1986. J Natl Cancer Inst 1992; 84: 313–20. 4. Davis DL, Hoel D, Fox J, Lopez A. International trends in cancer mortality in France, West Germany, Italy, Japan, England and Wales, and the USA. Lancet 1990; 336:474–81. 5. Cole P, Rodu B. Declining cancer mortality in the United States. Cancer 1996; 78:2045–8. 6. Wingo PA, Ries LAG, Giovino GA et al. Annual report to the Nation on the status of cancer, 1973–1996, with a special section on lung cancer and tobacco smoking. J Natl Cancer Inst 1999; 91:675–90. 7. Ries LAG, Wingo PA, Miller DS et al. The annual report to the Nation on the status of cancer, 1973–1997, with a special section on colorectal cancer. Cancer 2000; 88:2398–424. 8. Levi F, La Vecchia C, Negri E, Lucchini F. Declining cancer mortality in European Union. Lancet 1997; 349:508–9. 9. Levi F, Lucchini F, Negri E, Boyle P. Cancer mortality in Europe and an overview of trends from 1955 to 1994. Eur J Cancer 1999; 35: 1477–516.

Cancer mortality in the elderly, 1960-98

61

10. Levi F, Lucchini F, La Vecchia C, Negri E. Trends in mortality from cancer in the European Union, 1955–94. Lancet 1999; 354:742–3. 11. Davis DL, Dinse GE, Hoel DG. Decreasing cardiovascular disease and increasing cancer among whites in the United States from 1973 through 1987. Good news and bad news. JAMA 1994; 271:431–7. 12. La Vecchia C, Negri E, Levi F et al. Cancer mortality in Europe: effects of age, cohort of birth and period of death. Eur J Cancer 1998; 34:118–41. 13. Doll R, Peto R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst 1981; 66:1191–308. 14. Monfardini S, Aapro M, Ferrucci L et al. Commission of the European Communities ‘Europe Against Cancer’ Programme European School of Oncology Advisory Report. Cancer Treatment in the Elderly. Eur J Cancer 1993; 29A: 2325–30. 15. Balducci L. Geriatric oncology: challenges for the new century. Eur J Cancer 2000; 36:1741– 54. 16. World Health Organization. International Classification of Diseases: 8th Revision. Geneva: WHO, 1967. 17. World Health Organization. International Classification of Diseases: 9th Revision. Geneva: WHO, 1977. 18. World Health Organization. International Statistical Classification of Diseases and Related Health Problems: 10th Revision. Geneva: WHO, 1992. 19. Doll R, Smith PG. Comparison between registries: age-standardized rates. In: Cancer Incidence in Five Continents, Vol IV (Waterhouse JAH, Muir CS, Shanmugaratnam K et al, eds). Lyon: IARC Press, 1982:671–5. 20. Doll R. Are we winning the fight against cancer? An epidemiological assessment. Eur J Cancer 1990; 26:500–8. 21. Franceschi S, Levi F, Lucchini F et al. Trends in cancer mortality in young adults in Europe, 1955–1989. Eur J Cancer 1994; 30:2096–118. 22. La Vecchia C, Franceschi S. Nutrition and gastric cancer with a focus on Europe. Eur J Cancer Prev 2000; 9:291–5. 23. Peto R, Darby S, Deo H et al. Smoking, smoking cessation, and lung cancer in the UK since 1950: combination of national statistics with two case-control studies. BMJ 2000; 321:323–9. 24. Franceschi S, Naett C. Trends in smoking in Europe. Eur J Cancer Prev 1995; 4:271–84. 25. World Health Organization. Tobacco or Health: A Global Status Report. Geneva: WHO, 1997. 26. Levi F, La Vecchia C, Lucchini F, Negri E. Lung cancer in Icelandic women. Eur J Cancer Prev 1999; 8:369. 27. Cuzick J. Screening for cancer: future potential. Eur J Cancer 1999; 35:685–92. 28. Early Breast Cancer Trialists’ Collaborative Group. Polychemiotherapy for early breast cancer: an overview of the randomized trial. Lancet 1998; 352:930–42. 29. Early Breast Cancer Trialists’ Coilaborative Group. Tamoxifen for early breast cancer: an overview of the randomized trial. Lancet 1998; 351:1451–87. 30. Fisher B, Costantino JP, Wickerman DL et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast Project P-2 Study. J Natl Cancer Inst 1998; 90:1371– 88. 31. Peto R, Boreham J, Clarke M et al. UK and USA breast cancer deaths down 25% in year 2000 at ages 20–69 years. Lancet 2000; 355:1822. 32. Levi F, Lucchini F, Negri E, La Vecchia C. Recent trends in prostate cancer mortality in the European Union. Epidemiology 2000; 11:612. 33. Tarone RE, Chu KC, Brawley OW. Implications of stage-specific survival rates in assessing recent declines in prostate cancer mortality rates. Epidemiology 2000; 11:167–70. 34. Boyle P, Levi F, Lucchini F, La Vecchia C. Trends in diet-related cancers in Japan. A conundrum? Lancet 1993; 342:752 35. Boyle P, Langman JS. Epidemiology. BMJ 2000; 321:805–8.

Comprehensive Geriatric Oncology

62

36. Franceschi S, La Vecchia C. Colorectal cancer and hormone replacement therapy: an unexpected finding. Eur J Cancer Prev 1998; 7: 427–38. 37. Cuzick J. Multiple myeloma. Cancer Surv 1994; 19/20:455–74. 38. Levi F, La Vecchia C, Lucchini F et al. Mortality from Hodgkin’s disease and other lymphomas in Europe, 1960–1990. Oncology 1995; 52:93–6. 39. Boyle P, Maisonneuve P, Saracci R, Muir CS. Is the increased incidence of primary malignant brain tumours in the elderly real? J Natl Cancer Inst 1990; 82:1594–6. 40. Modan B, Wagener DK, Feldman JJ et al. Increased mortality from brain tumours: a combined outcome of diagnostic technology and change in attitude toward the elderly. Am J Epidemiol 1992; 135:1349–57. 41. La Vecchia C, Lucchini F, Franceschi S et al. Trends in mortality from primary liver cancer in Europe. Eur J Cancer 2000; 36:909–15. 42. Levi F, Lucchini F, Boyle P et al. Cancer incidence and mortality in Europe, 1988–92. J Epidemiol Biostatist 1998; 3:295–373. 43. Levi F. Cancer prevention: epidemiology and perspectives. Eur J Cancer 1999; 35:1046–58. 44. Boyle P. Epidemiology in central and eastern Europe. Epidemiology 1992; 3:391–4. 45. Boyle P. Tobacco and cancer, the European perspective. Ann Oncol 1995; 6:435–7. 46. La Vecchia C, Levi F, Franceschi S. Epidemiology of cancer with a focus on Europe. J Epidemiol Biostatist 2000; 5:31–47. 47. Levi F, Lucchini F, Negri E et al. Changed trends of cancer mortality in the elderly. Ann Oncol 2001; 12:1467–77.

4 Cancer in older persons: Magnitude of the problem and efforts to advance the aging/cancer research interface Rosemary Yancik, Lynn AG Ries Introduction Persons 65 years and older bear the brunt of the cancer burden. Incidence data from the US National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) program for 1995–99 clearly indicate that aging is a high risk factor for cancer.1 The incidence rate for those aged 65 or more is 2208.1 per 100000 persons, as compared with 229.2 per 100000 for those younger than 65—a dramatic 10-fold difference in overall cancer incidence rates (i.e. the number of newly diagnosed cases occurring per 100000 persons during a given time). This chapter updates recent cancer statistics information and cites steps being taken to advance the aging/cancer research interface. Incidence of selected tumors Approximately 60% of all cancers occur in the elderly subgroup of the population. The impact of aging is made even more clear and apparent when specific tumors are considered. Table 4.1 lists the American Cancer Society’s (ACS) estimate of the number of new cancer cases for 2002 and the SEER estimates for individuals 65 and older to illustrate the scope of the problem of cancer in the elderly by individual tumors. Proportions for the elderly are derived from calculations using the SEER incidence by age.2 For the major sites of malignancies common to both men and women—lung, colon, rectum, stomach, pancreas, and urinary bladder—two-thirds to three-quarters occur in the elderly. The percentages of lung and bronchial cancers that occur in individuals aged 65 and older are 68% and 69% for men and women, respectively. These percentages have increased within the last several years as the US population has aged and the smoking exposure-time effects on birth cohorts has become more apparent, reflecting the high rates of smoking behavior of persons now in their late 60s and early 70s. As to the gender-specific malignancies, prostate cancer, with 69% occurring in this age group, is a predominant

Comprehensive Geriatric Oncology

64

Table 4.1 2002 estimates of cancer cases: men and women, all ages, and proportion 65 years of age and older Men Cancer site

Women

All ages

65+

All ages

65+

Lung

90200

61 336 (68%)

79200

54 648 (69%)

Colon

50000

35 000 (70%)

57300

43 548 (76%)

Rectum

22600

13 560 (60%)

18400

11 960 (65%)

Urinary bladder

41 500

29465 (71%)

15000

11 100 (74%)

Stomach

13300

8 778 (66%)

8300

5 976 (72%)

Pancreas

14700

9 555 (65%)

15600

12012 (77%)

Breast (female)

—

—

203 500

91 575 (45%)

Ovary

—

—

23300

10252 (44%)

189000

130 410 (69%)

—

—

Prostate

Data from Cancer Facts and Figures—2002. Atlanta: American Cancer Society, 2002. Number of persons 65 years and older diagnosed with cancer are estimated from National Cancer Institute SEER Program Data, 1995–99 and applied to American Cancer Society estimates.

Figure 4.1 Cancer incidence rates: (a) men; (b) women. health problem. Both breast cancer and ovarian cancer are special problems for older women. These two malignancies generally have been considered early postmenopausal rather than late postmenopausal tumors. In most discussions and research reports on prevention and treatment, a perimenopausal age-break of 50 years is generally used, with no reference to the actuality that 45% of breast cancers and 44% of ovarian cancers occur in women aged 65 and older.

Magnitude of the problem and efforts to advance the aging/cancer research interface

65

Incidence curves emphasize the escalation of increased cancer rates with advancing age and show contrasts by 5-year age groups beginning at 35 years of age. It is important to illustrate the increase in cancer incidence rates with advancing age. Incidence differentials are delineated by age for the selected tumors for men and women in Figure 4.1.1 The curves, based on incidence rates per 100000 persons (shown on the vertical axis), portray the gradients for selected tumors as they rise with advancing age (shown on the horizontal axis). Rates are per 100000 and age-adjusted to the year 2000 US population. The highest incidences and greatest numbers of cancer for men (Figure 4.1a) are associated with three tumor types: prostate cancer, lung cancer, and colon cancer. The scale shown for men reaches to a high of 1200 per 100000 to accommodate the high incidence rates for prostate cancer in the age-specific groups for men after the age of 65. Two other malignancies also have extremely high incidence rates in men: colon cancer rates range from 159.1 per 100000 for the 65–69 age group to 408.4 for those aged 85 and older. Lung cancer rates escalate to peak rates between 503.1 and 554.6 in the 70–84 age group. Unfortunately, as the population-based tumor registry data reveal, old age is the ‘normal time’ at which cancer develops. The numbers shown in Table 4.1 suggest the urgent need to address the problems unique to persons aged 65 and older. Compared with the rest of the population, these individuals suffer disproportionately from the morbidity, adversity, and hardship brought on by these malignancies. This age group, however, has been under-represented historically in clinical studies that generate knowledge about cancer treatment.3,4 Urinary bladder cancer rates crest at 300.4 for men aged 85 and older. Incidence rates for tumors of the rectum, stomach, and pancreas do not reach the elevated levels of the preceding three cancers, but all rates increase with advancing age to more than 100.0 per 100000 population. Eight malignancies that are most common in women are shown in Figure 4.1(b). The vertical axis scale extends to 500 per 100000 persons. Breast cancer has the highest incidence rates of all tumors affecting women. All age groups older than 65 have rates exceeding 400.0 per 100 000 persons. Two specific age groups, 75–79 (500.9) and 80–84 (487.7), show the highest rates per 100000 population. It should be noted here (and as discussed in detail in the literature) that less emphasis has been placed on knowledge of the need for regular mammograms in older age groups, even though cancer incidence is extremely high for older women. There has been a continuing debate in recent years regarding the effectiveness of breast cancer screening for women aged 40–49 years.5 Incidence rates of 118.2 and 200.5 per 100000 for women aged 40–44 and 45–49, respectively, are one-third to less than one-half the rates shown for women aged 65 and older. Even though rates are highest in the older age groups, especially those 70 and older, there has been no special emphasis on early detection for elderly women. Lung cancer incidence rates peak in the 70–84 age groups, with rates between 293.3 and 302.9 per 100000 persons. Colon cancer rates are highest for all women aged 65 and older, and are highest for women 80 and older, with rates of 380.5 and 408.4 per 100000 persons as indicated. Incidence rates for the next five tumors shown—pancreas, ovarian, rectum, urinary bladder, and stomach—have rates at similar levels. For these latter five

Comprehensive Geriatric Oncology

66

malignancies, all rates are under 100.0 per 100000 female population, with the highest rates being in women aged 65 and older. The unique SEER population-based data furnish the statistical framework to describe the magnitude of the cancer problem for older persons.1 The SEER program used for the analysis covers approximately 14% of the US population. Incidence, mortality, and stage of disease at initial diagnosis and age contrasts are made with SEER program data for selected cancer sites.1 Comprehensive descriptions of the SEER program and its procedures are available in several publications.1,5,6 Mortality data from the National Center for Health Statistics for 1999 and demographic data from the US Bureau of the Census complete the picture.7–11 Mortality Seventy-one percent of all deaths due to cancer in the USA occur in individuals in the 65 and older age group.1 Mortality rates have increased for the population aged 65 and older in numbers and proportion. Approximately a decade or so ago, the percentage of cancer deaths for persons in this age group was about 60%. The nine malignancies addressed in particular in this chapter represent approximately 63% of cancer mortality in the USA during 1999. In that year, 549829 cancer deaths occurred.2 This is a high proportion of the approximately 66 different categories of tumor registration on which SEER reports routinely.1,5,6 Figure 4.2 shows the numbers of cancer deaths and the percentages of those that occurred in individuals younger than 65 and those 65 and older for the nine tumors discussed in this chapter. First distinguishing the tumors common to men and women (colon/rectum, urinary bladder, stomach, and pancreas), the percentages of those aged 65 and older range from 68% (for pancreatic and stomach cancer deaths in men) to 88% (for urinary bladder deaths in women). For lung and bronchial cancer, 72% of cancer mortality is in older women; 70% is in older men. For the gender-specific malignancies, 93% of deaths due to prostate cancer occur in men aged 65 and older. The percentage proportion of deaths is 60% for breast cancer and 66% for ovarian cancers, for women aged 65 and older.

Magnitude of the problem and efforts to advance the aging/cancer research interface

67

Figure 4.2 Mortality rates for selected cancer sites (1999): (a) lung/bronchus, pancreas, stomach, colon/rectum, and urinary bladder; (b) breast, ovary, and prostate. Stage distribution by age As with most tumors, anatomic staging of the extent of tumor progression at initial diagnosis is extremely important. Staging governs prognosis and treatment. Early diagnosis of cancer is more likely to have positive consequences for the length and quality of survival and cure potential. The SEER data on the extent of disease at initial diagnosis—localized, regional, distant (metastatic), or stage unknown or not recorded— are stratified by age groups for selected tumors to illustrate the relationships between stage and age. The question for each age group is: What is the stage distribution? The progression of stage severity and stage-unknown categories for breast, ovarian, and

Comprehensive Geriatric Oncology

68

prostate cancer are shown in Figure 4.3(a–c). Stage distributions for colon and rectal cancers for both men and women are shown in Figure 4.3(d, e). Breast There is wide variation in breast cancer stage distribution for localized and regional disease. More than half of each age group is diagnosed with localized disease. An ascending pattern from younger to older age is noted for this disease stage. This is in contrast to a descending age profile difference in the regional-disease stage. The percentage of distant disease is similar across age groups. Women in the oldest age category, 75 and older, have a threefold higher percentage of stage-unknown disease. Ovary Differences in stage distribution are striking by age. The younger than 55 age group has the highest proportion of localized disease, whereas the older age groups have more

Figure 4.3 Stage distribution by age: (a) breast; (b) ovary; (c) prostate; (d) colon/rectum (men); (e) colon/rectum (women).

Magnitude of the problem and efforts to advance the aging/cancer research interface

69

distant disease. In addition, the oldest age group has the highest proportion of unstaged disease. The stage/age distribution for this cohort is consistent with reports on ovarian cancer in the elderly. Prostate Prostate cancer is diagnosed in the localized/regional stages for 90–92% for men in the age categories up to and including 74 for the patient cohort illustrated in Figure 4.3(c). Male patients aged 75 and older are diagnosed in this more favorable combination of stages to a much lesser extent (77%). In the distant-disease category, the high proportion shown (8%) for males aged 75 and older represents close to half of all individuals diagnosed with this tumor stage (n=6276). Similarly, in the stage-unknown category, the percentage for individuals aged 75 and older (15%) represents more than half of all individuals (n=9445) whose stage was unknown. Colon/rectum: men and women The distribution of colorectal cancer cases by disease stage, including those for which the stage was unknown, are shown for both genders. Once again, we see that the percentage in the stage-unknown category for the 75 and older age group is quite large. For both sexes, there is a consistency in the disease stage distribution across age groups. There is little variation in stage distribution by age for these malignancies. Age/stage relationship There does not appear to be an age/stage relationship in breast and colorectal cancers. In ovarian cancer, age does appear to be related to disease stage. In prostate cancer, of patients diagnosed initially with distant stage, the oldest patients comprise the greater proportion. Without classifying information on the patients in the stage-unknown category, it is difficult to make concrete statements. Because of the preponderance of percentages in the stage-unknown category for the older age group, one analytic interpretation derived from these data is that cancer in the older person’s disease stage cannot be labeled as ‘less often metastatic’ or ‘less aggressive’. Another interpretation is an inference that older cancer patients are receiving less than full workups (i.e. the greater proportion of older persons in the stage-unknown categories), resulting in less than complete staging procedures. Our aging nation The elderly population (i.e. persons aged 65 and older) in the USA is estimated at 35 million, constituting 12.4% of the total US population.11 The cancer control needs for this age group should receive prompt and systematic attention. Currently, there are 8.9 million individuals with a history of cancer or who have been newly diagnosed with a

Comprehensive Geriatric Oncology

70

malignancy according to the Annual Report to the Nation on Cancer.6 It is indicated that approximately 60% of these survivors are aged 65 or older. If the overall cancer rates remain the same, because of the aging of the population, the absolute number of cancers occurring in persons in the age group 65 and older is expected to double by 2030. Of cancer patients in 2030, 70% will be aged 65 or older. In preparation for the forthcoming dramatic expansion of this age group in the next 30 years, we should be anticipating the greater need for healthcare resources. Figure 4.4 describes the recent past and near future in a 10-decade comparison of population estimates and projections with data from the US Bureau of the Census.9–11 The total US population was estimated to have increased from 22.8 million in 1930 to 270.3 million in 1998. The proportion of the population aged 65 and older has almost doubled, from 1 in 15 of the population in the 1930s to 1 in 8 in the 1990s. Looking forward 30 years, 1 in 5 persons will be aged 65 or older in 2030.

Figure 4.4 US population growth: 10decade comparison, total population/age, 65 segments.

Magnitude of the problem and efforts to advance the aging/cancer research interface

71

Figure 4.5 Population by age and sex: (a) 1975; (b) 1990; (c) 2010; (d) 2030. From Taeuber CM. Sixty-Five Plus in America, revised edn. Washington, DC: US Government Printing Office, Current Population Reports, Special Studies, P23–178RV, 1993. Not only is the US population aging, the age structure is changing over time. More older people are living longer. There are and will continue to be more older-old persons (i.e. aged 75–84 and 85 and older) in the older-age segment of the population.11 Low fertility, elimination of certain infectious diseases, and longer life-expectancies are contributing to the US demographic imperative.12 Age pyramids, depicting age structure, are often featured in US Bureau of the Census publications. They portray the changes that have occurred and will occur. Figure 4.5 describes age-specific changes for selected years.8 The first age pyramid (Figure 4.5a) depicts the post-World War 2 ‘baby boom’ as it was in 1975, when the cohort was between 10 and 30 years of age. Changes over time for selected decades show the shifting age structure in the USA. The configurations seen in Figure 4.5(b–d) reflect the changes that will occur as the US population advances toward 2030. The age structure pyramid will become rectangular in shape. Figure 4.5(b) represents this cohort (the cohort now aged between 25 and 45) as it was in 1990. The first wave of the ‘baby boomers’ will become 65 in 2010, as indicated in Figure 4.5(c). By 2030, the entire cohort will be 65 or older (Figure 4.5d).

Comprehensive Geriatric Oncology

72

As the postwar baby-boom cohorts reach age 65, not only will the numbers of older persons rapidly increase, there will also be significant age shifts in the population, resulting in even more persons in the oldest-age category (i.e. 85 and older), as shown in Figure 4.5(d). The old will get older between now and the peak year of population growth (2030).

Table 4.2 Life-expectancy in 1900, 1950, and 1997: average number of years of life remaining at birth, at 65, and at 85, by sex Year/sex

At birth

At age 65

At age 85

Men

73.6

15.9

5.5

Women

79.4

19.2

6.5

Men

65.5

12.7

4.4

Women

71.0

15.0

4.9

Men

47.9

11.5

3.8

Women

50.7

12.2

4.1

1997:

1950:

1900:

Source: Federal Interagency Forum on Aging-Related Statistics. Older Amerkans 2000: Key Indicators of Well-Being. Washington, DC: US Government Printing Office, 2000.

Life-expectancy There have been vast improvements in life-expectancy at birth (i.e. the average number of years a person will live given the age-specific mortality rates of a particular year), which has increased from 47.9 and 50.7 years for men and women, respectively, in 1900 to 73.6 and 79.4 for men and women, respectively, in 1997. Table 4.2 shows average lifeexpectancy at birth, at 65, and at 85 for three selected years at approximate 50-year intervals in the 20th century. As indicated, there have been remarkable increases in lifeexpectancy even since 1950.10 We have been referring to the aged (or the elderly) using the traditional cut-off of 65 years. As we have emphasized elsewhere, definitions of old age for clinical purposes should be flexible and dependent on criteria other than calendar age.13,14 Persons aged 65 and older include the young old (i.e. 65–74), the older old (i.e. 75–84), and the oldest old (i.e. 85 and older). This subdivision into age cohorts is meant to reflect the heterogeneity of age within the older population, but to sharpen the focus on the unique problems that may be present in older persons in need of information on cancer prevention or those who have been newly diagnosed with cancer, we first must acknowledge the greater variability in health and age-related declines in functioning—the categorization does not

Magnitude of the problem and efforts to advance the aging/cancer research interface

73

do this. The pace of aging varies from individual to individual. It has been suggested that no two individuals accumulate identical environmental or other types of insults alike. It is preferable to ask which patients would benefit from which treatments. The use of chronologic age as a guide for cancer prevention and therapy is not a good strategy for the elderly.14 Further, with respect to cancer detection, there may be a non-specific presentation of a malignancy (sometimes unique to the aged) that requires clinicians to be alert to masked symptomatology or to look for subtle signs of additional adverse conditions in the presence of the presenting complaint.14–18 For many older cancer patients, there may be competing concurrent chronic conditions (i.e. comorbidity) and decreased physical and physiologic functioning.15 When cancer is linked with the other chronic conditions acquired over a lifetime, there is a high probability that the residual consequences of previous illnesses and the effects of the normal and pathologic processes of aging, including frailty, will be present. There are differences in drug metabolism and changing levels of absorption, distribution, metabolism, and excretion that predominate in older persons.16 Cancer treatment strategies are challenged also by the potential for secondary complications of disease and treatment and the development of unrelated conditions during the course of cancer therapy. Other relevant concerns are comprehension deficits, diminished social support, and limited financial resources.17 These are several examples of the multiplicity of agerelated conditions that may exist concurrently with cancer management for the elderly. Implications for research and practice Cancer is not inevitable for all older persons, but persons in the older age groups appear to be more vulnerable to malignancies. Cancer in the elderly is a major healthcare concern that is beginning to generate interest and attention. The stark and concise summary statistics on cancer and aging indicate that the older segment of the US population is an important target group for cancer research and control activities. Studies using the SEER information database, with documentation presented by descriptive analyses such as those presented in this chapter, are capable of stratifying large amounts of patient data to raise issues for targeting clinical trials, cancer control, and biologic and epidemiologic investigations. They tell us where we should concentrate our efforts. Advancing the aging/cancer research interface The scientific approach to cancer treatment has begun to introduce the complexities of older persons who have been afflicted with cancer. Many changes within the several years since the publication of the first edition of this book are cited in other chapters in this second edition. Special efforts have been initiated in the private and federal sectors: (i) there has been a focus on screening and early detection for malignancies that could be prevented or diagnosed in the early stages (e.g. breast cancer in older women and colon cancer in older persons); (ii) attempts have been made to heighten and increase the awareness of oncologists, primary care physicians, and geriatricians about masked signs of

Comprehensive Geriatric Oncology

74

malignancies and/or altered presentation of signs and symptoms of cancer in the elderly; (iii) the presence of concomitant diseases, illnesses, and the normal processes of aging and how they affect the treatment of cancers in older persons is receiving greater attention;15 (iv) the differences and sensitivities of older cancer patients with regard to conventional forms of treatment are more widely acknowledged and under study; (iv) quality of life issues for care of the elderly are increasingly being linked with the psychological and social support that older persons need to cope with cancer and its treatment;19 (vi) the American Society of Clinical Oncology (ASCO) has devoted prime time to the topic of aging and cancer in annual educational symposia and has supported cancer/aging symposia and interdisciplinary clinical training initiatives that include geriatricians, medical oncologists, social scientists, and other healthcare professionals; (vii) stimulating conferences and workshops have been held, and their proceedings, several review articles, and more research published; (viii) the Annual Report to the Nation on Cancer in 2002 featured the implications of age and aging on the US Cancer Burden;6 (ix) the US National Institute on Aging (NIA) and NCI have been collaborating on research initiatives at the aging/cancer interface. Some specific examples from the NIA/NCI partnership are provided below. NIA/NCI research pmmotion activities The NIA formally established an extramural research focus on aging and cancer in September 1996. In consultation with an advisory group, an excellent plan was developed shortly after the official formation of the NIA Geriatrics Program Cancer Section.18 The following selected research areas for extramural initiatives were recommended: (i) agerelated factors in development of tumors in older persons; (ii) time and its importance in developing cancer in a person’s lifespan; (iii) aggressive tumor behavior in the aged patient; (iv) pharmacology of aging and cancer– antitumor drug alterations; (v) prognostic indicators for patient evaluation and workup; (vi) comorbidity, previous illnesses, and disabilities in older cancer patients; (vii) occurrence of multiple primary tumors in elderly patients; (viii) cancer survivorship—the need for long-term data on older survivors; (ix) access issues relevant to older patients, their families, and physicians; (x) generic age-related issues in selected tumors that predominate in older persons (e.g. breast, prostate, and colorectal tumors).18 Ten research solicitation requests for applications (RFA) and program announcements (PA) relevant to cancer in older persons have been initiated since the inception of the NIA extramural research program focusing on cancer in older persons:20 1. NIA RFA-AG-02–003: Aging, Race and Ethnicity in Prostate Cancer, August 2001 2. NCI/NIA RFA 99–015: Diagnostic Imaging and Guided Therapy in Prostate Cancer, August 1999 3. NCI/NIA RFA 98–018: Interdisciplinary Studies in Genetic Epidemiology of Cancer, August 1998 4. NIA/NCI/NINR PA 00–001: Aging Women and Breast Cancer, October 1999 5. NIA/NIDCR PA 99–030: Aging and Age as Risk Factors for Multiple Primary Tumors, December 1998 6. NIA/NCI Letter RFA: Limited Competition, Studies on Older Cancer Patients in the NCI Clinical Trials Cooperative Groups, October 1998

Magnitude of the problem and efforts to advance the aging/cancer research interface

75

7. NIA/NCI PA 98–069: Cancer Pharmacology and Treatment in Older Patients, May 1998 8. NCI RFA 97–018: Long-Term Cancer Survivors: Research Initiatives, September 1997 9. NIA/NCI/NIEHS PA 97–019: Aging, Race, and Ethnicity in Prostate Cancer, December 1996 10. NIA/NCI/NINR/NIMH PA 96–034: Aging Women and Breast Cancer, April 1996. The NIA collaborates with the NCI in most efforts on cancer in the elderly. NIA or NCI takes the leadership role in the partnerships, depending on the topic. Some efforts are large-scale projects and/or co-sponsored workshops on research areas chosen to address knowledge gaps on discrete topics identified by the NIA; others involve establishing working relationships with individual NCI staff to develop key questions for research in common interest areas. An example of the former is the NIA/NCI partnership established under a cooperative agreement with the NCI by a memorandum of understanding. The NIA is sponsoring peer-reviewed research designed by the NCI Cooperative Groups with a focus on older-aged cancer patients. An example of the latter is demonstrated with the program announcements issued on breast cancer, prostate cancer, and pharmacology of aging and cancer. Comorbidity assessment of older cancer patients Cancer is diagnosed in bodies already rife with comorbid conditions. Therefore, there are competing diseases for treatment. There may be poor physical functioning due to ageassociated disabilities. It is not known to what extent concurrent health problems complicate cancer management in the older person or if non-specific signs and symptoms are masked by multiple pathology or frailty in the older person. The term ‘comorbidity’ in the NIA/NCI Workshop on Comorbidity Assessment referred to the concomitant age-related health problems (i.e. multiple pathology) often present in older persons. This topic continues as a needy area for research, and was the topic of a multidisciplinary working group initiated by the NIA and co-sponsored with the NCI in July 1999. A synopsis of the deliberations and specific issues has been published.15 The guiding questions were: • How do already-compromised older patients tolerate the stress of cancer and its treatment? • How do age-related conditions influence cancer treatment course and recovery? • How are the serious comorbid conditions managed in the presence of cancer?

Comprehensive Geriatric Oncology

76

Exploring the role of cancer centers for integrating aging and cancer research A major research initiative is in development. The NIA and NCI held an interdisciplinary workshop to discuss the evolution of research efforts in NCI-designated cancer centers. The workshop, Exploring the Role of Cancer Centers to Integrate Aging and Cancer Research, was held on the NIH Campus, Bethesda, MD in June 2001. The meeting provided a forum for the views of prominent cancer center directors, scientists, administrators, health professionals, and patient advocates on how to promote innovative studies within the cancer centers directed at cancer in the elderly. The final report from this workshop is available at http://nia.nih.gov/health/nianci.19 The NIA/NCI cancer centers’ objectives were to: 1. Identify promising scientific areas that could be pursued in the cancer centers with their unique resources and expertise. 2. Consider various strategies and approaches for implementation of integrating aging and cancer research. 3. Invite the input of investigators in the cancer centers by convening a workshop with cancer center representatives on the NIH Campus.

Final comments Oncology practice includes older cancer patients. Cancer prevention and early detection apply to older persons. The strong epidemiologic and demographic data are more than sufficient to urge us to go beyond mere description of cancer in the older population. The insights gained from this information help expand and direct the focus on the age segment of the US population that experiences the magnitude of the cancer problem. Acknowledgements This is an update of a paper, originally published in Cancer 1994; 74:1995–2003, © 1994 American Cancer Society, that was reprinted with permission of JB Lippincott Company, Philadelphia, PA in the 1st edition of this book. Demographic and cancer data have been updated; the chapter revision includes efforts made in recent years to advance the aging/cancer research interface. References 1. Ries LAG, Eisner, MP, Kosary CL et al (eds). SEER Cancer Statistics Review: 1973–1999. Bethesda, MD: National Cancer Institute. http://seer.cancer.gov/csr/1973_1999/,2002. 2. Cancer Facts and Figures—2002. Atlanta: American Cancer Society. http://www.cancer.org/downloads/STT/CancerFacts&Figures2002TM.pdf.

Magnitude of the problem and efforts to advance the aging/cancer research interface

77

3. Trimble EL, Carter CL, Cain D et al. Representation of older patients in cancer treatment trials, Cancer 1994:74:2208–14. 4. Hutchins LF, Unger JM, Crowley JJ et al. Underrepresentation of patients 65 years of age or older in cancer treatment trials. N Engl J Med 1999:341:2061–7. 5. National Institutes of Health Consensus Development Panel. National Institutes of Health Consensus Development Conference statement: breast cancer screening for women ages 40–49, January 21–23, 1997. J Natl Cancer Inst 1997; 89:1015–26. 6. Edwards BK, Howe HL, Ries LAG et al. Annual Report to the Nation on the Status of Cancer, 1973–1999, Featuring Implications of Age and Aging on US Cancer Burden. Cancer 2002; 94:2766–92. 7. Vital Statistics ofthe United States 1950–1999. Vol 2: Mortality, Parts A and B. Hyattsville, MD: National Center for Health Statistics. 8. Taeuber CM. Sixty-Five Plus in America, revised edn. Washington, DC: US Government Printing Office, Current Population Reports, Special Studies, P23–178RV, 1993. 9. US Bureau of the Census. 65+ in the United States. Washington, DC: US Government Printing Office, Current Population Reports, Special Studies, P23–190, 1996. 10. Federal Interagency Forum on Aging-Related Statistics. Older Americans 2000: Key Indicators of Well-Being. Washington, DC: US Government Printing Office, 2000. 11. US Census Bureau. Population Estimates Program. Washington, DC: Population Division, August 2002. 12. Yancik R, Ries LG, Yates JW. Ovarian cancer in the elderly: an analysis of Surveillance, Epidemiology, and End Results program data. Am J Obstet Gynecol 1986; 154:639–47. 13. National Institute on Aging/National Cancer Institute/American Cancer Society. Perspectives on ovarian cancer in older-aged women: current knowledge and recommendations for research. Cancer 1993; 71 (Suppl): 513–660. 14. Yancik R, Ries LAG. Cancer burden in the aged: an epidemiologic and demographic overview. Cancer 1997; 80:1273–83. 15. Yancik R, Ganz PA, Varricchio CG, Conley B. Perspectives on comorbidity and cancer in older patients: approaches to expand the knowledge base. J Clin Oncol 2001; 19:1147–51. 16. Yancik R, Wesley MN, Ries LAG et al. Effect of age and comorbidity on treatment and early mortality in postmenopausal breast cancer patients aged 55 years and older, JAMA 2001; 285:885–92. 17. Yancik R, Wesley MN, Ries LAG et al. Comorbidity and age as predictors of risk for early mortality of male and female colon carcinoma patients: a population-based study, Cancer 1998; 82:2123–34. 18. Yancik R, Integration of aging and cancer research in geriatric medicine. J Gerontol Med Sci 1997; 52:329–32. 19. NIA/NCI Workshop Report: Exploring the Role of Cancer Centers to Integrate Aging and Cancer Research. http://nia.nih.gov/health/nianci. 20. NIH Archives Website. http://grants1.nih.gov/grants/guide/index.html

5 Epidemiological research in aging: Perspectives and limitations Marion RS Bain, Jean C Harvey Introduction Improved standards of living, improved nutrition, and better prevention and healthcare have led to increased life-expectancy in many parts of the world. The birth rate has also declined substantially in many countries. The consequence of these changes is an increasing average age in many populations. United Nations population predictions suggest that globally the number of people aged over 60 years will more than triple, to reach nearly two billion by 2050. For the oldest old, those aged 80 and over, the predictions are even more marked. A fivefold increase to 379 million is estimated.1 As the risk of most epithelial cancers increases with age, numbers of people with cancers can also be expected to grow. The World Health Report2 predicts that cancer will remain one of the leading causes of death worldwide. However, the report also suggests that over the next 25 years, the risk of cancer will stabilize or decline in industrialized countries. In developing countries, the risk will continue to increase. Sources of information on cancer in a population The two main sources of information on cancer in a population are mortality (derived from death certificates) and incidence (collected by cancer registries). Populationbased survival data can be calculated when these two sources are available for the population as a whole. Mortality data The accuracy of mortality data has generally been assessed in studies by one of two methods: • comparison of the clinical diagnosis with autopsy findings; • comparison between the clinical diagnosis recorded in case notes and the death certificate diagnosis. Studies from several countries have compared clinical diagnoses with autopsy findings.3–8 These studies vary in the source of cases and the percentage of deaths autopsied.

Epidemiological research in aging: Perspectives and limitations

79

However, in general, cancer uncovered at autopsy had been diagnosed clinically in 80– 90% of cases. Within this group, in 10–25%, the cancer site was either not known or attributed to the wrong site. The cancers that were most often missed or wrongly assigned clinically were lung, liver, and pancreatic cancers. Missed clinical diagnoses of cancer were commonly attributed to vascular or respiratory causes. A high percentage of clinical diagnoses of cancer were confirmed by autopsy (80– 90%), although again up to one-quarter had an incorrect or unknown site. Clinically, over-diagnosed cancers were commonly large-bowel cancers and pancreatic cancers. Vascular causes were the most common autopsy-detected cause of death in incorrect clinical diagnoses of cancer. Incorrect diagnoses occur more frequently with increasing age. In one study looking at routine autopsies (25% of all deaths) in Edinburgh Royal Infirmary, less than 50% of all clinical diagnoses were confirmed in those over 74.5 This low confirmation rate probably reflects greater diagnostic uncertainty in cases undergoing routine autopsy. A further study,9 with a higher percentage of deaths being subjected to autopsy (65%), showed higher confirmation rates, but a similar pattern of increasing diagnostic inaccuracy with increasing age (Table 5.1). Therefore, death certificates completed before or without

Table 5.1 Percentage of clinical diagnoses of cancer confirmed by autopsy in different age groups9 Age

% confirmed

<55

100

55–64

88

65–74

90

>75

75

Table 5.2 Comparison of detection and confirmation rates for selected cancer sites12 High detection rates and high confirmation rates (>80%)

Low detection rates and low confirmation rates (<80%)

Detection rate higher than confirmation rate (over-reporting on death certificates)

Confirmation rate higher than detection rate (under-reporting on death certificates)

Stomach

Mouth NOS

Colon

Buccal cavity

Pancreas

Small intestine

Larynx

Rectum

Bronchus/lung

Connective tissue

Bone

Cervix uteri

Melanoma of skin

Uterus NOS

Corpus uteri

Breast

Pharynx NOS

Eye

Ovary

Ill-defined and unknown Myeloid leukemia sites Transverse colon

Prostate

Comprehensive Geriatric Oncology

80

Sigmoid colon

Bladder Thyroid Myeloma

The detection rate is the proportion of hospital diagnoses with cancer of a certain site in which the cause of death reflects the same hospital diagnosis. The confirmation rate is the proportion of cancer deaths in which the specified underlying cause is confirmed by the hospital diagnosis. NOS, not otherwise specified.

autopsy are frequently incorrect. The presence of cancer may be missed or wrongly diagnosed, or the wrong primary site may be identified. Diagnostic inaccuracy is more common in the elderly. This presumably reflects the complicating effects of coexisting diseases in the elderly and, in many countries, perhaps fewer diagnostic investigations in the older age groups. The frequency of autopsy in different areas will have an effect on the accuracy of death certificate data. Autopsies are carried out less frequently in the elderly in all countries.10 The overall frequency of autopsy is also generally falling.11 Inaccurate recording of the clinical diagnosis on the death certificate has also been shown to occur. A large study compared cause of death on the death certificate with the hospital diagnosis.12 For most of the leading causes of cancer mortality, the death certificate was a fairly reliable indicator of the hospital diagnosis (Table 5.2). However cancer of the colon was often over-reported and cancer of the rectum under-reported on death certificates. Rarer cancers showed considerable disagreement between the hospital diagnosis and the death certificate cause of death. Bone tumors were over-reported on death certificates, presumably because metastatic bone tumors from other primary sites were misclassified. For many sites, a non-specific site was stated on the death certificate, despite a specific diagnosis having been made in hospital. For example, over 60% of the death certificate cases of cancer of the uterus, not otherwise specified, had actually been diagnosed as cervical cancer or corpus cancer in hospital. There were no significant differences in accuracy of death certification with age. Coding rules for large intestine neoplasms may also lead to inaccuracies. The 9th edition of the International Classification of Diseases (ICD-9) requires neoplasms of the rectosigmoid junction to be allocated to the rectum. It may be difficult to decide whether a neoplasm is in the sigmoid colon or the rectosigmoid junction. In addition, the terms ‘sigmoid colon’ and ‘rectosigmoid junction’ may be used interchangeably by surgeons and pathologists.13 Many countries are now using the 10th edition (ICD-10), which allows specific coding of rectosigmoid neoplasms. The same coding rules assign cancer of the large bowel to the colon. Death certificates also frequently give a less precise diagnosis than the clinical record—for example, leukemia rather than acute myeloid leukemia. Incidence data Incidence data is collected by cancer registries throughout the world. Information from registries has been collected by the International Association of Cancer Registries (IACR) and the International Agency for Research on Cancer (IARC) and published in

Epidemiological research in aging: Perspectives and limitations

81

successive volumes of Cancer Incidence in Five Continents.14 Several indices of data reliability are requested from contributing registries, including the following: 1. The proportion of diagnoses reported to the registry with histological verification (HV%). For some sites, other reliable methods of diagnosis exist (e.g. serum fetoprotein levels for primary liver cancer, radiology for cancer of the esophagus, and exfoliative cytology of the cervix uteri). HV% may therefore vary between sites. Some registries include cytological diagnoses with histology; others do not. Registry practice should therefore be considered before making comparisons. 2. The proportion of all notifications for which the existence of a cancer was identified only from a state-ment on a death certificate (DCO%). This is usually less than 1 in 20 notifications. Higher values indicate incomplete registration or poor-quality death certification. 3. The proportion of notifications with age unknown. This should be very low (with the exception of non-melanoma skin cancer). 4. The ratio of mortality to incidence for a given cancer in the registration area at a particular time (M/I%). This varies substantially from site to site. Rapidly fatal forms of malignancy give values close to unity, while non-melanoma skin cancer gives very low ratios. For a given cancer site, this ratio will depend on the results of treatment (and possibly the definition of what constitutes a cancer). It will therefore vary between medical centers. Selected results from several areas are presented in Tables 5.3 and 5.4. Table 5.3 compares HV% and DCO% for stomach cancer in males from registries in Canada, Switzerland (Basel), Denmark, and Scotland, and from the US National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) registries (White population).16–18 The commonly held belief that diagnosis is less

Table 5.3 Indicators of data quality; stomach cancer in selected cancer registries, 1988–92 Age 0–34

35–64

65–74

75+

All ages

Canada: males HV% DCO%

90

92

90

81

88

0

1

1

5

2

100

100

100

100

100

—

—

—

—

—

100

97

94

90

94

0

0

1

2

1

Switzerland (Basel): males HV% DCO%a Denmark: males HV% DCO%

Comprehensive Geriatric Oncology

82

US (SEER): White males HV% DCO%

100

99

98

94

97

0

1

1

2

1

95

90

87

72

83

0

2

4

7

4

Scotland: males HV% DCO%

HV%, proportion of diagnoses reported with histological verification; DCO%, proportion of notifications for which existence of cancer was identified only from a death certificate statement. a DCO% not available for Switzerland because of medical confidentiality. Raw data were kindly supplied by Jacques Ferlay of the Unit of Descriptive Epidemiology, International Agency for Research on Cancer (IARC).

reliable in the elderly is supported by the findings in Canada, Denmark, Scotland, and the USA. HV% decreased and DCO% increased with age. However, this was not invariably the case in all countries. In Basel, HV% was very high across the age bands. (In Switzerland, it is not possible to identify ‘death certificate only’ cases because the problem of medical confidentiality prevents matching of pathology records with death certification data.) Large differences in the indices are seen in different parts of the world. More detailed data concerning the elderly population from the SEER registries of the USA are given in Table 5.4. Indices of data quality are given by age and sex for selected sites of cancer. The percentage with histological verification is generally the same for the sites listed at ages 65–69, 70–74, and 75–79, but after the age of 80, HV% gradually falls, along with an increase in those diagnosed clinically and an increase in DCO%. The indices are useful guides to data quality. However, they must be interpreted with an awareness of local circumstances. A high HV% may be due to complete reporting by pathologists and lesser degrees of reporting by other sources. A low HV% may reflect an inadequate number of pathologists, a high proportion of cancer that can be diagnosed by other means, failure to notify the registry that biopsy or autopsy was performed, or an unwillingness to investigate older persons exhaustively. A high DCO% (e.g. in Japan) may be due to the inability to link hospital records with death certificates. M/I% may be distorted by poor or imprecise death certification. For example, there are usually more deaths attributed to unspecified leukemia than there are incident cases, since the more precise data on cell type available to the clinician and cancer registry do not appear on the death certificate. Generally, the results support the commonly held view that diagnosis is less accurate in the elderly. This may reflect the reluctance to investigate patients in whom treatment is not contemplated. Concomitant disease may rule out cancer therapy. However, large differences are seen in different parts of the world. The enthusiasm of physicians to investigate and treat elderly people undoubtedly varies in different cultures.

Epidemiological research in aging: Perspectives and limitations

83

Survival data Estimating cancer survival for the population as a whole requires knowledge of all persons with newly diagnosed cancer, their date of diagnosis, and their date of death. Obtaining this information requires either national cancer registration, or, if registration covers only part of a country, the ability to determine whether registered cancer patients have died. In many countries, this is not possible. In several Western European countries, considerations of patient confidentiality prevent such matches being made. Population figures are required. Results from

Table 5.4 urveillance, Epidemiology, and End Results SEER) registries 1993–97: indices of data reliability Age 65–69 HV %

Site Esop hagus

Sto mach

Liver

Pan creas

Lung and bron chus

Breast

A %

Age 70–74 C %

DCO HV % %

A %

Age 75–79 C %

DCO HV % %

A %

Age 80–84 C %

DCO HV % %

A %

Age 85+ C %

DCO HV % %

A %

C %

DCO %

M 97.3 0.3

1.4

0.9 97.2 0.4

1.5

0.4 97.1 0.2

1.7

0.6 95.9 0.0

3.5

0.6 86.6

0.0

8.6

3.8

F

97.0 0.0

1.5

1.0 97.0 0.4

1.5

0.4 97.4 0.0

2.2

0.4 88.1 1.1

6.8

2.8 80.3

0.6 12.9

3.9

M 96.8 0.6

1.0

1.3 97.3 0.5

0.7

1.2 97.6 0.3

1.3

0.6 95.9 0.4

2.6

1.0 92.6

0.5

4.0

2.3

F

1.7

0.9 97.1 0.2

2.3

0.2 95.8 0.3

1.8

1.8 94.5 0.2

4.6

0.4 83.0

0.4 10.8

4.3

96.9 0.5

M 76.7 2.0 16.2

2.8 74.2 2.3 16.5

5.1 76.0 1.0 17.5

4.1 71.2 0.5 19.2

5.9 56.0

1.4 29.1

12.8

F

76.3 1.7 17.3

3.5 75.3 0.0 17.9

3.4 63.8 0.9 24.6

6.5 58.7 1.8 25.8

11.4 39.9

1.5 40.6

14.5

M 85.5 0.6 11.8

1.8 80.2 0.2 15.8

2.7 73.5 1.0 21.4

3.1 58.2 0.3 32.6

5.9 38.0

1.3 51.4

7.0

F

1.4 80.7 0.5 16.3

2.0 69.6 0.3 25.2

2.9 53.8 0.6 38.7

5.1 34.1

1.1 51.4

10.5 6.5

84.5 0.6 12.6

M 93.6 0.3

4.3

1.2 91.5 0.5

5.9

1.6 88.0 0.6

8.5

2.1 78.8 0.6 15.7

3.6 61.2 86.0 29.6

F

94.0 0.3

4.4

0.9 90.6 0.3

6.6

1.9 86.7 0.4

9.8

2.3 75.2 0.4 18.5

4.7 54.7

F

99.4 0.3

0.2

0.0 0.5

0.3

Prostate M 98.9 0.3

0.6

0.1 98.0 0.3

0.9

Brain

M 91.2 0.0

6.4

1.7 84.3 0.0 11.4

F

92.0 0.6

5.9

All sites

M 96.6 0.3

2.1

F

2.1

97.0 0.2

99.0

98.0

0.0 1.1

0.6

0.2 96.3 0.4

2.2

96.7

88.6

0.2

1.1 31.7 6.3

10.2

0.1 1.9

0.3

0.5 90.6 0.6

6.0

1.7 74.1

1.1 16.5

4.3 5.7

3.5 80.1 0.3 14.2

3.9 69.6 0.0 26.8

3.0 36.7

1.0 52.0

8.2

0.9 82.9 0.8 13.2

2.1 79.4 0.0 16.6

3.3 55.8 0.0 36.8

5.8 28.7

1.3 52.7

14.7

0.6 95.5 0.4

2.8

0.8 93.4 0.4

4.4

1.2 88.4 0.5

8.0

2.2 77.2

0.8 15.7

4.7

0.6 95.5 0.2

3.1

0.8 93.1 0.2

4.9

1.3 88.2 0.2

8.5

2.3 77.1

0.4 15.3

5.9

Totals are less than 100% because of small numbers of cases diagnosed in hospital for which the record did not indicate whether or not diagnosis was histologically confirmed. HV%, histological verification; A%, diagnosed at autopsy; C%, clinical diagnosis only; DCO%, death certificate only. Basic data were kindly provided by MS Lynn Ries of the US National Cancer Institute.

Comprehensive Geriatric Oncology

84

Table 5.5 ercentage relative survival at 5 years from lung, large-bowel, prostate, and breast cancer: Scotland (1991–95) by broad age group, both sexes combined15 Age group

Lung

Large-bowel

Prostate

Breast

All sites combined

15–44

17.6

46.6

—

76.0

69.9

45–54

10.2

45.9

45.1

79.8

52.4

55–64

8.7

47.0

65.8

80.4

42.0

65–74

5.2

46.4

58.3

71.0

31.5

75–84

2.6

42.6

51.0

60.7

26.0

85+

2.5

28.6

36.4

45.8

18.1

All ages

5.7

44.1

55.7

75.3

37.6

controlled clinical trials are not representative of the cancer survival of a given population, since patients entered in these trials are highly selected so that valid comparisons of comparable patient groups can be made between treatment regimes. Such trials frequently exclude patients over 65 years of age. Relative survival in Scotland has been analyzed.15 As, with the exception of malignant melanoma, survival was similar for both sexes, the data were published for both sexes combined for the non-sex-specific cancers. For the sites shown in Table 5.5, and for all sites combined, relative survival is poorest in the very old. However, there are differences in the patterns between sites. While survival generally decreases with age for lung, large-bowel, and breast cancer, in prostate cancer, mortality is second highest in those aged 45–54. For all sites combined, the rate for the 65–74 age group is less than half that of those in the 15–44 age group. For those aged 75–84, the chance of survival is further reduced. This pattern is found for 1-, 3-, and 5-year follow-up periods. Nearly 70% of 15- to 44-year-olds survived 5 years after diagnosis. Only 32% of the 65–74 age group survived and only 26% of those aged 75–84 remained alive. Of those aged over 85 years, only 18% were still alive at 5 years.

Table 5.6 Comparison of 5-year percdentage relative survival for selected cancer sites: Scotland (1991–95),a Denmark (1988–92),b Geneva (1986– 90),c and USA Whites (1989–96)d Site

Scotland M

Esophagus Stomach

F

Denmark M

Geneva

F

M

USA

F

M

F

8.0

11.9

2

9

12

8

13.2

13.2

11.5

14.0

13

15

27

22

17.1

23.6

Epidemiological research in aging: Perspectives and limitations

Large bowel

85

43.2

44.5

40

43

52

50

62.2

62.0

3.3

2.5

2

2

1

3

3.8

4.5

60.8

60.8

60

60

62

60

67.6

60.8

7.0

6.4

6

7

13

13

12.9

16.6

79.6

87.0

73

84

87

91

85.8

91.7

*

72.8

*

71

22

79

84.4

86.4

Cervix uteri

NA

58.3

NA

65

NA

66

NA

71.6

Corpus uteri

NA

73.9

NA

76

NA

72

NA

86.4

Ovary

NA

35.9

NA

32

NA

32

NA

50.1

Prostate

49.6

NA

42

NA

60

NA

94.1

NA

Testis

93.5

NA

92

NA

95

NA

95.7

NA

Bladder

67.8

61.4

51

54

54

60

84.0

75.7

Kidney

38.6

39.8

36

33

51

44

62.2

60.4

Brain and other central nervous system tumors

13.0

15.5

20

23

30

27

30.2

29.8

Thyroid

67.6

62.6

59

72

78

84

91.9

96.7

Hodgkin lymphoma

66.7

52.5

71

73

70

71

80.6

85.5

Non-Hodgkin lymphoma

45.1

49.2

46

49

47

42

48.7

57.5

Leukemia

33.8

34.1

29

27

38

34

46.5

43.8

All sites

33.9

45.2

32

47

40

55

60.1

63.0

Pancreas Larynx Lung Melanoma Breast

a

15

Population-based survival data for all of Scotland. In general, there is little difference in survival between the sexes, except for melanoma, a form of cancer with a 20% advantage for females. b Population-based survival data for Denmark (EUCAN).16 c Population-based survival data for the Canton of Geneva.17 d Population-based survival data providing information for the 10% of the US population covered by the Surveillance, Epidemiology, and End Results (SEER) program of the US National Cancer Institute.18 *Data not provided or not comparable; NA, not applicable

Table 5.7 Percentage 5-year relative survival in colon cancer by stage and age in Norway, 1991–95 Age Stage Localized

Regional

<55

55–74

75+

M

79.8

82.7

75.2

F

92.7

86.5

77.6

M

64.6

61

58.5

Comprehensive Geriatric Oncology

Distant

Total

86

F

65.8

61.3

57.7

M

6.3

4.5

4.4

F

11.9

6.5

4

M

47.4

52

49.4

F

56.2

56.3

50.6

Data were kindly provided by Ellen Melbye Langballe of the Cancer Registry of Norway.

Table 5.8 Percentage 5-year relative survival in breast cancer by stage and age in Norway, 1991–95 Age Stage

<55

55–74

75+

I

89.7

92

82.5

II

73.6

70.3

68

III

*

50

60.9

IV

17

16.8

13.6

Total

78.7

78

73.4

*The 5-year relative survival in breast cancer patients <55 is not included because of the small sample and large standard deviation. Data were kindly provided by Ellen Melbye Langballe of the Cancer Registry of Norway.

A decline in survival with advancing age is seen in all population-based series. Comparative figures of 5-year relative survival for selected cancer sites in four countries are given in Table 5.6. Survival differences need to be interpreted in the light of the stage distribution of the presenting cancer. Staging data are rarely available; however, the Norwegian Cancer Registry has kindly supplied such data. Five-year relative survival rates for colon cancer and breast cancer by stage are given in Tables 5.7 and 5.8. At any stage, survival is poorer in those over 75. However, at any age, stage is a more important prognostic factor than age per se. Staging data are required for analyzing survival data. The percentage of cancers staged in Scottish cancer patients is shown in Table 5.9. The percentage of cancers for which stage was available varied by site. However, sufficient information was given in the records for staging to be carried out in 80–90% of cases. The proportion that was staged or stageable generally decreased with age.

Table 5.9 Cancer registrations in Scotland, 1997: percentage of cases staged by age group for selected cancers Age group

Colorectal (n=3375)

Breast (n=3357)

Cervix (n=359)

Epidemiological research in aging: Perspectives and limitations

<50

93.4

67.5

90.1

50–64

92.1

64.4

88.0

65–74

88.6

60.7

79.5

75–84

83.4

53.8

91.9

85+

61.3

40.0

72.7

All ages

85.1

61.0

88.0

87

Data were kindly provided and analyzed by Julie Kidd of the Scottish Cancer Intelligence Unit (SCIU).

Table 5.10 Size of cancer burden in selected countries14 Average number of cancers/year (excludes non-melanoma skin cancer)a Country

Total populationb

All ages

75+ age group

% of total cancers/year in 75+ age group

Canada

27745385

105365

29514

28

Scotland

5100086

23406

7582

32

England and Wales

50678105

209 495 73428

35

Denmark

5145160

22756

7046

31

USA SEER Whites

18951774

86760

25906

30

a

Average over period 1988–92. Average annual population 1988–92 (except England and Wales: 1988–90).

b

Size of the cancer burden in the elderly Incidence data can be used to estimate the size of the cancer burden in the elderly. The average annual number of cancers registered for all ages and for those over 75 in the 5 years from 1983 to 1987 in selected countries is shown in Table 5.10. Between 28% and 35% of the overall cancer burden in these countries is found in those aged 75 and over. Future burden The effect of demographic changes on the future size of the cancer burden can be estimated on the assumption that current age-specific rates for the common cancers in those aged 75 and over would still apply. An estimate of the number of cancers occurring in this same age span in

Comprehensive Geriatric Oncology

88

Figure 5.1 Estimated number of cancer cases in the year 2029 in Scotland. 2029 in Scotland is given in Figure 5.1. This estimate is bound to be incorrect, since it does not take into account the likely continued fall in lung cancer in males or possible increases for other sites. However, the estimates of cancer incidence for all sites seem likely to be of the correct magnitude. Predicting age-specific rates beyond the year 2000 is difficult, since they depend on the cumulative effect of carcinogenic exposures. For older persons born at a particular time, much of this exposure has already taken place, cellular damage has occurred, and the resulting cancer risk is largely determined. However, it is believed that prolonged exposure to promoting agents is required for initiated cells to be transformed. If exposure to promoters can be reduced or avoided or antipromoters given, malignant transformation may be postponed or may not take place at all. Therefore, changes such as consuming more fresh fruit and vegetables or ceasing to smoke may reduce risk even in older persons. Only recently has extensive work begun in this area, including the search for short-term tests of promoting activity. Younger birth cohorts may experience new carcinogenic risks and/or avoid exposure to known causes, and hence their risk is much less easy to forecast. The Scottish Executive Health Department predicted cancer burden in Scotland up to the years 2010– 14 using age—period-cohort mathematical models.19 However, even these cannot take account of future risk in those who are presently relatively young.

Epidemiological research in aging: Perspectives and limitations

89

Cancer treatment in the elderly Place of treatment Many factors, including the stage of the tumor, the presence and extent of other diseases, and the distance from treatment centers, are likely to influence the place of treatment of older persons. In Scotland, 15 Health Boards are responsible for providing all health services in their

Figure 5.2 National Health Service, Scotland: Health Board boundaries. Crown copyright, reproduced with the

Comprehensive Geriatric Oncology

90

permission of the Controller of Her Majesty’s Stationery Office.

Figure 5.3 Percentage of cancer cases (excluding non-melanoma skin cancer) treated within and outside their Health Board of residence, by age at diagnosis, Scotland 1988–96. Data were kindly provided and analyzed by Julie Kidd of the Scottish Cancer Intelligence Unit (SCIU). own area (Figure 5.2). The proportion of cancer patients in Scotland aged less than 75 and aged 75 and over treated in their Health Board of residence has been examined by the Scottish Cancer Registry. The majority of patients, both under 75 and 75 and older, are treated within their Health Board of residence (Figure 5.3). However, in all areas except Orkney and Shetland, persons aged 75 and over seem less likely to be transferred to a different Health Board area compared with those under 75. This effect is especially marked in rural Health Boards. For Health Boards containing cities, such as Lothian and Greater Glasgow, very few patients of any age are treated elsewhere. Those not treated in their own area would be most likely to have their treatment in Health Boards with cities, since the medical facilities are concentrated there. A small proportion of cancer patients in Scotland are admitted to institutions that notify 10 or fewer patients with cancer a year to the cancer registry. The spectrum of cancers notified from these institutions is very similar to that for all cancers in Scotland. However, the age distribution is quite different, the majority of the patients being 75 or older (Table 5.11).

Epidemiological research in aging: Perspectives and limitations

91

Therefore, older patients in Scotland appear less likely to be referred outside their area of residence (especially in rural areas), and are more likely to be admitted to institutions that admit small numbers of cancer patients. These findings may be due to more advanced disease or comorbid conditions in the elderly, which make treatment

Table 5.11 Percentage age distribution of cancer (excluding non-melanoma skin cancer) notified for Scotland as a whole in 1997, compared with the age distribution of cancers notified for Scottish hospitals diagnosing fewer than 10 cases in 1997 Age group

Scotland(%)

Hospitals diagnosing <10 cases in 1997 (%)

<55

17.2

13.4

55–64

18.8

9.5

65–74

29.9

21.5

75+

34.1

55.6

Data were kindly provided and analyzed by Julie Kidd of the Scottish Cancer Intelligence Unit (SCIU).

less likely. There is no reason why elderly persons with cancer should not be treated as energetically as those who are younger (and, since the neoplasms often grow more slowly, with success). However, physicians may be reluctant to subject elderly patients to the discomfort of investigation and aggressive therapy. In addition, a proportion of elderly patients will be unsuitable for treatment because of coexisting cardiovascular, respiratory, or other diseases. Patient preference may also influence treatment decisions. Future research A significant proportion of the overall cancer burden occurs in the elderly. Cancer in the elderly is likely to be complicated by the presence of coexisting disease. More work needs to be done to attempt to quantify comorbidity and to assess its effects on cancer and its influence on decisions to treat elderly cancer patients. Clinically, decisions have to be made considering the risks and discomfort of investigation and treatment and the effects on survival and quality of life. The balance tends to result in less investigation of elderly patients. This leads to poorer characterization of cancer in this age group, which in turn affects the information available for planning of services. Treatment also appears to be less likely in the elderly. The conspicuous lack of clinical trials involving the elderly means that information on which to base treatment decisions in this age group is often not available. More trials involving the elderly are required. Surveys of attitudes of general practitioners and hospital consultants to treatment of the elderly are also required. Whether funding for treatment has any effect may also be important in countries with private healthcare systems. In addition, the needs,

Comprehensive Geriatric Oncology

92

expectations, and wishes of older people with cancer need to be studied. The failure to refer older patients to cancer centers is especially important given recent studies on the effect of type of hospital and treating physician on survival.20–22 References 1. United Nations Organization. United Nations Long-Range World Population Projections: Based on the 1998 Revision. New York: UNO. 2. WHO. The World Health Report 1998. Life in the 21st Century—A Vision for All. Geneva: World Health Organization, 1998. 3. Heasman MA, Lipworth L. Accuracy of Certification of Cause of Death. London: HMSO, 1966. 4. Engel LW, Stauchen JA, Chiazze L Jr, Heid M. Accuracy of death certification in an autopsied population with specific attention to malignant neoplasms and vascular diseases. Am J Epidemiol 1980; 111:99–112. 5. Cameron HM, McGoogan E. A prospective study of 1152 autopsies: 1. Inaccuracies in death certification. J Pathol 1981; 133:273–83. 6. Goldman L, Sayson R, Robbins S et al. The value of the autopsy in three medical eras. N Engl J Med 1983; 308:1000–5. 7. Holzner JH. The role of autopsy in the control of mortality in Austria. In: Autopsy in Epidemiology and Medical Research (Riboli E, Delendi M, eds). Lyon: IARC Press, 1991:25– 35. 8. Modelmog D, Rahlenbeck S, Trichopoulos D. Accuracy of death certificates: a population based, complete-coverage, one-year autopsy study in East Germany. Cancer Causes Control 1992; 3:541–6. 9. Cameron HM, McGoogan E, Watson H. Necropsy: a yardstick for clinical diagnoses. BMJ 1980; 281:985–8. 10. WHO. World Health Statistics 1990. Geneva: World Health Organization, 1991:15–21. 11. Riboli E, Delendi M (eds). Autopsy in Epidemiology and Medical Research. Lyon: IARC Press, 1991. 12. Percy C, Stanek E, Gloeckler L. Accuracy of cancer death certificates and its effect on cancer mortality statistics. Am J Publ Health 1981: 71:242–50. 13. Puffer RR, Griffith GW. Patterns of Urban Mortality. Washington, DC: Pan American Health Organization, 1967. 14. Parkin DM, Whelan SL, Ferlay J et al. Cancer Incidence in Five Continents, Vol VII. Lyon: IARC Press, 1997. 15. Scottish Cancer Intelligence Unit. Trends in Cancer Survival in Scotland 1971–1995. Edinburgh: Information and Statistics Division, 2000. 16. European Network of Cancer Registries. EUCAN: Cancer in the European Union, 1995. Version 2.0 (created 24–06–1999). IARC Cancer Base No. 4. Lyon: International Agency for Research on Cancer, 1999. 17. Registre Genevois des Tumeurs. Le Cancer à Genève. Incidence, Mortalité, Survie: 1970–1994. Geneva: Registre Genevois des Tumeurs, 1997. 18. Ries LAG, Eisner MP, Kosary CL et al (eds). SEER Cancer Statistics Review 1973–1997. Bethesda, MD: National Cancer Institute, 2000. 19. Black R, Stockton D (eds). Cancer Scenarios: An Aid to Planning Cancer Services in Scotland in the Next Decade. Edinburgh: Scottish Executive Health Department, 2001. 20. Gillis CR. Medical audit, cancer registration and survival in ovarian cancer for the West of Scotland. Newsletter of the Scottish Cancer Therapy Network, 1993; 1:2–4. 21. Junor EJ, Hole DJ, Gillis CR. Management of ovarian cancer referral to a multidisciplinary team matters. Br J Cancer 1994; 70:363–70.

Epidemiological research in aging: Perspectives and limitations

93

22. McArdle CS, Hole DJ. Impact of variability among surgeons on postoperative morbidity and mortality and ultimate survival. BMJ 1991; 302:1501–15.

6 Factors affecting the diagnosis and treatment of older persons with cancer James S Goodwin, Cynthia Osborne Introduction Men and women over age 75 are different from men and women in their 50s. A recurring theme of geriatrics is that one cannot make rules generated from the study of the medical treatment of 50-year-olds and unquestioningly apply them to the medical treatment of 80year-olds. Yet, most of the ‘rules’ of oncology and the rest of internal medicine are generated from studies of those under the age of 65.1 There are no compelling a priori reasons to think that these rules will work very well in older patients. A corollary of this statement is the fact that older cancer patients are treated differently from younger cancer patients does not prove that older patients are being treated incorrectly. In this chapter, we shall begin with an overview of the current status of how older patients with cancer are diagnosed and treated. The evidence shows that older patients are less likely to be diagnosed at an early stage with those cancers for which there are accepted screening procedures. In addition, older patients are less likely to receive treatments that are considered definitive or potentially curative. Because of the concepts raised in the first paragraph, we shall then turn to a discussion of the evidence that the decrease in definitive treatment for older cancer patients is indeed inappropriate; that is, that it is associated with poor outcomes. We shall discuss the specific characteristics of older cancer patients that put them at risk for delays in diagnosis and inadequate treatment. Finally, based on our understanding of the barriers to adequate medical care experienced by some older cancer patients, we shall discuss ways to improve the diagnosis, treatment, and outcomes of older men and women with cancer. Older patients are less likely to be diagnosed with early-stage cancer One relatively recent breakthrough in the examination of medical practices is the use of large-scale disease registries, such as cancer registries, to examine issues such as patterns of diagnosis and treatment. It is important to realize that this was not the purpose for which these registries were created. Cancer registries were created to produce reliable data on the incidence of various cancers and how the incidence might vary with gender, race, age, or geographic area. However, the growth of effectiveness research has led to a greater appreciation that results of clinical trials were not always indicative of whether a particular treatment was effective in the ‘real world’ (Table 6.1). Thus, the need arose for mechanisms to look at diagnosis and treatment of the entire population—so-called

Factors affecting the diagnosis and treatment of older persons with cancer

95

‘population-based’ data. This is precisely what cancer registries provide. However, because these registries were not constructed to help us analyze appropriateness of diagnosis and treatment, one should be sensitive to the limitations of these data. Holmes and Hearne2 used data on 31000 cancers between 1944 and 1979 in a regional cancer registry for Kansas and western Missouri to examine the relationship between stage at diagnosis and age of the patient. They found significant positive trends between age and stage for cancers of the bladder, breast, cervix, kidney, ovary, stomach, and uterus; that is, the older the patient, the more likely he or she was diagnosed at an advanced stage. Breslow3 reported an increase in stage at diagnosis of cervical cancer in elderly patients in data from the California Tumor Registry, which receives information on cancer patients treated at 40 California hospitals. New Mexico Tumor Registry data were utilized to examine the relationships between stage of cancer at

Table 6.1 Effectiveness versus efficacy • Efficacy: Demonstration of beneficial effect of a treatment in a prospective controlled clinical trial • Effectiveness: Demonstration of beneficial effect of a treatment when used in a community

Table 6.2 Percentage of patients diagnosed at advanced stage by age, in nine SEER areas in 1988 and in 1997 Site

Stage

Age <55

Age 55–64 Age 65–74 Age 75–84 Age 85+

1988 1997 1988 1997 1988 1997 1988 1997 1988 1997 Bladder

Regional, distanta

18.5

18.3

19.4

21.2

20.7

22.4

27.5

25.6

26.3

31.2

Breast

Regionalb

313

26.9

27.9

23.2

26.2

19.1

27.7

18.4

26.7

19.9

Distantb

4.4

4.3

6.0

5.0

5.2

4.6

5.7

5.0

7.7

6.5

Regional, distantb

3.9

31.0

23.5

49.9

36.0

54.9

41.8

61.5

60.9

68.4

Melanoma Regional, distanta

6.9

7.5

9.2

8.1

12.6

8.7

15.7

11.0

23.6

18.6

Cervix

Ovary

Regional, distantb

57.0

57.5

79.0

79.1

82.5

86.5

81.4

86.4

85.7

92.5

Thyroid

Regional, distanta

35.6

29.5

34.7

28.8

33.9

33.9

41.0

61.5

58.3

53.6

Uterus

Regional, distanta

16.3

19.8

20.6

21.8

23.7

23.8

27.3

25.9

41.9

29.9

Denominators include all stages of cancers except for unknown stage. a p<0.01 by chi-square statistics for linear trend across the five age groups. b p<0.0001 by chi-square statistics for linear trend across the five age groups

Comprehensive Geriatric Oncology

96

diagnosis and age, ethnic group, marital status, and place of residence (urban or rural) of men and women diagnosed with cancer in New Mexico.4–6 Cancers of the bladder, breast, cervix, ovary, thyroid, and uterus, and melanoma were more likely to be diagnosed at more advanced stages in older patients. The most striking relationship between stage at diagnosis and age was found for cervical cancer. More than 20% of cervical cancers were diagnosed at a remote stage in women older than 75 compared with 3% for women of 55 or younger. With breast cancer, there was an increase in the percentage of remote-stage cancers, balanced by a decrease in the percentage of regional-stage cancers with age. Yancik et al,7 in a more recent study utilizing the US National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) database, noted no significant age/stage trend in breast, ovary, colon, prostate, or urinary bladder cancers, which had been previously observed in multiple earlier studies. However, while no significant age/stage trend was noted, a disproportionate number of older women were found to be incompletely staged or to have unknown stage as compared with younger women. In other words, there was an increasing trend of incomplete diagnostic staging carried out in those with advancing age. Table 6.2 is generated from SEER data obtained in 1988 and contrasted with more recent data obtained in 1997. As suggested by Yancik et al,7 there is little age/stage relationship seen for breast cancer, and for uterine and thyroid cancers the age/stage disparity noted in 1988 appears somewhat lessened in 1997. Cancers of the urinary bladder and cervix and melanoma demonstrate an increasing stage of diagnosis with increasing age, which looks relatively stable over time. The apparent differences from the SEER data presented by Yancik et al and that presented here are likely explained by the way in which the data were considered. Yancik et al viewed each tumor site by American Joint Committee on Cancer (AJCC) stage and did not include in situ tumors. The data presented here lump regional and distant disease together as advanced-stage disease, and early-stage disease combines both local and in situ disease. A comparable pattern was observed in the New Mexico Tumor Registry.4 Stage of cancer at diagnosis is influenced by the extent of the diagnostic evaluation: a less extensive evaluation would tend to misclassify advanced cancers as local. Although 99% of cancers in those under 55 are diagnosed by histopathology or cytopathology, more than 20% of cancers in those older than 85 are diagnosed on a clinical or radiologic basis without pathologic confirmation. Thus, less extensive evaluation may partially explain the finding that some cancers are diagnosed more frequently at local stages in elderly subjects. Table 6.3 shows the percentage of patients diagnosed with unstaged cancers by age for both 1988 and 1997. Throughout all tumor types with increasing age, an increasing percentage of patients are incompletely staged. Older patients are less likely to receive definitive therapy for cancer The New Mexico Tumor Registry database was used to assess the relationship between patient age and the use of potentially curative therapy, termed definitive treatment.8 For most sites, there was a significant decline with age in

Factors affecting the diagnosis and treatment of older persons with cancer

97

Table 6.3 Percentage of patients diagnosed with unstaged cancers by age, in nine SEER areas in 1988 and 1997 Site a

Bladder

Age <55

Age 55–64

Age 65–74

Age 75–84

Age 85+

1988

1988

1988

1988

1988

1997

1997

1997

1997

1997

4.6

4.2

3.3

3.8

5.1

4.2

4.3

4.5

11.8

9.5

b

2.4

2.3

2.3

2.2

2.7

2.1

5.1

4.6

15.8

16.3

Cervix

0.6

7.0

3.4

6.8

5.7

8.3

12.7

15.2

16.4

34.5

Melanoma

3.8

4.2

4.1

3.8

3.1

4.2

6.1

4.5

9.8

9.5

Ovary

2.9

3.5

2.5

5.1

6.1

7.8

10.3

13.9

33.7

21.5

Thyroid

3.2

3.6

6.4

4.4

11.0

9.0

11.6

6.2

25.0

12.5

Uterus

4.3

3.8

3.5

3.3

3.8

5.3

7.0

7.0

25.6

24.2

Breast

Denominators include all stages of cancers. a p<0.01 by chi-square statistics for linear trend across the five age groups. b p<0.0001 by chi-square statistics for linear trend across the five age groups.

the percentage of patients receiving definitive therapy. The pattern was generally similar for regional-stage cases. To confirm the relationship between definitive treatment and age, the proportion of patients in each age group that received no treatment recorded by the New Mexico Tumor Registry was also examined. The trends were the inverse of those found for definitive treatment. For all sites combined, the proportion of patients with no treatment increased progressively from 3% in those younger than 55 to 29% for those 85 and older. Table 6.4 shows data generated from the SEER database for 1988 and 1997; demonstrating the percentage of patients with local disease receiving definitive treatment by age. For most sites, there is a decline in the percentage

Table 6.4 Percentage of patients with local-stage cancers receiving definitive treatment by age, in nine SEER areas in 1988 and in 1997 Age Bladder Breast

Age <55

Age 55–64

Age 65–74

Age 75–84

Age 85+

1988

1997

1988

1997

1988

1997

1988

1997

1988

1997

95.5

95.5

97.3

97.7

95.6

93.9

95.3

95.8

96.0

94.8

a

91.2

80.5

92.8

84.7

90.4

82.9

79.0

69.8

44.7

36.6

a

87.7

92.8

71.1

78.8

56.0

81.6

55.0

79.3

20.0

50.0

97.9

99.1

98.9

96.8

98.1

97.6

97.3

96.9

93.3

91.6

25.0

44.2

47.1

52.7

32.9

32.0

11.8

14.9

15.8

12.5

Cervix

a

Colon

b

Esophagus

Comprehensive Geriatric Oncology

Gallbladder

98

100.0

100.0

100.0

100.0

87.5

100.0

95.5

100.0

100.0

100.0

97.7

99.0

94.9

95.8

94.2

92.7

84.1

86.1

77.8

56.7

96.0

95.7

94.0

97.1

94.1

94.6

94.2

93.6

93.3

86.7

71.2

67.1

61.3

58.6

55.4

53.7

37.0

36.3

6.6

12.1

97.5

98.7

97.7

98.3

97.0

98.6

96.1

98.4

96.6

98.4

99.6

99.7

100.0

100.0

98.8

96.6

95.9

97.7

88.9

71.4

Pancreas

50.0

60.0

26.7

40.7

16.9

34.6

11.8

15.6

0

8.0

Prostatea

63.5

68.8

53.7

60.3

35.9

33.9

9.5

5.5

4.2

1.8

a

95.1

93.8

99.1

96.5

95.6

95.0

93.1

93.2

78.6

85.1

84.0

70.9

88.4

76.7

80.2

70.3

71.3

61.7

57.1

35.8

96.7

96.4

97.3

96.2

98.1

96.7

95.2

93.7

80.4

71.8

Kidney

a

Lip Lung

a

Melanoma Ovary

b

Rectum

Stomach a

Uterus

a

a

p<0.0001 by chi-square statistics for linear trend across the five age groups p<0.01 by chi-square statistics for linear trend across the five age groups.

b

of patients receiving definitive treatment with advancing age, and this trend remains relatively stable over time. Tumor registry data also allow for analysis of changes over time in the provision of treatments.9 For cancer patients over the age of 75, there was a clear increase in the percentage over time (from 1969 to 1982) of those receiving definitive therapy.8 Older cancer patients are less likely to receive chemotherapy after the diagnosis of local or advanced cancer. For example, Mor et al10 analyzed 1891 cancer cases from the National Hospice Survey, and found decreasing chemotherapy use with age in patients with breast, lung, and colorectal cancer. Much of the attention to possible undertreatment of older patients has focused on breast cancer.11–26 Several studies conducted in a variety of healthcare settings and geographic regions have shown that many women diagnosed with breast cancer receive less extensive diagnostic evaluations and initial treatments than are generally thought to be appropriate. For example, 56% of women aged 65 or older who received breastconserving surgery between 1981 and 1985 in New Mexico received no adjuvant radiotherapy.13 Older women have also been less likely to receive axillary dissection,17–19 oncology referrals,16,20 and chemotherapy,10,14,16,19 in addition to being less likely to receive radiation.14,15,17–19,23,27,28 On the other hand, Du and Goodwin29 demonstrated that, over time, older women were more likely to receive chemotherapy. Older women in 1996 were 30% more likely to receive chemotherapy than older women in 1991. This increase was most noted, though, in the ‘young old’ (i.e. those 65–69 years of age). Age continued to exert a strong influence on chemotherapy use, with those aged 65–69 being twice as likely to receive chemotherapy as those over the age of 70. A meta-analysis performed by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) reported data combined from 47 trials and included more than than 18 000 women.30 They were able to demonstrate a quantitative risk reduction for recurrence of breast cancer for all women below the age of

Factors affecting the diagnosis and treatment of older persons with cancer

99

70, although the benefit lessened with increasing age. For women over the age of 70, no clear benefit was found. However, it should be noted that of the more than 18000 women combined from all 47 trials, only 600 were aged 70 or older, and therefore evidence of small benefit may have been missed. Similar results were shown for all-cause mortality; however, the trend was less pronounced, and again no clear benefit was demonstrated for women over the age of 70. An increasing use of radiation therapy in older women over time has also been demonstrated by Du et al.31 In contrast to chemotherapy use, however, the greatest increase in radiation therapy use when comparing the period 1983–87 with the period 1992–95 was seen in women over the age of 75 versus those aged 65–74. Might cancer therapy considered less than definitive actually be appropriate for some older patients? The answer to the question posed in the title to this section is yes. This is made obvious by considering an extreme case. Does one recommend definitive surgery for local rectal cancer in a 114-year-old man? Does one perform either a modified radical mastectomy or breast-conserving surgery with subsequent radiation on a 95-year-old woman? Would it not be more appropriate to remove the lump and prescribe tamoxifen? It is not ageist to recognize the medical realities of extreme old age; indeed, not doing so involves sacrificing common sense and humane care to a false standard of ideological purity: the concept that differences in care are de facto evidence of inadequacies of care.32 Thus, the decrease in receipt of definitive therapy in older cancer patients that was documented in the previous section is potentially justifiable—it may represent appropriate clinical decision-making by patients and their physicians faced with the complex task of balancing several potentially conflicting values. Some patients may appropriately be judged to be unable to tolerate the rigors of diagnostic testing and treatment (e.g. those with serious comorbidities). Furthermore, the patient with dementia poses a special problem. If the treating physician cannot obtain informed consent, if the patient cannot understand the necessity of the treatment and give permission to the treating physician, any treatment, no matter how necessary to preserve health, can be seen as a form of assault. This takes an emotional toll on the physician, the other members of the healthcare team, and the patient’s family, in addition to the patient. The above comments not withstanding, there is a clear consensus among those investigating the issue that that the decrease in definitive treatment for older cancer patients is indeed inappropriate, or at least frequently inappropriate. The arguments supporting this opinion can be presented in four parts: First, the observed less aggressive approach does not appear to be largely explained by comorbidity.18,19,24,33,34 For example, in a study of breast cancer care at seven southern California hospitals, 17% of women with local or regional disease aged 70 or older and with low comorbidity did not receive definitive therapy, compared with 4.4% of women under 70. Second, there are substantial geographic variations in the cancer care received by women that would be difficult to explain on the basis of distributional differences in

Comprehensive Geriatric Oncology

100

comorbidity and physical frailty. This is best documented for breast cancer. For example, the percentage of women aged 65 or more with local breast cancer who underwent

Table 6.5 Odds ratios (95% confidence intervals in parentheses) for not receiving any surgery or radiation therapy after the diagnosis of cancer in older subjects Factor

Categories compared

No surgery

No radiation

Age

Increase of 10 years

0.96 (0.66–1.40)

2.14(1.47–3.12)

Drives or lives with driver

No versus yes

0.72 (0.26–1.99)

3.35 (1.28–8.76)

Activities of daily living

Some problems versus none

0.80 (0.40–1.60)

2.49 (1.34–4.62)

Physical activity

Bottom 20% versus others

0.70 (0.37–1.31)

2.46 (1.31–4.64)

Mental status

Incompetent versus no errors 0.29 (0.64–1.32)

13.5 (1.78–101.6)

>2 errors versus no errors

1.18(0.55–2.56)

1.60 (0.78–3.28)

1 Error versus no errors

0.99 (0.54–1.80)

1.44 (0.86–2.40)

Adapted from data in reference 24. The cases include in situ, local, and regional stages of colorectal, breast, and prostate cancer. Odds ratios were computed from separate logistic regressions with terms for site and stage.

breast-conserving surgery in 1986 varied from 3.6% in Kentucky to greater than 20% in New York, Pennsylvania, Massachusetts, and Vermont.35 The percentage of nonHispanic White women aged 65–74 with local breast cancer who did not receive breast irradiation following breast-conserving surgery varied from 14% in Seattle to 46% in Connecticut.28 Other studies have demonstrated considerable variation in the types of care received by breast cancer patients among hospitals within a given state.27,36 Third, several investigators have found that characteristics of patients other than their medical status or comorbidity are more important determinants of treatment received. These include ethnicity,28,37–40 advanced age,16,17,21–24,27,28 educational level,24,41 marital status,6,27,42 place of residence,27,36,43 cognitive status,24 access to transportation,24 and social support.24 Definitive therapy often involves several modalities. As shown in Table 6.5, advanced age, impaired access to transportation, functional dependence, and impaired cognition all had a significant effect on receipt of radiation therapy, but not on receipt of surgery.24 This reinforces the concept that the decrease in definitive treatments has more to do with issues of access to care than to medical considerations per se. Fourth, choice of treatment has a strong influence on outcomes in older cancer patients. For example, breast-conserving surgery without radiation is associated with a high rate of local recurrence in older women.44,45 Receipt of breast-conserving surgery without radiation was associated with a twofold higher death rate compared with breastconserving surgery plus radiation in a population-based study of women of all ages with breast cancer in Orange County, California.26 In a longitudinal study of older women diagnosed with breast cancer in New Mexico, women who did not receive definitive

Factors affecting the diagnosis and treatment of older persons with cancer

101

treatment for stage I or II breast cancer had twice the death rate (hazard ratio 2.2; 95% confidence interval 1.43–3.4) during 8 years post diagnosis as those receiving definitive treatment, after controlling for age, race income, comorbidity, and such indicators of physical frailty as functional status, cognitive function, and activity level.46 A similar pattern of results was reported for older men and women with local colorectal cancer.46 In summary, the evidence for inappropriate under-treatment of some older cancer patients is substantial. However, it cannot be considered definitive for several reasons. First, increased mortality associated with certain treatments in population-based studies does not prove that those treatments are inappropriate. One can always posit that the same forces that influenced choice of therapy also influenced mortality. It is virtually impossible in large population-based studies to completely control for comorbidity or other factors that might simultaneously decrease survival and increase the choice of a ‘non-definitive’ treatment. Second, geographic variation in the use of treatments is not necessarily inappropriate—for example, if two treatments were roughly comparable. Similarly, if treatments are roughly comparable in outcome, variation in treatment by any patient characteristic (age, ethnicity, marital status, etc.) is not necessarily inappropriate. Personal goals and values may vary across these groups, and those values could appropriately influence choice of therapy. The above arguments are dependent on therapies being ‘roughly comparable’, which brings us to the third reason why we cannot conclude with absolute certainty that older patients receiving ‘less than definitive’ treatments are being inappropriately treated: the lack of comprehensive information on outcomes of various cancer treatments in the elderly. While it is fairly well recognized that there are insufficient numbers of older people, particularly those over the age of 70, enrolled in clinical trials of cancer treatments, we should also consider the possibility that this may always be the case.1 The heterogeneity of the aging population, as well as the volunteer nature of prospective trials, may render unrealistic the goal of obtaining information on outcomes of cancer treatments on all the definable subpopulations of older men and women. Nevertheless, the recent attention given to enrolling older subjects in clinical trials, as well as the growing sophistication of population-based comparisons of treatment outcomes in large populations, ensures that our level of knowledge about appropriate cancer treatments for older men and women will increase dramatically over the next decade. Are older cancer patients also at risk for overtreatment? The same underlying factors that put the older patient at risk for undertreatment can also contribute to overtreatment. These factors are the heterogeneity among the elderly and the relative lack of information about effectiveness. Lack of sound data invariably leads to variation in practice patterns, and within that variation there will exist both too much and too little treatment. There is better documentation for undertreatment, reviewed in the previous section, than for overtreatment. Every primary care physician has at least one ‘horror story’ of a frail elderly patient spending the last weeks of life being shuttled from doctor to doctor, from treatment to treatment, with little time for reflection, for leavetaking. Ever since we declared the ‘war on cancer’ in the late 1970s, there has been a tendency, particularly at academic medical centers, to see all patients as potential recruits,

Comprehensive Geriatric Oncology

102

potential soldiers in that war. In the metaphorical structure, choosing no additional cancer-specific therapy can be viewed as a form of surrender. In addition, cancer therapists can become overly identified with their therapy, be it drugs or radiation, so that the patient may feel overly obligated to choose the proffered therapy so as not to reject the physician. Overtreatment has always been difficult to define with sufficient rigor to allow study using population-based methods,47 but the recent growth of interest and expertise in measuring quality of life as an outcome of cancer therapy should change that.48 The greatest concerns about overtreatment have been raised for cancer of the prostate, where improvements in screening tests have led to a dramatic increase in diagnoses.49 This in turn has led to a fourfold increase in the use of radical prostatectomy, a procedure of unproven benefit in this disease.50 This issue is discussed in the chapters of this book dealing with screening for and treatment of prostate cancer (Chapters 29 and 55).51,52 Perhaps easier to document than overtreatment of cancer is over-utilization of cancer screening tests in the elderly. The forces promoting over-utilization are complex, but include the high emotional content attached to cancer and a lack of understanding among most health professionals and the general public that over-utilization of screening tests can actually cause real harm. The arguments against screening are generally framed in economic terms—whether a given test is ‘cost-effective’ in a given population. In actuality, the strongest argument against over-utilization of screening tests is not economics: it is that they cause more harm than good. The emotional content of discussions of cancer has contributed to two strong but rarely enunciated belief systems. The first is that ‘more is better’: if Pap smears every two years are good, then yearly Paps are better: if routine mammograms in 50- to 70-year-olds reduces breast cancer deaths, then mammograms in 40-year-olds and 80-year-olds must also reduce cancer deaths, no matter what the data show. The second belief system is that any cancer screening system is efficacious until proven otherwise. The typical approach to a potential therapy is that it should be shown in rigorous prospective controlled trials to be efficacious, to reduce morbidity and/or mortality compared with no treatment or another treatment. However, with screening tests, that standard is often put on its head, and the skeptic is asked to prove that the test is not efficacious. This can lead to fairly absurd practices in the community. For example, a publication for health professionals put out by the American Association of Retired People (AARP) contained a long article describing the underutilization of mammography in nursing home patients, and several programs were proposed to overcome this deficiency.53 There was no realization that comorbidity and shortened life-expectancies often undermine the theoretical underpinnings of screening for cancer.54 A small study of primary care physicians found that some physicians felt that all nursing home residents should undergo yearly testing for occult blood in the stool as a screen for colon cancer; these physicians used no upper age cut-off and felt that the testing should proceed in the face of essentially any comorbidity.55 No screening test is benign. The test itself may be painful. False-positive results lead to undue concern as well as to follow-up testing of increasing invasiveness and morbidity.56–59 Thus, the concept that ‘it may help and certainly does not hurt’ cannot be applied to cancer screening tests, as it often seems to be. There must be convincing evidence that use of the test improves health outcomes. A more general recognition of

Factors affecting the diagnosis and treatment of older persons with cancer

103

this reality may serve to balance the forces that now advocate an unquestioning acceptance of screening for cancer in the elderly.

Table 6.6 The ‘seven danger signals of cancer’: go to your doctor to learn if your signal means cancer • Unusual bleeding or discharge • A lump or thickening in the breast or elsewhere • A sore that does not heal • Change in bowel or bladder habits • Hoarseness or cough • Indigestion or difficulty in swallowing • Change in a wart or mole These ‘danger signals’ were developed by the American Cancer Society to increase public awareness of cancer in the 1940s and 1960s. Several of them would have very poor specificity in the elderly.

Why are older people at risk for delays in diagnosis and inappropriate treatment? When the medical care system is performing some task less than well, one can assume that the task is difficult. This is an obvious but important conclusion to draw from the evidence reviewed in the previous two sections of this chapter. It is very very difficult to recognize the symptoms of cancer in an 80-year-old. As an example of the difficulties in recognizing cancer, let us consider the ‘seven danger signals of cancer’, a list of cancer symptoms that were widely publicized by the American Cancer Society from the 1940s through the 1960s (Table 6.6). The problem is that there is a high prevalence of these symptoms in the elderly without cancer. There is a background of symtomatology in the elderly population: sleep disturbance, aches and pains, constipation, lumps and bumps, and cognitive changes. A cancer-specific symptom appearing against that background is not as noticeable as it would be in a younger population. It is also difficult to make treatment decisions. Both patientand physician-related factors influence the decision to treat and the selection of a particular treatment after the diagnosis of cancer. Patient and physician decisions concerning treatment may be influenced by numerous age-dependent variables.60 These have been mentioned previously, and are summarized in Table 6.7. Adding to the difficulty is the fact that general surgeons practicing in community hospitals perform the primary treatment of most cancers. For example, most women with breast cancer are operated on in hospitals that perform fewer than 15 such cases yearly.11 The great majority of older cancer patients do not experience the multidisciplinary approach available in a typical cancer center.

Comprehensive Geriatric Oncology

104

Table 6.7 Difficulties in treating cancer in the elderly • There are few controlled trials containing sufficient numbers of elderly to allow for conclusions about efficacy • The decrease in bone marrow reserve with age leads to increase in complications from chemotherapy • There is increased perioperative mortality from cancer surgery in the elderly • The limited normal life-expectancy in the very elderly can make information on 5- and 10-year survivals in younger patients irrelevant • Older patients may have difficulty getting to multiple appointments for radiation therapy or chemotherapy because they do not drive and/or they have difficulty using public transportation • Oral prescription cancer drugs (e.g. tamoxifen and methotrexate) are expensive and not covered by Medicare • Cognitive dysfunction can lead to errors in medication and non-compliance with physician appointments and instructions

Improving the outcomes of older cancer patients Those interested in improving the lives of older cancer patients are in a bind. On the one hand, to impose standard protocols or practice guidelines on this highly heterogeneous population would be inappropriate. On the other hand, it does not seem enough to simply state that clinicians must use good judgment in tailoring the therapeutic plan depending on the specific physiologic and social state of the individual elderly patient. How does one form good judgments in the absence of information? The best approach available to the older person today is to seek care at a cancer center with special programs for the elderly.61 Clearly, several of the difficulties in cancer treatment for the elderly, as outlined in Table 6.7, are most amenable to a multidisciplinary approach, with participation by social work and nursing, supplemented by ongoing case management. Other difficulties in Table 6.7 are purely medical in nature, but presumably would also be dealt with best in a multidisciplinary facility with a sufficient volume of elderly patients to generate good clinical experience in making difficult decisions.61 Increased volume is associated with decreased complications and mortality for technically difficult procedures such as coronary angioplasty.62 One might expect a similar relationship between volume and quality for the cognitively difficult procedure of caring for the older cancer patient. References 1. Goodwin JS, Hunt WC, Key CR et al. Cancer treatment protocols. Who gets chosen? Arch Intern Med 1988; 148:2258–62.

Factors affecting the diagnosis and treatment of older persons with cancer

105

2. Holmes FF, Hearne E. Cancer stage-to-age relationship: implications for cancer screening in the elderly. J Am Geriatr Soc 1981; 29:55. 3. Breslow L. Early case finding, treatment, and mortality from cervix and breast cancer. Prevent Med 1971; 1:141. 4. Goodwin JS, Samet JM, Key CR. Stage at diagnosis varies with age of the patient. J Am Geriatr Soc 1986; 34:20–6. 5. Goodwin JS, Hunt C, Samet J. Relationship of marital status to stage at diagnosis, choice of treatment, and survival in individuals with cancer. JAMA 1987; 258:3125–30. 6. Samet JM, Hunt WC, Goodwin JS. Determinants of stage and size of cancer in elderly New Mexicans: a population based study. Cancer 1990; 66:1302–7 7. Yancik R, Havlik RJ, Wesley MN et al. Cancer and comorbidity in older patients: a descriptive profile. Ann Epidemiol 1996; 6:399–412. 8. Samet J, Key C, Hunt C, Goodwin JS. Choice of therapy varies with the age of the patient. JAMA 1986; 255:3385–90. 9. Goodwin JS, Hunt WC, Key CR, Samet JM. Changes in surgical treatments: the example of hysterectomy versus conization for cervical carcinoma in situ. J Clin Epidemiol 1990; 43:977– 82. 10. Mor V, Guadagnoli E, Silliman RA et al. Relationship between age at diagnosis and treatments received by cancer patients. J Am Geriatr Soc 1985; 33:585–9 11. Nattinger A, Gottlieb M, Hoffman RG et al. Minimal increase in use of breast-conserving surgery from 1986 to 1990. Med Care 1996; 3495:479–89. 12. Yancik R, Ries LB, Yates JW. Breast cancer in aging women: a population-based study of contrasts in stage, surgery, and survival. Cancer 1989; 63:164–9. 13. Mann B, Samet J, Key C et al. Changing treatment of breast cancer in New Mexico from 1969 through 1985. JAMA 1988; 259:3413–17. 14. Allen C, Cox EB, Manton KG et al. Breast cancer in the elderly. Patterns of care. J Am Geriatr Soc 1986; 34:637–42 15. Samet J, Hunt WC, Key C Goodwin JS. Choice of cancer therapy caries with age of patient. JAMA 1986; 255:3385–90. 16. Chu J, Diehr P, Feigl P et al. The effect of age on the care of women with breast cancer in community hospitals. J Gerontol 1987; 42:185–90. 17. Greenfield S, Blanco D, Elashof RM, Ganz PA. Patterns of care related to age of breast cancer patients. JAMA 1987; 257:2700–60. 18. Busch E, Kemeny M, Fremgen A et al. Patterns of breast cancer care in the elderly. Cancer 1996; 78:101–11. 19. Lash TL, Silliman RA, Guadagnoli E, Mor V. The effect of less than definitive care on breast carcinoma recurrence and mortality. Cancer 2000; 89:1739–47. 20. Siminnoff LA, Zhang A, Saunders Strum CM, Colabianchi N. Referal of breast cancer patients to medical oncologists after initial surgical management. Med Care 2000; 38:696–704. 21. Bergman L, Dekker G, VanLeeuwen FE et al. The effect of age on treatment choice and survival in elderly breast cancer patients. Cancer 1991; 67:2227–34. 22. Satariano ER, Swanson GM, Moll PP. Nonclinical factors associated with surgery received for treatment of early stage breast cancer. Am J Publ Health 1992; 82:195–8. 23. Bergman L, Klukck HM, VanLeewen FE et al. The influence of age on treatment choice and survival of elderly breast cancer patients in South-Eastern Netherlands. Eur J Cancer 1992; 28:1475–80. 24. Goodwin Js, Hunt WC, Samet JM. Determinants of cancer therapy in elderly patients. Cancer 1993; 72:594–601. 25. Hand R, Sener S Imperato J et al. Hospital variables associated with quality of care for cancer patients. JAMA 1991:266:3429–32. 26. Lee-Feldstein A, Anton-Culver H, Feldstein PJ. Treatment differences and prognostic factors related to breast cancer survival. JAMA 1994; 271:1163–8.

Comprehensive Geriatric Oncology

106

27. Lazovich D, White E, Thomas D et al. Underutilization of breast conserving surgery and radiation therapy among women with Stage I or II breast cancer. JAMA 1991; 266:3433–8. 28. Farrow DC, Hunt WC, Samet JM. Geographic variation in treatment of localized breast cancer. N Engl J Med 1992; 326:1097–101. 29. Du XL, Goodwin JS. Increase of chemotherapy use in older women with breast carcinoma from 1991 to 1996. Cancer 2001; 92:730–7. 30. Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomized trials. Lancet 1998; 352:930–42. 31. Du XL, Freeman JL, Freeman DH et al. Temporal and regional variation in the use of breast conserving surgery and radiotherapy for older women with early-stage breast cancer from 1983 to 1995. J Gerontol Med Sci 1999; 54:M474–8. 32. Goodwin IS. Geriatric ideology: the myth of the myth of senility. J Geriatr Soc 1991; 39:627– 32. [Also translated into German in Intercura 1992; 377:50–2.] 33. Hodgson DC, Fuchs CS, Ayanian JZ. Impact of patient and provider characteristics on the treatment and outcomes of colorectal cancer. J Natnl Cancer Inst 2001; 93:501–15. 34. Yancik R, Wesley MN, Ries LA et al. Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older. JAMA 2001; 285:885–92. 35. Nattinger AB, Gottlieb MS, Veum J et al. Geographic variation in the use of breast conserving treatment for breast cancer. N Engl J Med 1992; 326:1102–7. 36. Hand R, Sener S, Imperato J et al. Hospital variables associated with quality of care for cancer patients. JAMA 1991; 266:3429–32. 37. Samet JM, Key CR, Hunt WC, Goodwin JS. Survival of American Indians and Hispanic cancer patients in New Mexico and Arizona. J Natl Cancer Inst 1987; 79:457–63. 38. Bain RP, Greenberg RS, Whitaker JP. Racial differences in survival of women with breast cancer. J Chronic Dis 1986; 39:631–42. 39. Eloy JW, Hill H, Chun VW et al. Racial differences in survival from breast cancer. JAMA 1994; 272:947–54. 40. Bach PB, Cramer LD, Warren JL, Begg CB. Racial differences in the treatment of early-stage lung cancer. N Engl J Med 1999; 341: 1198–205. 41. Silliman RA, Troyan SL, Guadagnoli E et al. The impact of age, marital status, and physician— patient interactions on the care of older women with breast carcinoma. Cancer 1997; 80:1326– 34. 42. Goodwin IS, Hunt C, Key C, Samet JM. The effect of marital status on stage, treatment, and survival of cancer patients. JAMA 1987; 258: 3125–30. 43. Samet J, Goodwin JS. Patterns of cancer care for non-Hispanic Whites, Hispanics, and American Indians in New Mexico. In: Cancer in the Elderly (Yancik R, Yates J, eds). New York: Springer-Verlag, 1989. 44. Cantharis DA, Pouleter CA, Sischy B et al. Treatment of breast cancer among elderly women with segmental mastectomy or segmental mastectomy plus postoperative radiotherapy. Int J Radiat Oncol Biol Phys 1988; 15:263–70. 45. Clark RM, McCulloch PB, Levine MN. Randomized clinical trial to assess the effectiveness of breast irradiation following lumpectomy and axillary dissection for node-negative breast cancer. J Natl Cancer Inst 1992; 84:683–9. 46. Goodwin JS, Hunt WC, Samet JS. Determinants of survival in older cancer patients. J Invest Med 1995; 43:127A. 47. Roos NP, Black C, Roos LL et al. A population-based approach to monitoring adverse outcomes of medical care. Med Care 1995; 33: 127–38. 48. Litwin MS, Hays RD, Fink A et al. Quality of life outcomes in men treated for localized prostate cancer. JAMA 1995; 273:129–35. 49. Potosky A, Miller BA, Albeertsen PC, Kramer BS. The role of increasing detection in the rising incidence of prostate cancer. JAMA 1995; 273:548–52.

Factors affecting the diagnosis and treatment of older persons with cancer

107

50. Albertsen PC, Fryback DG, Storer BE et al. Long term survival among men with conservatively treated localized prostate cancer. JAMA 1995; 274:626–31. 51. Beghe’ C, Balducci L. Prevention of cancer in the older person. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004: 365–75. 52. Moon T. Prostate cancer in the elderly. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:725– 41. 53. Anon. Breast screening for frail and disabled older women—an over-looked population. Perspect Health Promotion Aging 1995; 10:10–12. 54. Satariano WA Ragland DR. The effect of comorbidity on 3-year survival of women with primary breast cancer. Ann Intern Med 1994; 120:104–10. 55. Klos SE, Drink P, Goodwin JS. The utilization of fecal occult blood testing in the institutionalized elderly. J Am Geriatr Soc 1991; 39: 1169–73. 56. Liberman DA. Colon cancer screening, the dilemma of positive screening tests. Arch Intern Med 1990; 150:740. 57. Allison JE, Feldman R, Tekawa IS. Hemoccult screening in detecting colorectal neoplasm: sensitivity, and predictive value. Ann Intern Med 1990; 112:328. 58. Skegg DCG. Cervical screening blues. Lancet 1995; 345:1451–2. 59. Lang CA, Ransohoff DF. Fecal occult blood screening for colorectal cancer. JAMA 1994; 271:1011–13. 60. Levy SM. The aging cancer patient: behavioral research issues. In: Perspectives on Prevention and Treatment of Cancer in the Elderly (Yancik R, ed). New York: Raven Press, 1983:83–96. 61. Schipper H, Dick J. Herodotus and the multi disciplinary clinic. Lancet 1995; 346:1312–13. 62. Jollis JG, Peterson ED, DeLong ER et al. The relationship between the volume of coronary angioplasty procedures at hospitals treating Medicare beneficiaries and short term mortality. N Engl J Med 1994; 331:1625–9.

PART 3 Biology of aging and cancer

7 Biology of aging and cancer William B Ershler Introduction Cellular senescence and malignant transformation share certain basic pathways. In fact, molecular biologists examining genes that control cellular proliferation and cell death have discovered that mutations or alterations in function of some of these genes can result in immortalized cells with malignant properties (i.e. growth factorindependent proliferation and invasiveness). Thus, at the cellular level, aging and cancer can be considered distinct steps on a spectrum of cell behavior. Recently, there has been an increased awareness of this paradigm, and basic scientists in aging and cancer are opening a dialogue that has been mutually beneficial. In this chapter, currently prevalent theories of aging will be discussed and presented in the context of their applicability to cancer biology. These include programmed (genetic) aging, protein and DNA glycation, and free-radical theories. Experimental models will be reviewed, with mention of the influence of dietary restriction in both aging and cancer development. Several key research questions will be presented for which both oncological and gerontological perspectives are critical. These include providing an explanation for the increase in cancer with advancing age as well as any change in tumor aggressiveness occurring in older hosts. Other questions, such as the frequency of multiple primary cancers in older individuals and an explanation of the apparent resistance to malignancy in the oldest old, will also be offered as subjects of importance for biomedical gerontology. Aging versus disease It is a central geriatric dogma that aging is not a disease and being old does not mean being infirm. The functional declines that accompany normal aging have been well characterized,1 but under normal circumstances do not account for symptoms of disease. For example, decline of kidney function with age is well recognized,2 and, in fact, has proven to be a useful biological marker of aging (see below). Yet, clinical consequences of this change in renal function, in the absence of a disease or the exposure to an exogenous nephrotoxic agent, do not occur commonly. Similarly, the bone marrow changes with age. Marrow stem cells are fewer and the proliferative potential of progenitor cells is less.3,4 Erythropoietin responses are blunted with advancing age,5 and low levels of anemia are commonly observed in otherwise-healthy older people. The

Comprehensive Geriatric Oncology

110

diminished bone marrow reserve is also of clinical importance in considering cytotoxic chemotherapy, since myelotoxicity is clearly greater in older cancer patients.6 There have also been distinct changes in measurable immune functions described with age (reviewed by Miller7), but the clinical consequences of these are minimal or even non-existent in the absence of disease (see the discussion below). Whether they contribute to a heightened susceptibility to infection is a subject of debate. Aging is not a disease process, but the changes of aging may make an individual susceptible to disease. For example, those described for the immune system, although not primarily a problem, may render an individual susceptible to reactivation of tuberculosis8,9 or herpes zoster10 and less capable of responding to influenza vaccine with protective titers of antibody.11,12 The immune decline, however, is not of sufficient magnitude or duration to account for the increased incidence of cancer in old people.13 In fact, we14,15 and others16–19 have shown in experimental models that immune senescence, paradoxically, may contribute to the observed reduced tumor growth and spread in a variety of tumors (see below). Lifespan, median and maximum survival From the perspective of those who study aging, an important distinction is made between median lifespan (life-expectancy) and maximum lifespan. Over the past several decades, with the advent of modern sanitation, refrigeration, and other public health measures, including vaccination and antibiotics, there has been a dramatic increase in median survival.20 Early deaths have been diminished and more individuals are reaching old age. In the USA today, life-expectancy now approaches 80 years.21 Median survival is what concerns public health officials and healthcare providers. In contrast, maximum survival is the focus of those gerontologists interested in the biology of aging and longevity. It is worthwhile to note that it has been estimated that if atherosclerosis and cancer were eliminated from the population as a cause of death, about 10 years would be added to the average lifespan, yet there would be no change in maximum lifespan.22 The oldest human being alive today is approximately 120 years old. What is intriguing is that the record has remained stable, unchanged by the public health initiatives mentioned above. In fact, data have been presented indicating that the maximum survival is actually declining in the USA.23,24 In the laboratory, similar limits have been established for a variety of species. Drosophila melanogaster, free of predators, can live 30 days, whereas C57BL/6 mice in a laboratory environment and allowed to eat a healthy diet ad libitum may survive 40 months. What is interesting is that, unlike the public health initiatives in humans, experimental interventions in lower species have been associated with a prolongation of maximum survival. In Drosophila, for example, transgenic offspring producing extra copies of the free-radical-scavenging enzymes superoxide dismutase and catalase survived about 33% longer than controls.25 However, there has been some criticism of this work based on the claim that the controls were unusually short-lived. In mammalian species, the only experimental intervention that characteristically prolongs maximum survival is the restriction of caloric intake. In fact, dietary restriction (DR) has become a common experimental paradigm exploited in the investigation of primary processes of aging (reviewed by Weindruch26).

Biology of aging and cancer

111

Briefly, DR typically involves a reduction of 30–40% in caloric intake, with careful attention being paid to the provision of adequate amounts of essential nutrients. It is associated with both a delay in the acquisition of age-related diseases and a reduction in the rate of achieving certain established biomarkers of aging (i.e. a retardation in primary aging). Furthermore, DR significantly reduces the incidence of cancer in cancer-prone animals whether the carcinogen is viral or chemical. Critical questions remain as to the nature of the mechanism of the DR effect and whether it is applicable to higher species. With regard to the latter, there are now at least four comprehensive and interactive studies within the USA in which DR is being examined in non-human primates. Although it appears that the calorie-restricted monkeys in these studies are assuming a more youthful phenotype in a variety of physiological measures,27,28 it is clearly too early to predict whether maximum survival will be affected. Aging versus time Another distinction at the heart of gerontology is that between time and aging. Time, itself, is the standard by which we predict ‘aging’, but in fact it is commonly appreciated that cells, tissues, organs, and organisms ‘age’ at different rates. In contrast, ‘aging’ is thought of as the phenotypic change that occurs over time and results in alteration of function or appearance. By and large, these changes result in limitations on functional reserve and in an increased susceptibility to disease. However, it is currently nearly impossible to predict what the rate of aging will be in any particular system. There is no question that humans age at different rates, and yet, at birth, there is no certain way to know for an individual what their aging pattern will be like. Genetic composition is critical, but it does not tell the whole story. For example, genetically identical mice may have quite diverse rates of acquiring biological hallmarks of advancing age and even remarkably different lifespans. Nonetheless, there are genes that portend lifespan, and inbred species have been very instructive in their elucidation. Thus, there are long-lived and short-lived strains, and their genetic composition is the subject of intense investigation with regard to the identification of longevity-associated genes and biological aging. Some short-lived strains have shortened survival due to the predisposition to certain diseases, and these are not considered good models for normal aging. The New Zealand Black (NZB) mouse, for example, acquires a dysregulated immune system and a disease similar to lupus erythematosus that leads to premature death.29 Although an excellent model for lupus, the NZB mouse dies young (at about 12 months) without achieving disease-independent markers of older age, and is not a good animal for aging research. In contrast, it appears that the heartiest strains—those with the longest survival and the least predisposition to early disease—are genetic hybrids that have a demonstrated maximum survival of 4 years or beyond when subjected to DR paradigms.30 It is important to note that, within a specific strain, there is some homogeneity in the pattern of aging. Accordingly, C57BL/6 mice fed ad libitum are likely to live 24–26 months, and half at this age will have or will develop lymphoma.31 Fisher 344 rats have a slightly longer survival, but have a propensity to develop renal failure late in life.32 Biomedical gerontologists have become familiar with these patterns of aging and disease,

Comprehensive Geriatric Oncology

112

and, by necessity, have selected relevant animal models for their investigations. A general rule, however, is that short-lived strains, particularly those with a genetic susceptibility to life-threatening diseases, are not good models for aging research. In contrast, factors that influence maximum survival in robust hybrid strains probably do so by interfering with primary aging processes, and make excellent models. Cellular versus organismal aging Much has been written about cellular senescence and the events that lead up to cell death (reviewed by Cristofalo and Pignolo33). After a finite number of divisions, normal somatic cells invariably enter a state of irreversibly arrested growth—a process termed ‘replicative senescence’.34 In fact, it has been proposed that escape from the regulators of senescence is what oncologists term ‘malignant transformation’. However, the role of replicative senescence as an explanation of organismal aging remains the subject of vigorous debate. The controversy relates, in part, to the fact that certain organisms (e.g. Drosophila and Caenorhabditis elegans) undergo an aging process, yet all of their adult cells are postreplicative. What is clear is that the loss of proliferative capacity of human cells in culture is intrinsic to the cells and is not dependent on environmental factors or even culture conditions.34 Unless transformation occurs, cells age with each successive division. The number of divisions turns out to be more important than the actual amount of time passed. Thus, cells held in a quiescent state for months, when allowed back into a proliferative environment, will continue approximately the same number of divisions as those that were allowed to proliferate without a quiescent period.35 The question remains whether this in vitro phenomenon is relevant to animal aging. One suggestive observation is that fibroblasts cultured from samples of old skin undergo fewer cycles of replication than those from young.36 Furthermore, when various species are compared, replicative potential is directly and significantly related to lifespan.37 An unusual β-galactosidase, whose activity peaks at pH 6 has proved to be a useful biomarker of in vitro senescence because it is expressed by senescent but not presenescent or quiescent fibroblasts.38 This unusual β-galactosidase isoform was found to have the predicted pattern of expression in skin from young and old donors.38 Thus, there was an age-associated increase in pH 6 β-galactosidase present in dermal fibroblasts and epidermal keratinocytes, providing an in situ correlate of replicative senescence. The nature of the expression of this in vivo biomarker of aging in other tissues will be important to discern. Biomedical gerontology: key research areas Although by no means a comprehensive list, in the subsections below, we mention topics of current investigative interest for biogerontologists.

Biology of aging and cancer

113

Table 7.1 Theories of aging Intrinsic-stochastic

Somatic mutation40,41 Intrinsic mutagenesis45 Impaired DNA repair46 Error catastrophe47

Extrinsic-stochastic

Ionizing radiation40,41,43,49 Free-radical damage52,53

Genetically determined

Neuroendocrine91 Immune68

Theories of aging Providing a rational, unifying explanation for the aging process has been the subject of a great number of theoretical expositions (Table 7.1). Yet, no single proposal suffices to account for the complexities observed. That genetic controls are involved seems obvious when one considers that lifespan is highly species-specific. That is, mice generally live about 2 years and humans about 90. However, the aging phenomenon is not necessarily a direct consequence of primary DNA sequence. For example, mice and bats have 0.25% difference in their primary DNA sequence, but bats live for 25 years—10 times longer than mice. Thus, regulation of gene expression seems likely to be the source of species’ longevity differences. Although within a species there is considerable variation in longevity, this variability is much less with inbred strains or among monozygotic twins, when compared with dizygotic twins or non-twin siblings. Also, various genetically determined syndromes have remarkable (albeit incomplete) features of accelerated aging. These include Hutchinson-Gilford syndrome (early-onset progeria), Werner syndrome (adult-onset progeria), and Down syndrome.39 Although no progeria syndrome manifests a complete phenotype of advanced age, the identification of the genes responsible for these particular syndromes is beginning to pay dividends by providing clues to the molecular mechanisms involved in the aging process. For example, Werner syndrome is now known to be caused by mutations in a single gene on chromosome 8 that encodes a protein containing a helicase-like domain.40,41 The future functional characterization of this specific protein will, no doubt, increase our level of understanding of the aging process. Examination of aging in yeast has also been informative with regard to the genetic controls of aging. These single-cell organisms follow the replicative limits of mammalian cells, and it has been observed that ‘lifespan’ is related to silencing large chromosomal regions. Mutations in these silencing genes lead to increased longevity.42 Thus, if there are certain genes that regulate normal aging—or at least are associated with the development of an aged phenotype—then it stands to reason that acquired damage to those genes might influence the rate of aging. Over the years, several theories have been proposed that relate to this supposition. In general, they hypothesize a random or stochastic accumulation of damage—to either DNA or protein—that leads eventually

Comprehensive Geriatric Oncology

114

to dysfunctional cells, cell death, and subsequent organ dysfunction and ultimately organism death. Prominent among these is the somatic mutation theory,43 which predicts that genetic damage from background radiation, for example, accumulates and produces mutations and results in functional decline. A variety of refmements have been suggested to this theory, invoking the importance of mutational interactions,44 transposable elements,45 and changes in DNA methylation status.46 A related hypothesis is Burnet’s intrinsic mutagenesis theory,47 which proposes that spontaneous or endogenous mutations occur at different rates in different species and that this accounts for the variability observed in lifespan. Closely related to this notion is the DNA-repair theory.48 Initially, there was great excitement about this, since it was found that long-lived animals had demonstrably greater DNA-repair mechanisms than shorterlived species.48 However, longitudinal studies within species have not revealed a consistent decline in repair mechanisms with age. This, of course, does not rule out the possibility that repair of certain specific and critical DNA lesions is altered with advancing age. We now understand that there are multiple DNA-repair mechanisms, including base excision repair, transcription-coupled repair, and, most recently, even DNA-repair mechanisms based in mitochondria. Disorders involving one or a subset of repair mechanisms could lead to accumulation of DNA damage and dysfunction. In yet another intrinsic/stochastic model—the error catastrophe theory proposed by Orgel49—it is suggested that random errors in protein synthesis occur, and when the proteins involved are those responsible for DNA or RNA synthesis, there is resultant DNA damage and the consequences thereof to daughter cells. Although this model has appeal, there has been no reported evidence of impaired or inaccurate protein synthesis machinery with advancing age. However, a candidate protein that may eventually be shown to be so affected is telomerase. This critical enzyme composed of protein plus an RNA template is necessary for maintaining telomere length and cell replicative potential. As cells senesce in vitro, telomerase activity declines, telomeres shorten, and ultimately replicative potential is lost.50 Evidence that exogenous factors are involved in the acquisition of age-associated damage to DNA and protein is derived from a number of observations, many of which are circumstantial or correlative, but nonetheless provocative. It now appears that the accumulation of abnormal protein within senescent cells, as predicted by the error catastrophe theory, actually reflects postranslational events, such as oxidation or glycation and resultant crosslinking. There is theoretic appeal to the concept that key proteins, such as collagen or other extracellular matrix proteins, and DNA become dysfunctional with age due to the impairment produced by these crosslinks.51–53 One mechanism producing crosslinks is called glycation, the non-enzymatic reaction of glucose with the amino groups of proteins. Presumably, glycation would occur more readily in the presence of higher serum levels of glucose, and thus this theory fits well with the observed, age-associated dysregulation of glucose metabolism and prevalent hyperglycemia in geriatric populations. Of course, this also points out its deficiency as a unifying mechanism, since there is no question that individuals with well-maintained glucose levels throughout their lifespan will still be subject to acquired changes typical of aging. Another mechanism held responsible for crosslinking is the damage produced by free radicals, and this forms the basis of the free-radical hypothesis initially promoted by

Biology of aging and cancer

115

Harman.54,55 This theory proposes that aging is the result of DNA and protein damage (e.g. mutagenesis or crosslinking) by atoms or molecules that contain unpaired electrons (free radicals). These highly reactive species are produced as byproducts of a variety of metabolic processes and are normally inhibited by intrinsic cellular antioxidant defense mechanisms. If free-radical generation increases with age, or the defense mechanisms that scavenge free radicals (e.g. glutathione) or repair free-radical damage decline, then the accumulated free-radical damage may account for altered DNA and protein function. Evidence to support this widely held notion is incomplete. It is known that free-radical generation in mammals correlates inversely with longevity,56 and, similarly, the level of free-radical-inhibiting enzymes (e.g. superoxide dismutase) were higher in those species with longer lifespans.57 However, efforts at enhancing antioxidant mechanisms with dietary vitamin E have resulted in only a modest enhancement of median survival in mice and no effect on maximum lifespan.58 Much attention has been focused on mitochondrial function in the context of freeradical damage, because the bulk of oxidative metabolism and the production of reactive oxygen species occurs in these organelles. Although mitochondrial DNA codes for antioxidant enzymes in addition to enzymes involved in energy production, it is currently believed that energy production declines with age, owing to mitochondrial DNA damage by those reactive products. Indeed, mitochondrial damage increases with age in experimental models,59–61 and the shortened survival of knockout mice deficient in mitochondrial antioxidant enzymes has supported the potential importance of this mechanism.62 The most compelling data to date in support of the free-radical hypothesis come from the experiments of Orr and Sohal25 in which transgenic Drosophila producing enhanced levels of superoxide dismutase and catalase had a maximum survival 33% greater than that of controls. Furthermore, it is known that flies produce high levels of free radicals associated with their impressive metabolic requirements, and that survival is enhanced dramatically when the ability to fly is experimentally hindered.63 However, the generalizability of these findings has been questioned. Some have criticized the transgenic Drosophila experiment, claiming that the controls were rather short-lived. Furthermore, transgenic mice overexpressing free-radical-scavenging enzymes have shown very modest effects on lifespan.64 Thus, the conclusion that augmentation of freeradical-scavenging mechanisms increases longevity cannot be considered a proven fact. From a different perspective, there is also very good evidence implicating nonrandom, perhaps genetically regulated, endogenous mechanisms involved in aging. For example, the neuroendocrine theory suggests that the decrements in neuronal and associated hormonal function are central to aging. It has been suggested that ageassociated decline of hypothalamic-pituitary-adrenal axis function results in a physiological cascade leading ultimately to the ‘frail’ phenotype. This hypothesis is appealing because it is well established that this neuroendocrine axis regulates much of development and also the involution of ovarian and testicular function. Furthermore, ageassociated declines in growth hormone and related factors,65 in dehydroepiandrosterone,66 and in secondary sex steroids67 have been implicated in age-associated impairments, including a reduction in lean body mass and bone density. Furthermore, pharmacological reconstitution using these or related hormones has met with some success in reversing age-associated functional decline.68,69

Comprehensive Geriatric Oncology

116

Similarly, it has been argued that involution of the thymus gland and subsequent decline in immune function is a key regulator of aging.70 The argument is based upon the observation that the decline in immune function occurs in all mammalian species, but occurs later in those with longer survival.71 Furthermore, dietary restriction is associated with maintained thymic mass and measurable immune function, as well as prolonged survival, suggesting an association of a decline in immunity with primary aging processes. The possibility is highlighted by the observation that differences in maximum survival of different mouse strains have been associated with specific alleles in the major histocompatibility complex (MHC), which in turn code for immunological determinants.72 This hypothesis, although not without its appeal, is not widely accepted as a major explanation for aging. Perhaps this relates to the fact that biological aging is a universal phenomenon and certain features are held in common, even in organisms with primitive or no immune function. (The same could also be said for the neuroendocrine theory.) It is obvious that the immune system is of great importance in minimizing the chance of early death, particularly from infectious diseases. Accordingly, median lifespan is clearly influenced by competent immunity. However, immunological reconstitution of middle-aged or old animals has not been shown to prolong survival.73 Biological markers of aging A major concern for researchers in the field is the ability to measure aging, as distinct from disease, in a whole animal or human. Accordingly, the concept of a panel of species-specific biological markers of normal aging has been espoused (reviewed by Baker and Sprott74), and the US National Institute on Aging has sponsored a major program initiative to develop such a panel of markers. The ideal biomarker would be one that changes in a characteristic pattern with the passage of time, is not (or is only minimally) altered by age-associated diseases, and allows prediction of both ‘physiological age’ and expected lifespan. Candidate biomarkers in various species are listed in Table 7.2.

Table 7.2 A sampling of candidate biomarkers of aging Marker Cells in culture

β-Galactosidase36 Telomere length48 Marrow stromal colony size92

Flies

Protein carbonyl content93 Mitochondrial H2O2 relaease94

Mice, rats

Striatal dopamine receptors95 Ca2+ ionophore lymphocyte response96 Tail tendon fiber strength97

Biology of aging and cancer Monkeys

117

Mitochondrial DNA damage57 Presbyopia98 Fingernail growth rate99 lnterleukin-6 level100

Humans

Glycation end-products101 Mitochondrial DNA damage59 β-Galactosidase in skin biopsy36 Lenticular glutathione102 Presbyopia103 DNA unwinding rate104

Immunity and aging There is a well-characterized deficit in immune function with advancing age (reviewed by Miller7), but, as mentioned above, the consequences are not fully established. It is apparent that otherwise-healthy older individuals are more susceptible to reactivation of tuberculosis8,9 or herpes zoster,10 and responses to vaccines, such as the commercially available and widely used influenza hemagglutinin, are lower.11,12 However, it has been postulated that other age-associated diseases, such as cancer,75 atherosclerosis,76 diabetes,77 and even Alzheimer’s disease,78,79 have been related to the decline in immune function with age. More recent evidence, though, would argue that inflammation may contribute to Alzheimer’s disease (see below). What can be said with confidence is that there are changes in T-cell function with age that result in decreased proliferation when measured in vitro.80 When studied as a population, there appears to be an accumulation of T cells with cell surface characteristics of memory cells, whereas, in contrast, there is a relative decrease in naive T cells.81 B-cell function, including the capacity to make antibody, remains intact, although certain intrinsic alterations have been noted.82 Immunoregulatory functions are affected by the aging process, and paraproteinemia and autoantibody are observed with increasing frequency with each advancing decade. In general, the paraproteinemia is an indicator of dysregulated immunity, but it is considered not to be the antecedent of multiple myeloma.83–85 However, myeloma does increase in incidence in geriatric populations, and it must be distinguished from the benign paraproteinemia of aging. Typically, this is accomplished by examination of bone marrow, skeletal X-rays, and renal function.86 Another indication of dysregulated immune function is the alterations in certain key cytokines, measured in plasma, culture supernatants, or the appropriate tissue microenvironment. Notably and consistently, interleukin2 (IL-2) levels and function decrease with age,87 and IL-6 levels increase.88 The decline in IL-2 may account for a significant component of the measured decline in T-cell function, and the increased IL-6 has been implicated in the pathogenesis of certain age-associated diseases, including osteoporosis, Alzheimer’s disease, and cancer.89,90

Comprehensive Geriatric Oncology

118

Common ground: cancer and aging By virtue of demography, cancer may now be considered a geriatric syndrome, and clinicians trained to treat adults with cancer should be aware that their patient population will be gradually becoming older. The focus upon common pathways in malignant transformation, cellular immortality, and senescence by both gerontologists and oncologists is a clear indication that the disciplines of gerontology and oncology have much in common. Thus, free radicals, telomeres and telomerase, tumor suppressor genes, cellular proliferation, and genetic control are among the many common research fronts. With the aging of the population, and the increased frequency of cancer, a research agenda that relates both to primary aging and cancer biology is of obvious importance. Among the important basic clinical research questions to address are the following: 1. What determines whether the accumulation of genetic damage in a particular cell leads to death, growth arrest/senescence, or neoplasia? 2. Which genes regulate cellular aging, and do they relate to organismal aging? 3. To what extent does free-radical damage contribute to aging and/or cancer, and can this damage be prevented? 4. How can we explain the increased frequency of multiple primary tumors that occurs with advancing age? 5. What is the influence of comorbidity on cancer outcome in the elderly? 6. What functional assessments will best predict how an individual patient will respond to treatment (i.e. toxicity versus response)? 7. What cancers are biologically similar across the lifespan, and what cancers seem to be biologically distinct as a function of age? 8. Is there an inherent resistance to cancer development in the oldest-old age group (i.e. those over the age of 85), and if there is, then what is the mechanism? References 1. Duthie EH. Physiology of Aging: Relevance to Symptoms, Perceptions and Treatment Tolerance. Singapore: UTAPS, 1997. 2. Lindeman RD. Overview: renal physiology and pathophysiology of aging. Am J Kidney Dis 1990; 16:275–82. 3. Harrison DE. Proliferative capacity of erythropoietic stem cell lines and aging: an overview. Mech Ageing Dev 1979; 9:409–26. 4. Harrison DE, Astle CM, Stone M. Numbers and functions of transplantable primitive immunohematopoietic stem cells. Effects of age. J Immunol 1989; 142:3833–40.

Biology of aging and cancer

119

5. Artz AS, Fergusson D, Drinka PJ et al. Prevalence of anemia in skilled nursing home residents. Submitted. 6. Balducci L, Hardy CL, Lyman GH. Hemopoietic reserve in the older cancer patient: clinical and economic considerations. Cancer Control 2000; 6:539–47. 7. Miller RA. Aging and immune function. Int Rev Cytol 1991; 124: 187–209. 8. Dubrow EL. Reactivation of tuberculosis; a problem of aging. J Am Geriatr Soc 1976; 24:481–7. 9. Nagami PH, Yoshikawa TT. Tuberculosis in the geriatric patient. J Am Geriatr Soc 1983; 31:356–63. 10. Gelato MC. Aging and immune function: a possible role for growth hormone. Hormone Res 1996; 45:46–9. 11. Arden NH, Patriarca PA, Kendal AP. Experiences in the use and efficacy of inactivated influenza vaccine in the nursing home. In: Options for the Control of Influenza (Kendal AP, Patriarca PA, eds). New York: Alan R Liss, 1986:155–68. 12. Powers DC, Sears SD, Murphy BR et al. Systemic and local antibody responses in elderly subjects give live or inactivated influenza A virus vaccines. J Clin Microbiol 1989; 27:2666–71. 13. Kaesberg PR, Ershler WB. The importance of immune senescence in the incidence and malignant properties of cancer in hosts of advanced age. J Gerontol 1989; 44:63–6. 14. Ershler WB, Stewart JA, Hacker MP et al. B16 melanoma and aging: Slower growth and longer survival in old mice. J Natl Cancer Inst 1984; 72:161–4. 15. Ershler WB, Moore AL, Shore H, Gamelli RL. Transfer of age-associated restrained tumor growth in mice by old to young bone marrow transplantation. Cancer Res 1984; 44:5677–80. 16. Stjernsward J. Age-dependent tumor host barrier and effect of carcinogen-induced immunodepression on rejection of isografted methylcholanthrene-induced sarcoma cells. J Natl Cancer Inst 1966; 37:505–12. 17. Yuhas JM, Pazmino NH, Proctor JO, Toya RE. A direct relationship between immune competence and the subcutaneous growth rate of a malignant murine lung tumor. Cancer Res 1974; 34:722–28. 18. Rockwell SC. Effect of host age on transplantation, growth and radiation response of EMT6 tumors. Cancer Res 1981; 41:527–31. 19. Tsuda T, Kim YT, Siskind GW et al. Role of the thymus and T cells in slow growth of B16 melanoma in old mice. Cancer Res 1987; 47: 3097–102. 20. Christensen K, Vaupel JW. Determinants of longevity: genetic, environmental and medical factors. J Intern Med 1996; 240:333–41. 21. Guyer B, Strobino DM, Ventura SJ et al. Annual summary of vital statistics—1995. Pediatrics 1996; 98:1007–19. 22. Greville TNE. US life tables by cause of death: 1969–1971. In: US Decennial Life Tables for 1969–1971, Vol 1. Washington, DC: US Government Printing Office, 1971:5–15. 23. Riggs JE. Longitudinal Gompertzian analysis of adult mortality in the US, 1900–1986. Mech Ageing Dev 1990; 54:235–47. 24. Hirsch HR. Can an improved environment cause maximum survival to decrease? Comments on lifespan criteria and longitudinal Gompertzian analysis. Exp Gerontol 1994; 29:119–37. 25. Orr WC, Sohal RS. Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster. Science 1994; 263:1128–30. 26. Weindruch R. Caloric restriction and aging. Sci Am 1996; 274:46–52. 27. Nakamura E, Lane, MA, Roth GS, Ingram DK. Evaluating measures of hematology and blood chemistry in male rhesus monkeys as biomarkers of aging. Exp Gerontol 1994; 29:151–77. 28. Kemnitz JW, Weindruch R, Roecker EB et al. Dietary restriction of adult male Rhesus monkeys: design, methodology, and preliminary findings from the first year of study. J Gerontol 1993; 48: B17–26. 29. East J, Prosser PR. Autoimmunity and malignancy in New Zealand black mice. Proc R Soc Med 1967; 60:823–5.

Comprehensive Geriatric Oncology

120

30. Weindruch R, Walford RL. Dietary restriction in mice beginning at 1 year of age. Science 1982; 215:1415–18. 31. Pattengale PK, Taylor, CR. Experimental models of lymphoproliferative disease. The mouse as a model for human non-Hodgkin’s lymphomas and related leukemias. Am J Pathol 1983; 113:237–65. 32. Weindruch R, Masoro, EJ. Concerns about rodent models for aging research. J Gerontol 1991; 3: B87–8. 33. Cristofalo VJ, Pignolo, RJ. Replicative senescence of human fibroblast-like cells in culture. Physiol Rev 1993; 73:617–38. 34. Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 1965; 37:614–36. 35. Cristofalo VJ, Palazzo, R, Charpentier, RL. Limited lifespan of human fibroblasts in vitro: metabolic time or replications? In: Neural Regulatory Mechanisms During Aging (Adelman RC, Roberts J, Baker GT, eds). New York: Alan R Liss, 1980. 36. Schneider EL, Mitsui Y. The relationship between in vitro cellular aging and in vivo human age. Proc Natl Acad Sci USA 1976; 73: 3584–88. 37. Rohme D. Evidence for a relationship between longevity of mammalian species and lif-spans of normal fibroblasts in vitro and erythrocytes in vivo. Proc Natl Acad Sci USA 1976; 78:5009–13. 38. Dimri GP, Lee X, Basile G et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 1995; 92:9363–7. 39. Martin GM. The genetics of aging. Hosp Pract 1997; 32:47–50. 40. Yu CE, Oshima J, Fu YH et al. Positional cloning of the Werner’s syndrome gene. Science 1996; 272:258–62. 41. Yu CE, Oshima J, Wijsman EM et al. Mutations in the consensus helicase domains of the Werner syndrome gene. Am J Genet 1997; 60:330–41. 42. Kennedy BK, Guarente L. Genetic analysis of aging in Saccharomyces cerevisiae. Trends Genet 1996; 12:355–9. 43. Szilard L. On the nature of the aging process. Proc Natl Acad Sci USA 1959; 45:30–5. 44. Morley AA. Is aging the result of dominant or co-dominant mutations? J Theor Biol 1982; 98:469–74. 45. Cummings DJ. Mitochondrial DNA in Podopora anserina: a molecular approach to cellular senescence. Monogr Dev Biol 1984; 17: 254–66. 46. Fairweather S, Fox, M, Margison BP. The in vitro lifespan of MRC-5 cells is shortened by 5azacytidine-induced demethylation. Exp Cell Res 1987; 168:153–8. 47. Burnet M. Intrinsic Mutagenesis: A Genetic Approach for Aging. New York: Wiley, 1974. 48. Hart RW, Setlow RB. Correlation between deoxyribonucleic acid excision-repair and lifespan in a number of mammalian species. Proc Natl Acad Sci USA 1974; 71:2169–73. 49. Orgel LE. The maintenance of the accuracy of protein synthesis and its relevance to aging. Proc Natl Acad Sci USA 1963; 49:517–21. 50. Allsop RC, Vaziri H, Patterson C et al. Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci USA 1992; 89:10114–8. 51. Bjorksten J. Cross linkage and the aging process. In: Theoretical Aspects of Aging (Rothstein M, ed). New York: Academic Press, 1974: 43. 52. Kohn RR. Aging of animals: Possible mechanisms. In: Principles of Mammalian Aging, 2nd edn. Englewood Cliffs, NJ: Prentice-Hall, 1978. 53. Kreisle RA, Stebler B, Ershler WB. Effect of host age on tumor associated angiogenesis in mice. J Natl Cancer Inst 1990; 82:44–7. 54. Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol 1956; 11:298–300. 55. Harman D. The aging process. Proc Natl Acad Sci USA 1981; 78: 7124–8. 56. Sohal RS, Svensson I, Sohal BH, Brunk UT. Superoxide radical production in different animal species. Mech Ageing Dev 1989; 49: 129–35.

Biology of aging and cancer

121

57. Sohal RS, Sohal BH, Brunk UT. Relationship between antioxidant defenses and longevity in different mammalian species. Mech Ageing Dev 1990; 53:217–27. 58. Sohal RS, Allen RG. Oxidative stress as a causal factor in differentiation and aging: a unifying hypothesis. Exp Gerontol 1990; 25:499–522. 59. Lee CM, Chung SS, Kaczkowski JM et al. Multiple mitochondrial DNA deletions associated with age in skeletal muscle of rhesus monkeys. J Gerontol 1993; 48: B201–5. 60. Schwarze SR, Lee CM, Chung SS et al. High levels of mitochondrial DNA deletions in skeletal muscle of old rhesus monkeys. Mech Ageing Dev 1995; 83:91–101. 61. Melov S, Shoffner JM, Kaufman A, Wallace DC. Marked increase in the number and variety of mitochondrial DNA rearrangements in aging human skeletal muscle. Nudeic Acids Res 1995; 23:4122–6. 62. Li Y, Huang YY, Carlson EJ et al. Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat Genet 1995; 11:376–81. 63. Sohal RS. Hydrogen peroxide production by mitochondria may be a biomarker of aging. Mech Ageing Dev 1991; 60:189–98. 64. Epstein CJ, Avraham KB, Lovett M. Transgenic mice with increased Cu/Zn-superoxide dismutase activity: animal model of dosage effects in Down’s syndrome. Proc Natl Acad Sci USA 1987; 84:8044–8. 65. Harris TB, Roubenoff RR, Langlois J et al. Association of insulin-like growth factor-I with body composition, weight history, and past health behaviors in the very old: the Framingham Heart Study. J Am Geriatr Soc 1997; 45:133–9. 66. Birkenhager-Gillesse EG, Derkson J, Lagaay AM. Dehydroepiandrosterone sulfate (DHEAS) in the oldest old, aged 85 and over. Ann NY Acad Sci 1994; 719:543–2. 67. Rudman D, Drinka PJ, Wilson CR et al. Relations of endogenous anabolic hormones and physical activity to bone mineral density and lean body mass in elderly men. Clin Endocrinol 1994; 40:653–61. 68. Rudman D, Feller AG, Nagraj HS et al. Effects of human growth hormone in men over 60 years old. N Engl J Med 1990; 323:1–6. 69. Hobbs CJ, Plymate SR, Rosen CJ, Adler RA. Testosterone administration increases insulin-like growth factor-1 levels in normal men. J Clin Endocrinol Metab 1993; 77:776–9. 70. Walford R. The Immunologic Theory of Aging. Copenhagen: Munksgard, 1969. 71. Makinodan T, Kay MMB. Age influence on the immune system. Adv Immunol 1980; 29:287– 330. 72. Smith GS, Walford RL. Influence of the main histocompatibility complex on aging in mice. Nature 1977; 270:727–9. 73. Hirokawa K, Albright JW, Makinodan T. Restoration of impaired immune function in aging animals. I. Effect of syngeneic thymus and bone marrow grafts. Clin Immunol Immunopathol 1985.; 5:371–6. 74. Baker GT, Sprott RL. Biomarkers of aging. Exp Gerontol 1988; 23: 223–39. 75. Gatti RQ, Good RA. Aging, immunity and malignancy. Geriatrics 1979; 25:158–68. 76. Bulychev W. Longevity, atherosclerosis and cellular immunity. Klin Med (Mosk) 1993; 71:51– 4. 77. Lehuen A, Bendelac A, Bach JF, Carnaud C. The nonobese diabetic mouse model. Independent expression of humoral and cell mediated autoimmune features. J Immunol 1990; 144:2147–51. 78. Hull M, Strauss S, Berger M et al. The participation of interleukin6, a stress-inducible cytokine, in the pathogenesis of Alzheimer’s disease. Behav Brain Res 1996; 78:37–41. 79. Hull M, Fiebich BL, Lieb S et al. Interleukin-6-associated inflammatory processes in Alzheimer’s disease: New therapeutic options. Neurobiol Aging 1996; 17:795–800. 80. Gillis S, Kozak R, Durante M, Weksler ME. Decreased production and response to T cell growth factor by lymphocytes from aged humans. J Clin Invest 1981; 67:937–42. 81. Miller RA. The aging immune system: primer and prospectus. Science 1996; 273:70–4.

Comprehensive Geriatric Oncology

122

82. Stephan RP, Sanders VM, Witte PL. Stage-specific alterations in murine lymphopoiesis with age. Int Immunol 1996; 8:509–18. 83. Radl J, Sepers JM, Skvaril F. Immunoglobulin patterns in humans over 95 years of age. Clin Exp Immunol 1975; 22:84–90. 84. Radl J. Animal model of human disease. Benign monoclonal gammopathy (idiopathic paraproteinemia). Am J Pathol 1981; 105: 91–3. 85. Radl J. Age-related monoclonal gammopathies: clinical lessons from the aging C57BL/6 mouse. Immunol Today 1990; 11:234–6. 86. Kyle RA. Monoclonal gammopathy of undetermined significance and solitary plasmacytoma. Implications for progression to overt myeloma. Hematol Oncol Clin North Am 1997; 11:71–87. 87. Thoman M, Weigle WO. Lymphokines and aging: interleukin-2 production and activity in aged animals. J Immunol 1981; 127: 2102–6. 88. Ershler WB, Sun WH, Binkley N. Interleukin-6 and aging: blood levels and mononuclear cell production increase with advancing age and in vitro production is modifiable by dietary restriction. Lymphokine Cytokine Res 1993; 12:225–30. 89. Ershler WB. Interleukin-6: a cytokine for gerontologists. J Am Geriatr Soc 1993; 41:176–81. 90. Ershler WB, Keller ET. Age-associated increased IL-6 gene expression, late-life diseases and frailty. Annu Rev Med 2000; 51:245–270. 91. Knight JA. The biochemistry of aging. Adv Clin Chem 2000; 35: 1–62. 92. Justesen J, Stenderup K, Erksen EF et al. Maintenance of osteoblastic and adipocytic differentiationpotential with age and osteoporosis in human marrow stromal cell cultures. Cakif Tissue Int 2002; 71:36–44. 93. Das N, Levine RL, Orr WC et al. Selectivity of protein oxidative damage during age in Drosophila melanogaster. Biochem J 2002; 15:209–16. 94. Huamg H, Manton KG. The role of oxidative damage in mitochondria during aging: a review. Front Biosci 2004; 9:1100–17. 95. Anderson B, Gattley SJ, Rapp DN et al. The ratio of striatal Dl to muscarinic receptors changes in aging mice housed in an enriched environment. Brain Res 2000; 28:262–5. 96. Wu J, Zeng YX, Hirokawa K. Signal pathway of mitogen-induced Ca2+ activated K+ currents in young and aged T cell clones of C57BL/6 mice. Cell Sign 1999; 11:391–8. 97. Bochantin J, Mays LL. Age-dependence of collagen tail fiber breaking strength in Sprague Dawley and Fischer 344 rats. Exp Gerontol 1981; 16:101–6. 98. Glasser A, Croft MA, Brumback L et al. Ultrasound biomicroscopy of the aging Rhesus monkey ciliary. Optom Vis Sci 2001; 78: 417–24. 99. Williams DD, Short R, Bowden DM. Fingernail growth rate as a biomarker of aging in pigtailed macaque. Exp Gerontol 1990; 25: 423–32. 100. Mascarucci P, Taub D, Saccani S et al. Cytokine responses in young and old rhesus monkeys: effects of caloric restriction. J Interferon Cytokine Res 2002; 22:565–71. 101. Wu X, Monnier VM. Enzymatic deglycation of proteins. Arch Biochem Biophys 2003; 419:16–24. 102. Sweeney MH, Truscott RJ. An impediment to glutathione diffusion in older normal humans: a possible precondition for nuclear cataracts. Exp Eyes Res 1998; 67:587–95. 103. Haron G, Charman WN, Gray LS. Accommodation dynamics as a function of age. Ophthalm Physiol Opt 2002; 22:389–96. 104. Chicca MC, Nesti C, Muzzoli M et al. Correlation between age and DNA damage detected by FADU in human peripheral blood lymphocytes. Mutat Res 1996; 316:201–8.

8 Age as a risk factor in multistage carcinogenesis Vladimir N Anisimov Introduction Cancer is a common cause of disability and death in the elderly: over 50% of malignant neoplasms occur in persons over 70.1–3 The relationship between aging and cancer is not clear: considerable controversy surrounds the mechanisms that lead to increased incidence of cancer in the aged. Two major hypotheses have been proposed to explain the association of cancer and age. The first holds this association to be a consequence of the duration of carcinogenesis. In other words, the sequential carcinogenic steps that are required for the neoplastic transformation of normal tissues develop over several years and cancer is more likely to become manifest in older individuals by a process of natural selection.4,5 In an article entitled, ‘There is no such thing as aging, and cancer is not related to it’, Peto et al5 have proposed that the high prevalence of cancer in older individuals simply reflects a more prolonged exposure to carcinogens. In the view of these authors, the incidence of cancer is a power function of the duration of carcinogen exposure, rather than a power function of the tumor host age. The second hypothesis proposes that age-related progressive changes in the internal milieu of the organism may provide an increasingly favorable environment for the induction of new neoplasms and for the growth of already-existing, but latent malignant cells.6,7 The internal milieu includes cells and tissue microenvironment. Predisposing factors to carcinogenesis include age-related disturbances in metabolism and DNA repair, immune senescence, and decreased ability of the tissue microenvironment to inhibit cell proliferation and to favor cell differentiation.6,8–10 These hypotheses have been reviewed elsewhere.6–8 The elucidation of causes of an age-related increase in cancer incidence may be the key to a strategy for primary cancer prevention. Age and spontaneous tumor development It is well documented that the incidence of malignant tumors increases progressively with age, in both animals and humans.1–3,6,11 The term ‘spontaneous tumors’ may be misleading, since the majority of these neoplasms are caused by environmental factors, including tobacco smoking, diet, alcohol consumption, sexual promiscuity, industrial byproducts, ultraviolet radiation, drugs, and oncogenic viruses.12 The overall incidence of cancer increases with age, but this increment is not uniform for all types of cancer. In animals, genetic influences seem to control the occurrence of age-related cancers, which are to a large extent speciesand strain-specific.6 For example, 80–90% of AKR mice develop fatal leukemia between the ages of 7 and 10 months,

Comprehensive Geriatric Oncology

124

whereas 90% of 18-month-old strain A mice develop pulmonary adenomas. A similar incidence of spontaneous hepatoma is seen in 14-month-old male C3H mice, whereas mammary adenocarcinoma affects 90% of 18-month-old females of the same strain. Endocrine tumors arise in 80–85% of older rats from some specific strains. To examine whether a cooperative role exists between inherited p53 and Rb deficiency in tumorigenesis, crosses were made between p53- and Rb-deficient mice, and these animals were monitored for subsequent tumor incidence.13 It was shown that mice containing Rb or p53 mutant alleles developed pituitary adenomas or lymphomas and sarcomas, respectively, whereas mice deficient in both Rb and p53 showed a faster rate of tumorigenesis and a wider array of tumors than animals deficient only in Rb or p53. These are only a few examples of the well-known interactions of genetics, age, and cancer in laboratory animals. In humans, more than 80% of malignancies are diagnosed after age 50. In older humans, the influences of inheritable genetic abnormalities on carcinogenesis are unknown. A well-known site-specific variation in the age-related incidence of cancer (Figure 8.1) suggests a different susceptibility of different tissues to carcinogenesis. Dix et al1 subdivided all human tumors (except for chorionepithelioma) into two classes. The first class included all tumors whose incidence presents a single peak after age 50. The majority of tumors belong to this class. The second class comprises tumors having two peaks of incidence: the first before age 35 and the second after age 50. This class includes acute lymphoblastic leukemia, osteosarcoma, and Hodgkin lymphoma.

Figure 8.1 Incidence of cancer at various sites at different ages.

Age as a risk factor in multistage carcinogenesis

125

For completeness, the relationship of age to the incidence of benign tumors has not been satisfactorily studied, though benign neoplasms are more common than malignant ones. Also, data are scarce on the age-related distribution of tumors of different histogenesis found in the same organ. For example, epithelial carcinomas account for only a minority of ovarian cancers in women under 15, while germ cell neoplasms are most common in this group of women. The opposite is the case in women over 40. The example of ovarian cancer supports a variation in age-related incidence of tumors from different tissues and suggests two questions: 1. Do different tissues age at a different rate? 2. Does the susceptibility of different tissues to carcinogens vary with the person’s age? Susceptibility to carcinogenesis at different ages Age-related variations in carcinogenesis from different agents (chemical, radioactive, hormonal, and viral) were explored in experimental studies with inconclusive results (Table 8.1). Overall, these experiments seem to confirm the hypothesis that there are agerelated differences in carcinogen sensitivity in some tissues.6,7 Our own experiments at the NN Petrov Research Institute of Oncology, St Petersburg, and data from the literature show that, with age, susceptibility to carcinogens of some murine tissues decreases (mammary gland, small intestine and colon, thyroid, and ovarian follicular epithelium), in other tissues it increases (subcutaneous tissue, cervix uteri, and vagina), and in others it remains stable (lung and hematopoietic tissues).6,8 There are several possible reasons for this wide variation in experimental results. These include factors related to the experimental model and factors related to the tumor host. Model-related factors involve the characteristics of different carcinogens (direct or indirect action, chemical structure, and mechanism of action), route of administration, duration of exposure, presence of local and systemic activity, and time of observation. Host-related factors involve animal species, strain, sex, and age. The effective dose of an indirect carcinogen, requiring metabolic activation, may vary significantly in old and young animals, because the activity of the enzymes necessary for carcinogen activation in the liver and/or target tissue(s) may change with age. Age-related changes in the activity of enzymes responsible for activation and inactivation of carcinogens are summarized in Table 8.2.6,14–16 As a result of age-related body weight gain, older animals may receive a greater relative amount of a carcinogen when dose is calculated per animal body weight. When these weight-related differences are eliminated by giving a dose of carcinogen sufficient to induce tumors in the majority of animals, it becomes difficult to detect differences in age-related sensitivity to that carcinogen.

Comprehensive Geriatric Oncology

126

Table 8.1 Effect of aging on susceptibility to carcinogenesis Target tissue

Species Carcinogenic agent

Age groups (months)

Effect of aging

Skin

Mouse

BP, DMBA, MCA, TC

2–4; 12–13

No effect or decrease

DMBA

10; 24

Decrease

14–20; 22–24

Increase

NMU

2; 13

No effect

Ultraviolet

2–3 10–12

Decrease or no effect

12; 24

Increase

β-rays

2; 10; 20

Increase

Fast neutrons

1–3; 21

Decrease

Electrons

1; 8; 13–15

Decrease

Hamster Vinyl chloride

1; 7; 13; 19

Decrease

Rat

1; 8

Decrease

1; 15

Increase

1; 12

Increase

12; 23

Decrease

1; 8

Increase

1; 15

Decrease

BP, DMBA

1–4; 6–13

Increase

MCA

3–4; 12

Decrease

MCA

6; 20

Increase

DMBA

2–6; 13

Increase

DMBA

1–2; 18; 36

Decrease

Moloney virus

3; 30

Increase

Rat

BP, NMU

3–4; 9–14

Increase

DMAB

2; 15

No effect

Mouse

224

1; 5–6

No effect

0.5–1; 4–12

Decrease

Rat

Zymbal gland

DMAB

NMU

Prepucial gland

Soft tissues

Bone

Rat

Mouse

DMAB

Ra,

227

Th

90

Sr; 137Cs

Age as a risk factor in multistage carcinogenesis

127

144

Ce

Rat

Dog

Vessel wall

Increase

Radionuclides

2–3; 8–10

No effect

239Pu,

3; 17; 60

Increase

Ra

17; 60

Decrease

DENA

2.5; 17

Increase

DMH

3; 12–13

No effect

DENA

1;4; 6; 12

Decrease

Vinyl chloride

1.5–4; 7–19

Increase or decrease

X-rays, y-rays

1–4; 12

Decrease

Friend virus

2; 24–25

Decrease

D-RadL virus

1; 3; 12

No effect

NMU

3; 12

No effect

NMU

12; 24

Increase

Pristan

2–12; 17–19

Increase

Estrogens

1; 4; 7

Decrease

PMS

6; 10

No effect

X-rays

3–4; 12–14

No effect or decrease

Radionuclides

3; 8–10

No effect

NMU

3; 14–15

No effect

NMU

1; 12; 23

Decrease

Frog

DMNA, DMNO

1.5–2; 12–18

Decrease

Mouse

Estrogens

1;4; 7

Decrease

Vinyl chloride

1.5; 13.5

Decrease

DMBA, MCA, NMU

Maximum susceptibility at the age of 50–75 days

DMBA, NMU, FBAA

1–6; 12–16

Decrease

Mouse

Mouse

Rat

Mammary gland

1; 6; 12

pu

226

Rat

Hematopoietic system

239

Rat

226Ra

X-rays β-rays

1; 12

No effect

137

2; 4

Decrease

60

1–1.5; 4

Increase

Cs

Co

Comprehensive Geriatric Oncology

Uterus

Cervix and vagina

Ovary

Testis

128

[75Se]selenomethionine 3; 12; 24

Increase

DMH

2; 12

Increase

NMU

3; 12

No effect

Rat

NMU, MAMNA

3; 14; 14–15

No effect

Mouse

DMBA

3; 18

No effect

MCA

2; 15

No effect

Mouse

X-rays

2; 12

Decrease

Rat

X-rays

3; 14

Decrease

NMU

3; 15

Decrease

DEH

3; 14

Increase

Fast neutrons

3; 21

Increase

DMAB

1, 8; 15

Increase

Mouse

Rat

Prostate

Rat

DMNA

1; 8; 15

No effect

Thyroid gland

Rat

Fast neutrons

1;21

Decrease

X-rays

2–3; 14–15

Decrease

Dog

131

2; 15

Decrease

Mouse

DENA

1.5–2; 12

Increase

NMU

3; 12; 24

Increase

DBA, urethane

2–4; 11–12

Decrease

Vinyl chloride

1.5; 13.5

Decrease

X-rays

1–2; 6

Increase

X-rays

1–1.5; 18–24

Increase

MAMNA

3; 14

No effect

NBOPA

2; 15

Decrease

Fast neutrons

3; 21

Increase

Lung

Rat

I

Pleura

Rat

Asbestos

2; 10

Increase

Liver

Mouse

PB

1.5; 12

Increase

DMTAA

1; 4

Decrease

FBAA, DENA,

1–6; 12

Decrease

DMNA, DENA

1; 5–18

Decrease

Nitrosomorpholine

2; 8

No effect

Rat

Aflatoxin B1

Age as a risk factor in multistage carcinogenesis

Pancreas

Tongue

Esophagus

Forestomach

Stomach

Small bowel

Colon

129

NBOPA

2; 8

Increase

Mouse

NMU

3; 12; 24

Increase

Rat

NMU

1; 12

No effect

12; 23

Decrease

DMAB

1, 8; 15

Decrease

Azaserine

0, 5; 4–5

Decrease

Rat

NMU

1; 12

Increase

NMU

12; 23

Decrease

DENA

1–6; 12

Decrease

DENA

1–1, 5; 5

No effect

N-Nitrosomorpholine

2; 12

No effect

Mouse

DENA, NMU

2–3; 12–17

Decrease

Rat

NMU

1; 12

No effect

NMU

12; 23

Decrease

Rat

MNNG

1. 5–6; 9–12

Decrease

Hamster

Vinyl chloride

1.5; 7–19

Decrease

Rat

DMAB, MAMNA

1.3; 14–15

Decrease

NMU

1; 12

Increase

NMU

12; 23

Decrease

DMH

3; 12

Increase

NMU

3; 12; 24

Increase

DMH

2; 7

Decrease

DMH

8–10; 18

Decrease

MAMNA, NMU

3; 14–15

Decrease

NMU

1; 12

Increase

NMU

12; 23

Decrease

Rat

Mouse

Rat

Peritoneum

Rat

DMAB

1; 8; 15

Decrease

Kidney

Mouse

NMU

3; 12

Decrease

Rat

FBAA, DMNA, NMU

1–6; 12–18

Decrease

Kidney

Mouse

BHBNA

1.5–3; 10

Increase

pelvis

Rat

NBOPA

2; 15

Increase

NMU

1; 12; 23

No effect

Comprehensive Geriatric Oncology

Bladder

Mouse

Rat

130

BHBNA

1.5–3; 10

Increase

DMBA (in vitro)

1.5–2; 28–30

Increase

BHBNA

2; 5

Increase

BHBNA

1.5; 12; 23

Increase

NMU

1; 12; 23

No effect

BHBNA, N-butyl-N-(4-hydroxybutyl)nitrosamine; BP, benzo[a]pyrene; DBA, 1, 2, 5, 6dibenzanthracene; DEH, 1, 2-diethylhydrazine; DENA, N-nitrosodiethylamine (diethylnitrosamine); DMAB, 3, 2'-dimethyl-4-aminobiphenyl; DMBA, 7, 12-dimethylbenz[a]anthracene; DMH, 1, 2-dimethylhydrazine; DMNA, N-nitrosodimethylamine (dimethylnitrosamine); DMNO, N-nitrodimethylamine (dimethylnitramine); DMTAA, N, N-dimethyl-p-(m-tolylazo)aniline; FBAA, 4-fluoro-4'-acetylaminobiphenyl [N-4(fluorobiphenyl)acetamide]; MAMNA, N-nitroso(acetoxymethyl)methylamine [methyl(acetoxymethyl)nitrosamine]; MCA, 20methylcholanthrene; MNNG, N-methyl-N’-nitro-N-nitrosoguanidine; NBOPA, N-nitroso-bis(2-oxopropyl)amine; NMU, N-nitrosomethylurea; PB, phenobarbital; PMS, pregnant mare serum; TC, tobacco condensate; X-rays, whole-body X-ray irradiation.

Critical factors that determine the susceptibility of a tissue to carcinogenesis include DNA synthesis and proliferative activity of that tissue at the time of carcinogen exposure, and the efficacy of repair of damaged DNA.17–21 The available data concerning agerelated changes of these parameters have been discussed elsewhere6,8 and are briefly summarized in Tables 8.3–8.5. Obviously, there are no common patterns of age-related changes in DNA synthesis and repair or in proliferative activity of different tissues with age. The homeostatic regulation of cell numbers in normal tissues reflects a precise balance between cell proliferation and cell death. Programmed cell death (apoptosis) provides a protective mechanism from cancer, by removing senescent, DNA-damaged, or diseased cells that could potentially interfere with normal function or lead to

Table 8.2 Age-related changes of carcinogenmetabolizing enzymes in rat liver Enzyme

Age groups (months)

Effect of aging

Cytochrome P450

3; 12; 27

No effect

3–12; 27

Decrease

4–12; 18; 27

Decrease

3–5; 14

Decrease

3–6; 24–30

No effect

7; 24

Decrease

3–5; 14

Decrease

Cytochrome b5

NADPH-cytochrome c reductase

Age as a risk factor in multistage carcinogenesis

131

3, 4, 12, 24; 36

Decrease

3, 12; 27

No effect

6; 25

No effect

1; 3; 10; 20

Decrease

3; 6; 12; 24; 28

Decrease

Benzphetamine N-demethylase

3; 12; 27

Decrease

Nitroanisole N-demethylase

3–5; 14

Increase

3; 6; 12; 24; 28

Decrease

3; 12; 27

Decrease

16; 27

Decrease

Epoxide hydrase

3; 12; 27

Increase

Benzo[a]pyrene hydroxylase

3; 6; 12; 24; 27; 30

Decrease

Aniline hydroxylase

1–6; 18

Decrease

3; 6; 12; 24; 28

Decrease

7-Ethoxycoumarin o-deethylase

3; 6; 12; 24; 28

Decrease

p-Dimethylaminoazobenzene reductase

1, 3, 10, 20

Decrease

Nitroreductase

2; 9

Increase

Glutathione reductase

1; 3; 6

Increase

6; 12; 24

Decrease

3–4; 12; 26–27

decrease No effect or

3; 12

Increase

12; 24

Decrease

o-Glucuronyltransferase

4.5; 24

Decrease

p-Glucuronyltransferase

4.5; 24

Increase

UDP-glucuronyltransferase

2; 9

No effect

3; 6; 12; 24–26

No effect

2; 9

Increase

6; 28

Increase

Arylsulfatase A and B

3; 24

Decrease

Glutathione peroxidase

3; 6; 12; 24

Increase

12; 24

No effect

Aminopyrine N-demethylase

Ethylmorphine N-demethylase

Glutathione S-transferase

β-Glucuronidase

Comprehensive Geriatric Oncology

UDP-glycodehydrogenase

3; 6; 12; 24

132

Increase

neoplastic transformation.18,22,23 With some reservations,24 apoptosis plays a substantial role in many other aspects of aging and cancer, including control of the lifespan of most components of the immune complex, and the rate of growth of tumors.18,25 It has been suggested that p53 mediates apoptosis as a safeguard mechanism to prevent cell proliferation induced by oncogene activation.26,27 When female rats older than 15–17 months are used experimentally as the ‘old’ group, the majority of animals have a persistent estrus or anestrus that may strongly modify their susceptibility to some carcinogens.6 Comparison of carcinogenic effects in groups of animals with different lifeexpectancies presents an additional obstacle to the experimental study of carcinogenesis and age. The number of induced tumors may be underestimated in an animal with shorter life-expectancy, because competitive causes of death may prevent the clinical manifestations of cancer. A search for occult cancer should be performed at autopsy in all animals, and tumors should be classified as ‘fatal’ or ‘incidental’.28 This approach permits a more reliable comparison of incidence and lethality of tumors in young and old animals. Survival-related biases may be lessened when tumors discovered in an incidental context are analyzed by prevalence methods, while tumors discovered in a fatal context are analyzed by death-rate methods.28 Age-related factors limiting susceptibility to carcinogens are tissue-specific. This may explain, at least in part, both age-related changes in susceptibility to carcinogenesis in target tissues and organ and tissue variability in the age distribution of spontaneous tumor incidence. This raises a critical question: is normal aging associated with an accumulation in cells that have undergone advanced carcinogenesis and are susceptible to the effects of late-stage carcinogens? Molecular biology of aging: potential relationship to carcinogenesis Both carcinogenesis and aging are associated with genomic alterations, which may act synergistically in causing cancer.18,29–32 In particular, three age-related changes in DNA metabolism may favor cell transformation and cancer growth. These are genetic instability, DNA hypomethylation, and the formation of DNA adducts.20,31,33 Genetic instability involves activation of genes that are normally suppressed, such as cellular proto-oncogenes, and/or inactivation of some tumor suppressor genes (p53, Rb, etc.).18,20,27,33–37 The role of genetic instability in linking aging and cancer may soon be clarified by promising laboratory techniques.18,38 DNA hypomethylation is characteristic of aging, as well as of transformed cells.39–41 Hypomethylation, a potential mechanism of oncogene activation, may result in spontaneous deamination of cytosine and consequent base transition, i.e. substitution of the pair thymine:adenine. Accumulation of inappropriate base pairs may cause cell transformation as a result of activation of cellular proto-

Age as a risk factor in multistage carcinogenesis

133

Table 83 Age-related changes in DNA repair in tissues exposed to carcinogens Type of DNA damage

Carcinogen

Tissue

Species Age groups

Effect of aging

Pyrimidine dimers

Ultraviolet

Lymphocytes

Human

13–94 yr

Decrease

22; 54 yr

Decrease

17–69 yr

No effect

0–70 yr

No effect

17–77 yr

Decrease

Epidermis

Human

Skin

Mouse

2; 18 mo

Decrease

Kidney

Human

30–82 yr

No effect

Liver

Rat

6; 14 mo

Increase

14; 32 mo

Decrease

2–3; 28–30 No effect mo

DNA strand breaks

X-rays

Lens, epithelium

Rat

14; 40 mo

No effect

Ganglion oticum

Rat

1–6; 23 mo No effect

Kidney, lung, brain, liver

Hamster 1–2; 17–18 No effect mo

Fibroblasts

Mouse

2; 30 mo

Decrease

Rat

6–10; 32– 44 mo

Decrease

Chondrocytes

Rabbit

3; 36 mo

Decrease

Thymocytes

Mouse

2; 22 mo

No effect

Lymphocytes

Human

0–70 yr

Decrease

17–60; 60– Decrease 78 yr Cerebellum

γ-rays

Electrons

Dog

1 mo; 5 mo; 13 yr

No effect

Mouse

2; 22 mo

No effect

Lymphocytes

Human

0–70 yr

Decrease

Liver

Mouse

1; 5–2; 18– Decrease 22 mo

Thymus

Mouse

1; 18 mo

Skin

Rat

1–6; 13 mo Decrease

No effect

Comprehensive Geriatric Oncology

Apurinic sites

N-OH-2AAF

Lymphocytes

134

Human

0–10; 51– 60 yr

Decrease

51–60; 71– No effect 80 yr 4-NQO, DENA

Ganglion oticum

Rat

1–6; 23 mo No effect

4-HQO

Skin

Mouse

2; 18 mo

No effect

DENA

Fibroblasts

Rat

13 wk; 24 mo

Decrease

NMU

Skin, lung, brain, heart,

Rat

6; 24–26 mo

Decrease

Rat

6; 24–26 mo

No effect

spleen, gonads NMU

Liver, kidney, duodenum, muscle

NMU

Bone marrow

Mouse

2; 17 mo

Decrease

DMNA

Kidney, duodenum,

Rat

6; 24–26 mo

Decrease

No effect

lung, liver, spleen, gonads DMNA

Skin, brain, heart muscle

Rat

6; 24–26 mo

DMH

Colon

Rat

3–4; 13–15 Decrease mo

MAMNA

Colon, liver, ileum, lung, uterus

Rat 3; 14 mo Decrease

DMBA

Mammary epithelium

Rat

1, 5; 5 mo

Increase

Liver

Rat

3; 14 mo

Decrease

Kidney

Rat

3; 14 mo

Increase

Liver

Rat

3; 14 mo

Increase

Colon, ileum

Rat

3; 14 mo

Decrease

Lung

Rat

3; 14 mo

No effect

Alkylation of guanine DENA at the 06 position MAMNA

DENA, N-nitrosodiethylamine (diethylnitrosamine); DMBA, 7, 12-dimethylbenz[a]anthracene; DMH, 1, 2-dimethylhydrazine; DMNA, N-nitrosodimethylamine (dimethylnitrosamine); MAMNA, Nnitroso(acetoxymethyl)methylamine [methyl(acetoxymethyl)nitrosamine]; NMU, N-nitrosomethylurea; N-OH-2AAF, N-hydroxy-2-acetylaminofluorene; 4-HQO, 4hydroxyaminoquinoline 1-oxide; 4-NQO, 4-nitroquinoline oxide.

Age as a risk factor in multistage carcinogenesis

135

Table 8.4 Age-related changes of DNA synthesis in various tissues Organ, tissue

Species Age groups (months)

Effect of aging

Esophagus: basal layer of epithelium

Mouse

1–2; 19–21

Decrease

Kidney: cells of tubules

Mouse

2; 13

Decrease

Rat

6; 24

Decrease

17; 24

Increase

Rat

2; 24–36

Decrease

Mouse

6; 32

Decrease

Rat

2; 19

Decrease

19; 27

Increase

3; 12

Decrease

12; 24

No effect Increase

Liver

Tongue: basal layer of epithelium

Lung: epithelium of alveolar wall

Mouse

Spleen

Rat

6; 22–24

Mammary epithelium

Rat

Maximum at 50th day of life

Duodenal crypt epithelium

Mouse

1–2; 19–21

Decrease

Colonic crypt epithelium

Mouse

1–2; 19–21

Decrease

Vessel wall endothelium

Mouse

6; 12; 18; 25

Decrease

Table 8.5 Age-related changes of mitotic index in various tissues Organ, tissue

Species

Age groups (months)

Effect of aging

Epidermis of abdominal wall

Human

21–40; 71–77

Increase

Ear epithelium

Mouse

3–6; 30–33

Decrease

Oral cavity

Human

25–34; 50–78

Increase

Lacrimal gland

Rat

1–3; 30–33

Decrease

Forestomach

Mouse

3; 12

No effect

Lung alveolar wall

Mouse

3; 12

No effect

Rat

1–5; 6–38

Decrease

Mouse

3; 12

Decrease

Rat

4; 38

Decrease

Skin:

Epithelium:

Liver

Kidney: proximal tubules

Comprehensive Geriatric Oncology

136

Pituitary

Rat

1–2; 9–12

Decrease

Thyroid gland

Guinea pig

1–4; 12–36

Decrease

Rat

1–2; 9

Decrease

Guinea pig

1–4; 12–36

Decrease

Rat

1–2; 9

Decrease

Adrenal cortex

Guinea pig

1–4; 12–36

Decrease

Endometrium

Mouse

3; 12

No effect

Duodenum: crypts

Mouse

1–2; 19–21

Decrease

Small-intestine: mucosa

Rat

1–2; 9

Decrease

Descending colon

Rat

4; 18

Decrease

Mammary epithelium

Rat

Maximum at 50th day of life

Parathyroid gland

oncogenes.35,37,42 Age-related abnormalities of DNA metabolism may be, to some extent, tissue- and gene-specific. For example, hypomethylation of the c-myc proto-oncogene has been found in the hepatocytes but not in the neurons of old mice.43–45 Within the same cell, different DNA segments express different degrees of agerelated hypomethylation. The uneven distribution of hypomethylation may underlie selective overexpression of proto-oncogenes by senescent cells.46–49 For example, the transcription of c-myc is progressively increased in the liver but not in the brain of rats between the ages of 4 and 22 months, whereas the transcription of c-sis and c-src does not appear to be age-related in any tissues.45,47 The different extent of DNA abnormalities among aging tissues may account in part for the different susceptibilities of these tissues to carcinogens.32,41 The formation of DNA adducts in target tissues is one of the key events in the process of chemical carcinogenesis.50,51 The majority of known carcinogens react with DNA through one of only three general types of chemical reaction. These involve the transfer to DNA of alkyl, arylamine, or aralkyl residues.51 The sites of alkylation and polycyclic aralkylation on DNA do not overlap, but monocyclic aralkylating agents (and possibly arylaminating agents) attack some sites that are targets for polycyclic aralkylating agents and some that are targets for simple alkylating agents. Accumulation of these substances, particularly of 7-methylguanine adducts in nuclear and mitochondrial DNA, may represent the linkage of aging and carcinogenesis.52 It has been shown that the DNA of various tissues of intact rodents contains adductlike compounds (I-compounds) that accumulate with age.53 The production of Icompounds is not mediated by specific DNA-modifying enzymes, such as cytosine-5methyltransferase, but it may involve microsomal oxidases and other xenobioticmetabolizing enzymes. Important characteristics of I-compounds are their capability to cause mutations, DNA chain breaks, and gene rearrangements.53 The damage caused by endogenous oxygen radicals has been proposed as a major contributor to both aging and cancer.54–57 Oxygen radicals are mainly produced in vivo as by-products of natural metabolism, from lipid peroxidation and from phagocytes.55–57 A variety of cellular defense systems are involved in protecting cellular macro-molecules against the devastating action of oxygen-based radicals. These systems include

Age as a risk factor in multistage carcinogenesis

137

antioxidant enzymes (copper—zinc superoxide dismutase (SOD), manganese-containing SOD, catalase, glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase), some vitamins (α-tocopherol and ascorbic acid), uric acid, and the pineal indole hormone melatonin.54–58 There is evidence that an increased production of reactive oxygen species and/or a decreased efficiency of antioxidant defense systems are associated with aging.54–58 Endogenous oxidative damage to lipids and proteins increases with age.56 It has been shown that oxygen free radicals may induce active mutations of the human c-Ha-ras proto-oncogene.59 The level of one oxidized nucleoside, 8-hydroxy-2'-deoxyguanosine (oh8dG) in DNA increased with age in liver, kidney, and intestine, but remained unchanged within brain and testes of rats, whereas the urinary excretion of the nucleoside decreased with age of rats.60 It has been found that oh8dG may hamper the function of human DNA methyltransferase.61 Some oxidized mutagenic nucleosides, such as 1, N6ethenodeoxyadenosine and 3, N4-ethenodeoxycyti-dine, derived from spontaneous peroxidation of lipids and proteins, have also been detected in rodent tissues after treatment with chemical carcinogens.62 In recent years, the importance of telomeres in aging has been highlighted. Telomeres are DNA sequences found at the end of eukaryotic chromosomes in somatic cells. During cell replication, telomeres are preserved by the enzyme telomerase, a ribonucleoprotein enzyme that adds the telomere sequences TTAGGG to chromosome ends.63–65 In the absence of telomerase, telomeres are shortened with each cell division. Loss of the distal region of telomeres correlates with a decline in the proliferative lifespan of cells both in vitro and in vivo.63,65 There are strong arguments suggesting that telomere shortening and reactivation of telomerase are important components of aging and carcinogenesis, respectively.63–65 It has been suggested that a major function of wild-type p53 may be to signal growth arrest in response to telomere loss in senescent cells.66 This hypothesis is consistent with the behavior of most tumors that exhibit p53 mutation, and also explains the existence and characteristics of rarer tumor types in which p53 function appear to be retained.66 There is evidence of an age-related accumulation of spontaneous mutations in somatic and germ cells.67–70 Accumulation with age of some spontaneous mutations or mutations evoked by endogenous mutagens can induce genomic instability and hence increase the sensitivity to carcinogens and/or tumor promoters. The progeny of 25-month-old male rats mated with 3-month-old females to the chemical carcinogen N-nitrosomethylurea (NMU) was significantly increased in comparison with the progeny of young males.71 Thus, the available data show that some changes in structure and function of DNA evolve with natural aging. The character of these changes could vary in different tissues, and might cause uneven tissue aging. In turn, this may lead to both age-related increases in spontaneous tumor incidence and age-related changes in susceptibility to carcinogens in various organs.

Comprehensive Geriatric Oncology

138

Multistage model of carcinogenesis and aging Carcinogenesis is a multistage process: neoplastic transformation implies the engagement of a cell through sequential stages, and different agents may affect the transition between contiguous stages.11,72,73 Several lines of evidence support this conclusion:20 1. Histopathology of tumors reveals multiple stages of tumor progression, such as dysplasia and carcinoma in situ. 2. The two-stage model of chemical carcinogenesis in mouse skin shows that different chemicals affect qualitatively different stages in the carcinogenic process. 3. The existence of individuals with genetic traits manifested by an early occurrence of cancer (e.g. familial retinoblastoma and colonic and rectal adenomatosis) suggests that one of the carcinogenic steps is a germline mutation, but additional somatic effects are required for neoplastic development. 4. Mathematical models based on age-specific tumor incidence curves are consistent with the hypothesis that three to seven independent hits (effects of independent carcinogens) are required for tumor development. 5. Studies with chemical carcinogens in cell cultures reveal that different phenotypic properties of a tumor cell are required for tumor development. 6. Studies with viral and tumor-derived oncogenes in cell cultures show that neoplastic conversion of normal cells generally requires multiple cooperating oncogenes. 7. Transgenic mice that carry activated proto-oncogenes in their germline develop focal tumors, which are apparently monoclonal in origin, suggesting that additional somatic events are required for full malignant progression. The process of neoplastic development is often divided into three operationally defined stages: initiation, promotion, and progression. Initiation involves the induction of permanent and irreversible alterations in the genome of the target cell by a carcinogen called an initiator. Promotion completes the neoplastic transformation of the initiated cells through the intervention of agent(s) called promoter(s).73 Unlike initiation, promotion requires prolonged exposure to the carcinogen and may be reversible to a large extent. A carcinogen that is able to act as both initiator and promoter is referred to as a full carcinogen. The dissection of carcinogenesis into initiation, promotion, and progression is useful as a frame of reference. It should not be assumed, however, that only three stages of carcinogenesis exist: each stage can be subdivided into multiple substages. Promotion may involve the activation of several enzymes (e.g. protein kinase C and ornithine decarboxylase), enhanced hexose transport, increased polyamine production, prevention of cell differentiation, and inhibition of cellto-cell communication.19,74 It has been found that 12-O-tetradecanoylphorbol-13-acetate (TPA), a well-known skin tumor promoter, causes free-radical-mediated DNA alterations, such as sister chromatid exchanges and expression of proviruses and retroviruses.75 Discovery of oncogenes and of their function has provided new insight into carcinogenisis.33–35 One may view carcinogenesis as a ‘cascade’ phenomenon, resulting

Age as a risk factor in multistage carcinogenesis

139

in serial activation of multiple cellular oncogenes and/or inactivation of tumor suppressor genes (e.g. p53).33–36 To overcome the obvious limitations of the two (three)-stage model, a multistage model of carcinogenesis has been conceived, in which the number of stages is not

Figure 8.2 Integral scheme of carcinogenesis. t1,…, tn=time of passage of cells from the normal state to stages 1,…, n. (VLDL, very lowdensity lipoprotein; FFA, free fatty acids.) limited, the stages are envisioned as a continuum, and the influence of factors other than specifk carcinogens may be properly accounted for (Figure 8.2).11 The principles of this model are as follows. First, neoplastic transformation involves the transition of target cells through multiple stages, the number of which varies for different neoplasms (with a minimum of one intermediate stage). Secondly, passage from one stage to another is a stochastic event, the rate of which depends on the dose of a carcinogen that affects the cell. Finally, all cells at any stage of carcinogenesis may enter the next stage independently of each other.

Comprehensive Geriatric Oncology

140

According to this model, the tumor develops only if at least one cell goes through all the necessary stages, and the clonal growth of this cell causes clinical cancer, as a critical tumor volume is achieved. In this model, the exact origin of the various stages is ignored and the changes in cell function during the process of carcinogenesis are not assessed. The grade of malignancy is considered to increase with every stage. Various carcinogenic agents (exogenous as well as endogenous) may modulate the process. In addition, some agents act at early stages of carcinogenesis and others at later stages.11 Epidemiological data, analyzed within the framework of a multistage model, have helped to estimate the contribution of various factors to the development of cancer. These factors include the time from the beginning of carcinogenic exposure and the age of onset of exposure. Important differences between early- and late-stage carcinogens should be highlighted, to illustrate potential interactions of aging and carcinogenesis. Exposure to early-stage carcinogens requires a latent period for the development of cancer. During the latent period, the transformed cell goes through the subsequent carcinogenic stages. Clearly, elimination of early-stage carcinogens from the environment will not result in immediate cessation in the incidence of cancer. Carcinogens acting at late stages of carcinogenesis cause the tumor incidence

Table 8.6 Characteristics of early- and late-stage carcinogens Early-stage carcinogens •

Prolonged latency

•

Persistence of the effect after withdrawal of the carcinogen

Late-stage carcinogen •

Short latency

•

Rapid disappearance of the effect after withdrawal of the carcinogen

rate to rise after a relatively short period of time. The increased rate of tumor incidence will be reversed immediately on cessation of exposure (Table 8.6).11 This risk of cancer after exposure to a carcinogen may be calculated as follows: I=(age)k−1−tk−1 (1) where I is the risk of cancer, t is the time from initial exposure to the carcinogen, and k is the number of stages that the target cells have undergone before exposure to the carcinogen. This formula is based on the assumption that with aging there is a progressive accumulation of partially transformed cells primed to the effect of late-stage carcinogens (Figure 8.3). Both experimental and epidemiologic studies illustrate the interaction between aging and carcinogenesis. The malignant transformation of normal cells involves both quantitative and qualitative changes. Figure 8.2 shows an integrated scheme of multistage carcinogenesis. Carcinogenic agents not only cause genomic transformation of the cell,

Age as a risk factor in multistage carcinogenesis

141

but also create the conditions that facilitate proliferation and clonal selection in the cell microenvironment.6,7 Multistage carcinogenesis is accompanied by disturbances in tissue homeostasis and perturbations in nervous, hormonal, and metabolic factors, which may

Figure 8.3 Multistage carcinogenesis induced by single exposure to a carcinogenic agent at different ages. Groups 3–5 demonstrate the carcinogenic effect produced on a cell that has passed through one or more stages in accordance with the multistage model of carcinogenesis. Table 8.7 Incidence of skin tumors in young and adult mice exposed to a single application of DMBA Age (weeks)

Dose (µg) 300

100

30

10

8

30%

21%

0%

0%

48

47%

18%

6.3%

1.3%

affect antitumor resistance. The development of these changes depends on the susceptibility of various systems to a carcinogen and on the dose of the carcinogen. Changes in the microenvironment may condition key carcinogenic events and determine the duration of each carcinogenic stage, and sometimes they may even reverse the

Comprehensive Geriatric Oncology

142

process of carcinogenesis. These microenvironmental changes influence the proliferation rate of transformed cells together, the total duration of carcinogenesis, and consequently the latent period of tumor development. Numerous experiments support this model. Thus, a single skin application of 7, 12dimethylbenz[a]anthracene (DMBA) in mice aged 8 and 48 weeks at doses ranging from 10 to 300 µg caused increased skin papilloma incidence in older mice (Table 8.7).76 Also, the average diameter of the tumors was larger in the older animals. Likewise, the incidence of skin papillomas after application of TPA was skfold higher in 14-month-old than in 4-month-old mice. Of particular interest are the experiments using skin transplants. TPA failed to induce tumors in the skin of 2-month-old mice grafted to animals of different ages, but caused the same tumor incidence in the skin of 1year-old donors irrespective of the recipient’s age.77 These results indicate that the age of the target tissue, more than the age of the host, determines susceptibility to late-stage agents. Exposure of male C3H/HeNcr mice or F344 rats of various ages to phenobarbital resulted in hepatocarcinogenesis only in old animals.78,79 The incidence of proliferative foci and hepatic tumors induced by carbon tetrachloride or peroxisome proliferators in rodents is also a function of age (Table 8.8).80–83 A single intravenous injection of NMU at doses of 10, 20, and 50mg/kg was administered to female rats aged 3 and 15 months.84 The NMU carcinogenic dose dependence in different age groups was considered in the context of a multistage model. It was calculated that the number of events necessary for complete malignant transformation in 15-month-old rats under the influence of NMU was lower than in 3month-old rats. In this experiment as well as in another sets of experiments in rats and in mice, it was shown that tumors developed earlier in older than in younger animals after exposure to the same doses of NMU.85,86 Age-related accumulation of cells in advanced carcinogenic stages may also be inferred from other types of experiment. The mouse model of hepatocarcinogenesis is very convenient for this purpose because of the availability of strains of animals with different susceptibilities to hepatic carcinogenesis. In the livers of highly susceptible mice, the concentration of hepatocytes in advanced stages of carcinogenesis was increased early in life before exposure to experimental carcinogens.87 In the livers of F344 rats, the number of spontaneous proliferative foci is proportional to the animal’s age.79,83,88 Another pertinent model involves the induction of lymphomas in mice receiving transplants of splenic, thymic and lymphoid cells from syngeneic donors.89 The incidence of neoplasms is related to the age of the donor, but not to the age of the recipient. Thus, transplants from 1-month-old donors to

Table 8.8 Effect of aging on the susceptibility of unitiated tissues to non-genotoxic agents and tumor promoters Target tissue

Species Agent

Age groups (months)

Effect of aging

Liver

Rat

1; 12

Increase

8; 14

Increase

Phenobarbital

Age as a risk factor in multistage carcinogenesis

Mouse

143

Naphenopin

3; 13

Increase

Nafenopin, cyproterone, αhexachlorocyclohexane

8; 24

Increase

Carbon tetrachloride

1–3; 12

Increase

WY-14,d643

2; 15

Increase

Phenobarbital

1.5; 12

Increase

a

Skin

Mouse

TPA

4; 14

Increase

Soft tissues

Mouse

Polyurethane sponge

1; 15.5

Increase

Mammary gland

Rat

Estrone

1; 20

Increase

Ovary

Rat

Biskind’s surgery

3; 15

Increase

a

TPA, 12-o-tetradecanoylphorbol-13-acetate.

14-month-old hosts failed to produce tumors, whereas transplants from 14-month-old donors into 1-month-old mice caused lymphomas in 59–65% of the recipients. It is important to stress that in every tissue, the number of events occurring in the stem cell before its complete transformation is variable and depends on many factors, in particular the rate of aging of the target tissue and its regulatory system(s).6,90 This model is consistent with analysis of the age-related distribution of tumor incidence in different sites in humans and laboratory animals.1,6 It must also be emphasized that old animals can be used as an adequate model for long-term assay for carcinogenicity of suggested weak carcinogens and/or tumor promoters. The multistage model of carcinogenesis and the distinction between early- and latestage carcinogens are supported by epidemiologic studies in humans. The time from beginning of exposure, the duration of exposure, the time since exposure was stopped, and the age at first exposure are particularly important parameters. If an agent affects an early stage of cancer development, then the number of cells that pass through that stage will increase. These cells will have to pass through a series of further stages before expression of malignancy. Both the increase in tumor incidence after the start of exposure and the relative decrease after exposure has ceased will be considerably delayed. If a late stage is affected, the response to both the beginning and the end of the carcinogenic exposure will be much more rapid.11 As examples, the results of observations on patients treated with ionizing radiation or subjected to organ transplantation can be considered. Thus, following a comparatively short exposure to ionizing radiation, the excess risk of cancer tends to rise only after approximately 10 years and continues to rise fairly rapidly for at least several decades thereafter. This is typical example of an early-stage effect. In contrast, a marked excess of non-Hodgkin lymphoma following organ transplantation becomes evident within 6 months, which suggest a late-stage effect.11 As an example of a ‘late-stage’ effect, the incidence rate of lung cancer due to arsenic increases with the age at which the first exposure to arsenic occurs: persons exposed to arsenic at more advanced age are more likely to develop lung cancer. As an example of an ‘early-stage’ effect, the risk of mesothelioma for a given duration of exposure to

Comprehensive Geriatric Oncology

144

asbestos is independent of the age at first exposure. Analysis of lung cancer mortality among smokers and ex-smokers suggests that tobacco smoke contains both early- and late-stage agents.11,73,91 The terms ‘early’ and ‘late’ carcinogens do not necessarily imply specific events in experimental carcinogenesis. In addition to ‘mutagens’, early-stage carcinogens include substances that enhance the delivery of mutagens to the target tissue, substances that antagonize extracellular inhibition of mutagen effects, and substances that antagonize DNA repair mechanisms and stimulate cell proliferation and/or inhibit apoptosis. Latestage agents may include, in addition to promoters, agents that antagonize several homeostatic mechanisms, such as immunosurveillance, agents that cause irreversibility of the tumor phenotype, and other agents whose effect is poorly understood. It has been suggested that any carcinogen might in some circumstances act either early or late, or both, and a given agent might act early for one type of cancer and late for another.11,73 Research into the identification of tissue markers of early stages of carcinogenesis may yield insights into cancer prevention. An important question related to the integrated model of carcinogenesis6,8 concerns age-related changes in the tissue microenvironment, since these changes may favor or oppose carcinogenesis in different circumstances. Should aging tissues alter the environment in which a tumor develops, the growth rate of transplantable tumors may vary with the age of the tumor recipient.4,6 These experiments bypass the effect of age on carcinogenesis itself and explore the role of age-related changes in the organism on the growth and progression of transformed cells. Evaluation criteria for such experiments should include: (i) tumor transplantability, (ii) the rate of tumor growth, and (iii) survival time of tumor-bearing animals. The natural history of spontaneous tumors in humans (the rate of tumor doubling and the metastatic potential) and the survival of cancer patients newly diagnosed at different ages provide information on the effects of age on tumor growth in humans. Available data both in experimental animals and in humans are contradictory and support different effects of age on tumor development.6,91–96 In general, an ‘age effect’ may be recognized both in experimental and in human malignancies. The tissue origin (histogenesis) and immunogenicity of a tumor are the principal factors determining agerelated differences in the tumor growth. There is increasing evidence that age-related changes in the tumor microenvironent may also play a significant role. In our experiments, lung-affine cells of the rat rhabdomyosarcoma RA-2 were inoculated intravenously into rats of different ages.97 It was observed that the number of lung tumor colonies was highest in 1- and 15-month-old animals and lowest in 3- and 12-month-old animals. A positive correlation was found between the number of tumor lung colonies and somatomedine activity in the lung. In another experiment, RA-2 cells from a 3-month-old donor were inoculated into 2- to 3- or 21- or 23-month-old recipients, and 3 weeks later were taken separately from ‘young’ and ‘old’ hosts and transplanted into 3-month-old recipients. The number of lung colonies was significantly decreased in 3-month-old recipients injected with RA-2 cells passed via an ‘old’ host.98 The results obtained suggest critical roles for the host and donor microenvironments in the lung colony-forming potential of RA-2 cells. McCullough et al99 have observed that transformed rat hepatocytic cell lines were only weakly tumorigenic following transplantation into the livers of young adult rats. The tumorigenicity of these cell lines increased progressively with the age of the tumor

Age as a risk factor in multistage carcinogenesis

145

recipient. These results suggest strongly that the tissue microenvironment represents an important determinant in the age-related tumorigenic potential of transformed cells. Carcinogens as accelerators of aging Given the similarity of molecular changes of aging and carcinogenesis, it is reasonable to ask whether and how carcinogens may affect aging. The ability of carcinogens to influence aging has been discussed for many years. Larionov100 reported that the exposure of rodents to polycyclic hydrocarbons was followed by premature aging. Neonatal exposure to DMBA decreased the lifespan of mice and has been accompanied by premature cessation of estrus function, hair discoloration, and loss of body weight.101 In our own experiments, female rats treated with 20-methylcholanthrene (MCA) manifested a number of endocrine changes typical of aging animals. These included cessation of estrus.102 Chronic inhalation of tobacco smoke caused enhanced production of free radicals and signs of aging in rats.103 Acceleration of aging by ionizing radiation has been well documented, and epitomizes the dose-dependent effects of carcinogens on aging.104–107 Exposure to extremely low-frequency electromagnetic fields, which has weak tumor-promoting effects in some experimental systems,108–112 was followed by aging of the endocrine and immune systems.113 The effects of carcinogens on the neural, endocrine, and immune systems, and on carbohydrate and lipid metabolism which may lead to acceleration of aging,6 are summarized in Table 8.9. Radioactive and chemical carcinogens appear to cause disturbances in the internal tissue milieu, similar to those of normal aging, but at an earlier age. Carcinogenic factors (including irradiation) cause a sharp

Table 8.9 Similarity of changes developing in the organism during natural aging and carcinogenesis (modified from reference 6) Parameter

Aging

Chemical carcinogens

Ionizing radiation

Persistent estrus syndrome

Pineal melatonin secretion

Decreases

Decreases

Decreases

Decrease

Catecholamine level and turnover in the hypothalamus

Decreases

Decreases

Decreases

Decreases

Estradiol uptake by receptors

Decreases

Decreases

Decreases

Decreases

Threshold of sensitivity of the hypothalamus to steroid feedback

Increases

Increases

Increases

Increases

Serum estradiol level before switching-off of

Increases

—

—

Non-cyclic secretion

Comprehensive Geriatric Oncology

146

reproductive function Excretion of non-classic phenol steroids

Increases

Increases

Increases

Increases

Incidence of persistent estrus

Increases

Increases

Increases

Increases

Adrenal cortex function

Hypercorticism Disfunction

Disfunction

Hypercorticism

Tolerance to glucose

Decreases

Decreases

Decreases

Decreases

Sensitivity to insulin

Decreases

Decreases

Decreases

Decreases

Serum insulin level

Increases

Increases

Decreases

Serum cholesterol level

Increases

Increases

Hyperlipidemia

Increases

Amount of fat in the body

Increases

—

Increases

Increases

T-cell-mediated immunity

Decreases

Decreases

Decreases

Decreases

DNA-repair efficacy

Decreases

Decreases

Decreases

Decreases

DNA-adduct formation

Increases

Increases

Increases

—

Free-radical generation

Increases

Increases

Increases

—

Errors in DNA synthesis

Increases

Increases

Increases

—

Incidence of chromosome aberrations

Increases

Increases

Increases

—

Enzyme regulation

Changes

Changes

Changes

—

Cell bioenergetics

Changes

Changes

Changes

Changes

Clonal proliferation of stem cells

Increases

Increases

Increases

Increases

De-repression or Increases activation of endogenous oncogenes and oncoviruses

Increases

Increases

—

Tumor incidence

Increases

Increases

Increases

Increases

transition to an ‘older’ level of function in metabolic processes, hormonal, and immune status. This transition is asynchronous, and has different latent periods in various structures and systems of the exposed organism. Some in vitro and in vivo effects of the thymidine analogue 5-bromo-2′-deoxyuridine (BrdUrd), suggest that BrdUrd may be used to investigate the role of selective DNA damage both in carcinogenesis and in aging. BrdUrd is incorporated into replicating DNA in place of thymidine, and this effect is mutagenic.114 In addition to the usual keto form, BrdUrd may assume an enol tautomeric form, which forms hydrogen bonds with guanine instead of adenine, the normal pair for thymidine and 5-bromouracil. In the

Age as a risk factor in multistage carcinogenesis

147

absence of 5-bromouracil repair in rat DNA,115 if BrdUrd is incorporated into DNA as the enol tautomer, base-pair substitution mutations are expected to occur (GC→AT and AT→GC transitions) during subsequent DNA replication.114,116 Experiments with Drosophila melanogaster117 have shown that supplements of BrdUrd in the diet caused a reduction of insect lifespan. Craddock118 observed a dosedependent shortening of lifespan of rats exposed to BrdUrd in early life, in uncontrolled experiments, without data on tumor incidence or on biomarkers of aging. Assuming a fairly even level of BrdUrd incorporation into the DNA of various tissues of neonatal rats and long-term persistence in them,119,120 cells with highest proliferative activity would be more likely to undergo malignant transformation. Exposure to BrdUrd had dramatic effects on cellular functions, including cell differentiation, inactivation of regulatory genes or master switch,121 and proliferation.122 These changes in cellular function may favor tumor development. In one of our series of experiments,86,120,123–127 rats received subcutaneous injections of BrdUrd at 1, 3, 7, and 21 days of postnatal life at a single dose of 3.2mg per rat. BrdUrd persisted for up to 49 weeks in all tissues studied immunohistochemically, especially in tissues with normal or low cell turnover. For cells with high turnover, few or no BrdUrdlabeled cells remained at 49 weeks.120 The exposure to BrdUrd was followed by a decrease in the mean lifespan of the animals of 38% in males and 27% in females and by an increase in the rate of aging (calculated according to the Gompertz equation) in comparison with controls. Monitoring of estrus showed acceleration of natural agerelated switching-off of reproductive function in female rats, due to disturbances in the central regulation of gonadotropic function in the pituitary. Exposure of rats to BrdUrd was followed by signs of immunodepression and by increases in the incidence of chromosome aberrations and spontaneous tumors. The latency of these tumors was decreased. In offspring of rats treated neonatally with BrdUrd, increased incidences of congenital malformation and of spontaneous tumors and accelerated aging were both observed. Neonatal exposure of rats or mice to BrdUrd was followed by initiation of the neoplastic process and consequently by increased tissue susceptibility to ‘late-stage’ carcinogens such as NMU, X-irradiation, urethane, estradiol benzoate, persistent estrus syndrome, and TPA. This effect was tissue-specific, and increased the susceptibility of the animals to a wider array of tumors.126 We also evaluated the effect of DNA damage induced by neonatal exposure to BrdUrd on the susceptibility of target tissues to the carcinogenic effect of NMU injected at various ages.86 Rats exposed to BrdUrd in the neonatal period received single injections of NMU at doses of 10 or 50mg/kg at the age of 3 or 15 months. In the absence of BrdUrd pretreatment, the carcinogenic effect of NMU was dose-dependent in the 3month-old but not in the 15-month-old rats. The susceptibility to NMU-induced tumors was decreased, but the tumor-related survival was also decreased in the older animals. These data suggest an age-related decrease in the effect of NMU and, at the same time, an age-related decrease in the number of events that are necessary for tumor development. The exposure to BrdUrd was followed by an increased susceptibility to the carcinogenic effect of NMU in both 3- and 15-month-old rats. These effects were largely confined to NMU target tissues. The incidence of tumors in rats exposed to BrdUrd plus NMU at a dose of 10mg/kg was equal to that in the rats to whom the carcinogen was injected at the age of 3 or 15 months; however, the survival of fatal tumor-bearing rats was significantly

Comprehensive Geriatric Oncology

148

decreased for the older animals. When NMU was injected at a dose of 50mg/kg in BrdUrd-pretreated rats, both the relative risk of tumors and the tumor-specific survival were decreased in the older animals. Thus, our data have shown the long-term persistence of the initiating effect of neonatal treatment with BrdUrd and have provided evidence that a single perturbation of DNA induced by BrdUrd contributed substantially to the initiation of tumorigenesis and to the acceleration of aging. BrdUrd was found to induce in vitro a flat and enlarged cell shape, characteristics of senescent cells, and senescence-associated β-galactosidase in mammalian cells regardless of cell type or species.127 In immortal human cells, fibronectin, collagenase I, and p21WAF1/CIP1/SDI1 mRNAs were immediately and very strongly induced, and the mortality marker mortalin changed to the mortal type from the immortal type. Human cell lines lacking functional p21WAF1/CIP1/SDI1, p16INK4A, or p53 behaved similarly. The protein levels of p16INK4A and p53 did not change uniformly, while the level of p21WAF1/CIP1/SDI1 was increased by varying degrees in positive cell lines. Telomerase activity was suppressed in positive cell lines, but accelerated telomere shortening was not observed in tumor cell lines. These results suggest that BrdUrd activates a common senescence pathway present in both mortal and immortal mammalian cells.127 Premature aging and carcinogenesis It is well known that some syndromes of untimely aging (progeria) are associated with an increased incidence of cancer.128,129 Alongside the classical progeria syndromes, some diseases are accompanied by disturbances that might be regarded as signs of the intensified aging. For example, Stein-Leventhal syndrome (sclerocystic ovaries syndrome) occurs during puberty and is characterized by a bilateral sclerocystic enlargement of the ovaries, associated with a pronounced thickness of the capsule of the ovaries, which forms a mechanical obstacle to the ovulatory rupture of a mature follicle. Follicular cysts and hyperplasia of thecal tissue are found in such ovaries. Patients have anovulation, sterility, hirsutism, hyperlipidemia, lowered glucose tolerance, hyperinsulinemia, obesity, hypertension, and an increased incidence of breast and endometrial cancer.130 In rodents, the syndrome of persistent estrus, which normally completes the reproductive period of life, can be induced by several methods, including neonatal administration of sex steroids, exposure to some chemical carcinogens or to ionizing irradiation, housing under a constant-light regime, subtotal ovariectomy, orthotopic transplantation of an ovary into castrated animals, electrolytic lesion of anterior and/or mediobasal hypothalamus, etc.6 Regardless of the method of induction, premature aging and increased tumor incidence have been observed in rats with persistent estrus (Table 8.9).6 The induction of persistent estrus in rats using chemical carcinogens (DMBA or NMU) was associated with increased tumor incidence when compared with animals without persistent estrus exposed to a carcinogen alone.6,111,131 These observations suggest a promoting effect of the persistent estrus syndrome-associated intensified aging on carcinogenesis. In mice genetically predisposed to premature immunodeficiency, an increased incidence of spontaneous lymphoma has been observed.132 It must be emphasized that

Age as a risk factor in multistage carcinogenesis

149

some agents leading to reduced lifespans can result from genetic defects unrelated directly to mechanisms of normal aging.133 Aging and spontaneous tumorigenesis in mutant and genetically modified mice Mutant and genetically modified animal models characterized by shortening or extension of the lifespan provides a unique opportunity to evaluate the role in mechanisms of carcinogenesis of genes involved in aging. Transgenic and null mutant (‘knockout’) animal models also offer an important opportunity to identify and study both carcinogens and chemopreventive agents.134,135 Analysis of the available data on transgenic and mutant mice has shown that only a few models represent examples of lifespan extension. Ames dwarf mutant mice and MGMT transgenic mice live longer than wild-type strains.136–139 As usual, the incidence of spontaneous tumors in these mice was similar to those in controls, whereas the latent period of tumor development was increased. Practically all models of accelerated aging show increased tumor incidence and shortening of tumor latency (Table 8.10). It is noteworthy that this phenomenon has been observed both in mice that display a phenotype more closely resembling natural aging and in mice showing only partial features of the normal aging process. Why is this the case? Certainly, aging predisposes cells to accumulate mutations, some of which are necessary for the initiation of tumorigenesis in target tissues.161 Recent findings suggest that certain types of DNA damage and inappropriate mitogenic signals can also cause cells to adopt a senescent phenotype.162,163 Cells respond to a number of potentially oncogenic stimuli by adopting a senescent phenotype. These findings suggest that the senescence response is a failsafe mechanism that protects cells from tumorigenic transformation. Despite the protection from cancer conveyed by cellular senescence and other mechanisms that suppress tumorigenesis, the development of cancer is almost inevitable as mammalian organisms age. Certainly, aging predisposes cells to accumulate mutations,30,164 several of which are necessary before malignant transformation occurs. It has been shown that there is an increased incidence as well as an age-related accumulation of chromosome aberrations in the livers of short-lived strain A mice as compared with long-lived C57L/6 mice.165 Short-lived BDF1, SAMP6/Tan, and A/J mice showed significant age-related increases in spontaneous frequencies of micronucleated reticulocytes, whereas long-lived ddY, CD-1, B6C3F1, SAMR1, and MS/Ae mice did not show significant age-related differences in mean frequencies of spontaneous micronuclei.166 Long-live mutant Ames dwarf mice and p66shc−/− knockout mice were less vulnerable to oxidative damage than wild-type controls,156,167 whereas the senescence-prone SAMP strain had increased production of reactive oxygen species,140 DNA damage, and somatic mutation as compared with senescence-resistant SAMR strain.168 MGMT-overexpressing mice are more resistant to alkylating agents.138,169 whereas DNA-repair-deficient MGMT−/− and Parp−/− mice are more susceptible to the effects of alkylating agents and ionizing radiation.153,170 No significant differences were found in the mutation spectra and the mutation incidence between p53−/− and p53+/+

Comprehensive Geriatric Oncology

150

mice,171,172 whereas the incidence of spontaneous tumors in p53−/− mice was increased as compared with wild-type

Table 8.10 Longevity and tumor development in mutant and genetically modified mice Strain, mutation, gene, function

Effect on signs of Effect on aging longevity

Effect on tumor development Incidence

Latency

Refs

Mutant mice Ames dwarf mice

Postponed aging

+50−64%

No effect

Increases

137

SAMP (senescenceaccelerated mouse)

Accelerates

Decreases

No effect

Decreases

140

Klotho (kl−/−)

Accelerates

Less 100 days

No data

No data

141

Decreases

No effect

Decreases

142, 143

Accelerates

Decreases

Increases

Decreases

144, 145

hGH-releasing factor Accelerates

Decreases

Increases

Decreases

146

MGMT (DNA repair) No data

Increases

Decreases

No data

139

hSOD1 (Cu,Znsuperoxide dismutase)

Accelerates

Decreases

No data

No data

147

c-erbB-2 (HER2/neu) Accelerates (oncogene, EGF receptor)

Decreases

Increases

Decreases

148

L-myc (oncogene, DNA binding)

Accelerates

Decreases

Increases

Decreases

149

α-MUPA (urokinase plasminogen activator)

Postponed aging

Increases

No data

No data

150

GHR−/− (growth hormone receptor)

Postponed aging

Increases

No data

No data

151

XPA−/− (DNA nucleotide-excision repair)

Accelerates

Decreases

No effect

Increases

152

Parp−/− (base-

Accelerates

Decreases

Increased susceptibility to

153

nu/nu (athymic mice) Immunosenescence Transgenic mice hGH, bGH (growth hormone)

Knockout mice

Age as a risk factor in multistage carcinogenesis

excision and DNA strand-break repair)

151

alkylating agents and ionizing radiation

Ku86−/− (DNA double-strand break repair)

Accelerates

Decreases

Decreases

Decreases

154

Ku70−/− (DNA double-strand break repair)

Accelerates

Decreases

Increases

Decreases

155

p66shc−/− (adaptor protein)

No effect

+30%

No effect

No data

156

Atm−/− (ataxia telangiectasia)

Accelerates

Decreases

Increases

Decreases

157

p53−/− (tumor suppressor gene, apoptosis)

Accelerates

Decreases

Increases

Decreases

158

Cx32−/− (connexin 32, gap junction gene)

Accelerates

Decreases

Increases

Decreases

159

mTR−/− (telomerase)

Accelerates

Decreases

Increases

Decreases

160

control.173–175 Gap junction-deficient mice (Cx32−/−) have an extremely increased susceptibility to spontaneous and chemically induced carcinogenesis.160 Mice with a defect in the xeroderma pigmentosum group A (XPA) gene have a complete deficiency in nucleotide excision repair and have a more than 1000-fold higher risk of developing ultraviolet-induced skin cancer as well as an increased susceptibility of internal organs to mutagenesis and development of cancer after exposure to chemical carcinogens.152,176 However, the incidence of spontaneous tumors in these mice was relatively low—only 15% with tumors developing after the age of 18 months.152 It is very significant that the rate of accumulation of somatic mutations with age varies significantly between different tissues of mice.30,177–180 Many benign or relatively well-controlled tumors may also harbor a number of potentially oncogenic mutations, suggesting that the tissue microenvironment can suppress the expression of many malignant phenotypes.163,181 Cellular senescence has been proposed to contribute to aging of the organism. Senescent cells have been shown to accumulate with age in human tissues.181 One possibility is that the tissue microenvironment is disrupted by the accumulation of dysfunctional senescent cells. Thus, the accumulation of mutations may synergize with the accumulation of senescent cells, leading to the increasing risk for developing cancer that is a hallmark of mammalian aging. It worthy of note, however, that, in the context of the differences in human and mouse telomere biology, it has been suggested that it is possible that replicative senescence does not exist in the mouse.182 According to the multistage model of carcinogenesis, the proportion of partially transformed cells that have progressed through some stages will increase with age.6,90,183 The evidence supporting the thesis of age-related accumulation of ‘premalignant’ cells in

Comprehensive Geriatric Oncology

152

several tissues (skin, lymph node, thymus, spleen, liver, ovary, and mammary gland) have been summarized and discussed elsewhere.90 Most of the cancer susceptibility genes were originally thought to control cell proliferation and death directly, acting as ‘gatekeepers’. More recently, it has become clear

Figure 8.4 Targets in the effect of genes on aging and carcinogenesis in mouse models (the gene symbols here are for the mouse; for example, the murine Brca1 gene corresponds to the human BRCA1 gene). that genes that maintain the integrity of the genome (DNA-repair genes) are ‘caretakers’ and may be even more frequent causes of predisposition to cancer. Gatekeepers are genes that directly regulate the growth of tumors by inhibiting the growth or promoting cell proliferation. Inactivation of a given gatekeeper gene leads to a very specific tissue distribution of cancer. In contrast, inactivation of a caretaker gene leads to genetic instabilities that result in increased mutation of all genes, including gatekeepers.27 It is worth noting that this classification

Age as a risk factor in multistage carcinogenesis

153

Table 8.11 Candidates for ‘clocks of aging’ Suggested ‘clocks of aging’

Theory/hypothesis

DNA

Theories of ‘error catastrophe’; accumulation of somatic mutations; telomere shortening

Macromolecules

Crosslink theory; protein glycation theory

Mitochondria

Free-radical theory

Cell

Hayflick’s limit

Thymus

Immunoscenscence

Sex glands

Involution of sexual function

Adrenal glands

Dehydroepiandrosterone (DHEA) decrease with age

Thyroid gland

Denckla’s ‘death hormone’

Pituitary

Growth hormone decline with age

Hypothalamus

Neuroendocrine theories

Pineal gland

Melatonin as a counter of internal time

is an oversimplification of the real situation. For example, defects in the DNA-repair gene MSH2 result in a limited subset of colon cancers in humans. On the other hand, defects in the p53 and Rb pathways are present in 80–90% of all cancers. An important role in tumor promotion and progression is played by genes involved in tissue metabolic and growth pathways and by immune signaling genes, including GH, IGF1, APOE, and TCR. These genes acting as ‘homeostatic’ genes. It has been found that all of these types of genes are also involved in the control of aging (Figure 8.4). It is clear that both aging and carcinogenesis are complex multifactorial processes that can have many causes. New transgenic and knockout mouse models with prolonged or reduced longevity will thus be important for evaluating the role of genes involved in aging in mechanisms of carcinogenesis. Lifespan extension and carcinogenesis The effects of factors or drugs that increase lifespan on spontaneous tumor development may provide important clues to the interactions of aging and carcinogenesis. Some 20 compounds have been suggested as candidate agents leading to extension of lifespan.6,54,184–186 They have been selected on the basis of various theories of the mechanisms of aging (Table 8.11). The term ‘geroprotector’ was introduced for such substances,6,184,187–189 which, in contrast to ‘geriatric drugs’ (prescribed for elderly people), are intended for the treatment of younger age-groups. The question of the safety of long-term use of these preparations—including not only immediate adverse effects but also late effects (including cancer)—is a priority in this

Comprehensive Geriatric Oncology

154

field. Another aspect of the problem is related to observations on the age-related increase in cancer morbidity directly connected with the aging population.2,8,190 This is why evaluation of the possible risk of an increase in cancer incidence should be taken into account in considering the recommendation of means of life extension for practical use. Comparison of data on the mechanisms of action of geroprotectors and their influence on the development of spontaneous and experimentally induced tumors permits a deepened understanding of the interactions between two fundamental biological processes—aging and carcinogenesis. Lifespan-prolonging drugs and factors can be divided into three groups:184 (i) geroprotectors that prolong the lifespan equally in all members of the population (these substances postpone the beginning of population aging); (ii) geroprotectors that decrease the mortality of the long-lived subpopulation, leading to a rise in maximum lifespan (these substances slow down the population aging rate); (iii) geroprotectors that increase survival in the short-lived subpopulation without a change in the maximum lifespan (in this case, the aging rate increases) (Figure 8.5).

Age as a risk factor in multistage carcinogenesis

155

Figure 8.5 Types of aging delay (a) and incidence of spontaneous tumors (b) under the influence of geroprotectors of types (i), (ii), and (iii) (see text). The vertical axes show the proportion of surviving animals in (a) and the tumor rate (%) in (b). The solid curves represent the control population and the dashed curves those animals administered geroprotectors. Table 8.12 Effects of geroprotectors on spontaneous tumor development in rodents Type of geroprotector (i)

(ii)

Effect on: Tumor latency

Tumor incidence

2-Mercaptoethylamine

Increases

No effect

2-Ethyl-6-methyl-3-hydroxypyridine

Increases

No effect

Procaine (Gerovital)

No effect

No effect

Deprenyl

No effect

Decrease

Calorie restriction

Increases

Decreases

Tryptophan-deficient diet

No data

Decreases

Antidiabetic biguanides

Increases

Decreases

L-DOPA

No effect

Decreases

Phenytoin

No effect

Decreases

Succinic acid

No effect

Decreases

Epithalamin, Epitalon

Increases

Decreases

Thymalin

Increases

Decreases

Levamisole

Increases

Decreases

No data

Increases

Ethylenediaminetetraacetic acid, disodium salt

No data

Increases

Tritium oxide

No data

Increases

Benign tumors

Increases

Increases

Malignant tumors

Increases

Decreases

(iii) Selenium

Tocopherol (vitamin E):

Comprehensive Geriatric Oncology

Melatonin

Increases

156

Increases

Available data from the literature and our own studies show a good correlation between the type of geroprotector and the pattern of tumor development in the same population of animals (Table 8.12). As can be seen in Table 8.12 and Figure 8.5, geroprotectors of type (i) do not influence the incidence of tumors but do prolong tumor latency. Geroprotectors of type (ii) are effective in inhibiting spontaneous carcinogenesis, prolonging tumor latency, and decreasing tumor incidence. Drugs of type (iii) can sometimes increase the incidence of cancer.6–8 Thus, the use of growth hormone for elimination of wrinkles and prolongation of lifeexpectancy191–193 may be associated with an increased incidence of cancer.146,146,194 In the multistage model of carcinogenesis, growth hormone promotes initiated and partially transformed cells and acts like a late-stage agent or tumor promoter. Comparison of the data on the type of the slowing of mortality rate and the character of the antitumor effect of geroprotectors (Figure 8.5) suggests that the tumor incidence at a certain age is a function of the rate of aging. Taking into consideration the exponential dependence of mortality on age and data showing that the same sort of relation may exist between age and tumor incidence,2,6–8 we have suggested a correlation between the parameters characterizing these exponents. The material for the calculations was provided by data on lifespan, spontaneous tumor incidence, and the type (benign or malignant) in 22 experimental groups of male and female rats (>2000 animals in total) that served as controls in various chronic experiments or were treated with several geroprotectors. In each group, life tables were recorded, and mean lifespans and levels of mortality were calculated. Cumulative total and malignant tumor incidences at the age of 1000 days were calculated in each group by the actuarial method, and the constant characterizing the angle of the dependence of the logarithm of the age-specific tumor incidence on age was estimated.6 The calculations revealed a highly significant positive correlation between the mortality rates of the rat populations studied and the rates of agerelated increase of tumor incidence in these populations, while no positive correlation between mean lifespan and tumor incidence was found. Figure 8.5 illustrates this conclusion. It may be seen that different types of slowing of mortality may be associated with similar increases in mean lifespan. These results led to the conclusion that the incidence of tumors and the rate of their age-related increase depend directly upon the mortality rate of a population, whether or not the animals were exposed to a geroprotector. This dependence, together with data showing that environmental factors that promote tumor growth (overfeeding, constant illumination, chemical carcinogens, ionizing radiation, etc.) may cause an acceleration of aging,6–8 suggests that the mortality rate in these cases may be a function of the dose of carcinogenic agent. In the framework of multistage carcinogenesis, geroprotectors may both inhibit and enhance the passage of transformed cells through sequential carcinogenic stages. In general, the efficacy of geroprotectors in preventing cancer development decreases inversely with the age at exposure to the carcinogen. It is important to emphasize that geroprotectors of type (ii) delay aging by influencing the main regulatory systems of the organism (nervous, endocrine, and immune). These effects delay the development of agerelated changes in the microenvironment of cells exposed to carcinogens.

Age as a risk factor in multistage carcinogenesis

157

Geroprotectors may also be classified into two main groups according to their mechanism of action. The first group includes drugs that prevent stochastic lesions of macromolecules. The theoretical basis for using these drugs is provided by variants of the ‘error catastrophe’ theory, which regards aging as a result of the accumulation of stochastic damages. The second group includes substances that appear to delay intrinsic aging, i.e. programmed cellular aging. Antioxidants are the most typical representatives of the first class of geroprotectors. The age at initial administration and the doses of environmental carcinogens influence the geroprotective and tumor-preventing effects of antioxidants. The effectiveness of these substances increases when the initial administration occurs early in life and decreases with the dose of environmental carcinogen(s) to which the organism was exposed. The second class of geroprotectors includes antidiabetic biguanides (phenformin and buformin), the pineal peptide epithalamin, melatonin, and calorie-restricted diets. These factors influence the hormonal, metabolic, and immunologic functions of the body, delaying age-related changes in these functions.6 It has been suggested that calorie restriction retards cancer and aging by altering free-radical metabolism195,196 and by decreasing the incidence of age-related spontaneous mutations.197 However, there are data indicating the absence of changes in the spontaneous mutation frequency or specificity in dietary restricted mice.198 It has been shown that melatonin is a very potent endogenous scavenger of free radicals in vitro and in vivo.58,199 Melatonin inhibits the production of DNA adducts in carcinogen-exposed animals,199 protects chromosomes of human lymphocytes from radiation damage,200 and enhances gap junctional intercellular communications in vitro.201 The pineal peptide preparation epithalamin stimulates the synthesis and secretion of melatonin,202 and has antioxidant and lipid peroxidationinhibitory effects.203 We believe that the data presented above permit consideration of possible causes of the increase in cancer incidence in the last 100 years or so. The survival curves of human populations have been noted to be more and more ‘rectangular’.190,204 This is caused first of all by the decrease in infant and early mortality, which is connected with control of tuberculosis and other infectious and non-infectious diseases. As a result, a significant increase in the mean lifespan of the human population occurred. The maximum human lifespan, however, has stayed the same for centuries. Thus, the changes in the shapes of the survival curves of human populations respond to the third type of aging delay according to the classification of Emanuel and Obukhova.184 The changes of this type have been shown experimentally6,8 and epidemiologically205 to be associated with an increase in tumor incidence. In other words, for the increase in mean lifespan achieved by the decrease in mortality at early ages, we pay at later ages with an increased risk of cancer or other ‘diseases of civilization’ such as atherosclerosis and diabetes. There are two paths of development of stem cells that can be realized in an organism. One is cellular differentiation and aging, leading ultimately to individual cell death (apoptotic or necrotic). When anti-aging factors reach some limit in their ability to support tissue and functional homeostasis in essential organs, this leads to death of the organism as a whole. Another possibility is that the influence of harmful exogenous or endogenous factors could lead to dedifferentiation, immortalization, and the formation of a clone of neoplastic cells (Figure 8.6). Both processes are multistage in nature, and many of the steps involved are well characterized in relation to the process

Comprehensive Geriatric Oncology

158

Figure 8.6 Targets in the effect of geroprotectors on aging and carcinogenesis. of carcinogenesis.6,8,206 However, the multistage pattern of aging still requires further study.207 The simplified scheme presented here allows one to understand why drugs that prevent some factors from accelerating aging or, in contrast, that stimulate anti-aging factors—in different ways, affecting homeostasis in tissues and in the organism as a whole—may promote or inhibit tumor development. We believe that further progress in modern preventive medicine is impossible without radical changes in approaches to public health and to the prolongation of the human lifespan. In the burst of industrialization, urbanization, and increasing environmental pollution, one may hope only for partial alleviation of the unfavorable effects on human health. The achievement of significant results in this field will require the solution of very complex scientific and technical problems, as well as considerable economic expense. It is probably true that, even at present, changes in lifestyle (i.e. in dietary and sexual habits and in smoking and alcohol consumption), may be the most promising approach to achieving a decrease in cancer incidence and hence an increase in lifespan. It seems to be becoming more and more clear that approaches that normalize the age-related changes in hormonal status, metabolism, and immunity, and thus slow down the realization of the genetic program of aging (not postponing aging, but decelerating its rate), will be the most effective in protection from aging and the prevention of cancer. These approaches include the use of the pineal peptide preparations epithalamin202,208 and Epitalon (AlaGlu-Asp-Gly),209–211 and of calorie restriction or drugs mimicking it (e.g. antidiabetic biguanides, sugar substitutes, and possibly anorexants). Approaches that protect from the initiating action of damaging agents (antioxidants and antimutagens) may be important additional means of prophylaxis against accelerated aging, especially under conditions of an increased risk of exposure to harmful environmental agents. Generally speaking, antioxidants and antimutagens work as inhibitors of time-dependent processes in the

Age as a risk factor in multistage carcinogenesis

159

organism, whereas calorie-restricted diets, antidiabetic biguanides, and pineal peptide preparations influence mainly age-dependent processes in the organism.212 Table 8.13 presents a summary of the gene expression profiles of aging and carcinogenesis, based on data published by Lee et al,213,214 while Table 8.14 shows the corresponding (hypothetical) effects of geroprotectors. Although available data are scarce or absent, it seems that only a few geroprotectors involves genetic mechanisms in their anti-aging effects. The study of these mechanisms should be a priority for future gerontological research. It should be stressed that this critical review of the available data on the effect of lifeprolonging drugs has shown that the majority of studies are invalid from the point of

Table 8.13 Gene expression profiles of aging and carcinogenesis (↑, increase; ↓, decrease) Process

Stress response

Energy metabolism

Neuronal injury

Biosynthesis Cancer

Aging

↑

↓

↑

↓

↑

Carcinogenesis ↑

↓

↑

↑

↑

Table 8.14 Hypothetical effects of geroprotectors (↑, increase; ↓, decrease) Geroprotector Stress response

Energy metabolism

Neuronal injury

Biosynthesis Cancer

Calorie restriction

↓

↑

↓

↑

↓

Antioxidants

↓

?

↓(↑)

?

↓(↑)

Phenormin

↓

↑

↓

?

↓

Deprenyl

↓

?

↓

?

↓

L-DOPA

↓

?

↓(↑)

↑

↓

Succinic acid

↓

↑

↓

?

↓

Melatonin

↓

?

↓

?

↑(↓)

Epithalamin

↓

↑

↓

↑

↓

view of current guidelines for long-term testing of chemicals for carcinogenic safety and, to some extent, from the point of view of the appropriateness of gerontological experiments.215,216 Often, in experiments with rodents, the drugs to be tested were given to a only small number of animals (10–20); treatment started when animals were old and weaker animals had already died, with only the more robust still alive; observations were halted at an age with 50% mortality (or some other arbitrary figure), rather than at the natural death of the last survivor; autopsies and appropriate pathologic and morphologic

Comprehensive Geriatric Oncology

160

examinations were sometimes not performed; body weight gain and food consumption were not monitored, etc. Conclusions The incidence of cancer increases with age in humans and in laboratory animals alike, but patterns of age-related distribution of tumors are different for different tissues and different tumors. Aging may increase or decrease the susceptibility of individual tissues to early carcinogens and usually facilitates promotion and progression of carcinogenesis. Aging may predispose to cancer by two mechanisms: tissue accumulation of cells in late stages of carcinogenesis and alterations in internal homeostasis—in particular, alterations in the immune and endocrine systems. Increased susceptibility to the effects of late-stage carcinogens is found in both aged animals and aged humans, as predicted by the multistage model of carcinogenesis. Old animals should be included in standard protocols for long-term assay of carcinogenicity—in particular, of compounds with suggested tumor-promoting activity. Strategies for cancer prevention must include not only measures to minimize exposure to exogenous carcinogenic agents, but also measures to normalize age-related alterations in the internal milieu. Lifespan-prolonging drugs (geroprotectors) may either postpone population aging and prolong tumor latency or decrease mortality in long-lived individuals in populations and inhibit carcinogenesis. At least some geroprotectors may increase the survival of short-lived individuals in populations, but may increase the incidence of malignancy. It is pertinent to remember Bauer,217 who wrote six decades ago that ‘the problem of cancer apparently coincides with the problem of senility. The aim of science is to slow down the process of aging and to really decrease the probability of cancer development at the same time.’ References 1. Dix D, Cohen P, Flannery J. On the role of aging in cancer incidence. J Theor Biol 1980; 83:163–73. 2. Dix D, Cohen P. On the role of aging in carcinogenesis. Anticancer Res 1999; 19:723–6. 3. Parkin DM, Muir CS, Whelan SL et al. Cancer Inddence in Five Continents, Vol VII. Lyon: IARC Press, 1997. 4. Peto R, Roe FJC, Lee PN et al. Cancer and ageing in mice and men. Br J Cancer 1975; 32:411– 26. 5. Peto R, Parish SE, Gray RG. There is no such thing as ageing, and cancer is not related to it. In: Age-Related Factors in Carcinogenesis (Likhachev A, Anisimov V, Montesano R, eds). Lyon: IARC Press, 1985:43–53. 6. Anisimov VN. Carcinogenesis and Aging, Vols 1 and 2. Boca Raton, FL: CRC Press, 1987. 7. Anisimov VN. Age-related mechanisms of susceptibility to carcinogenesis. Semin Oncol 1989; 16:10–19. 8. Anisimov VN. Aging and cancer in transgenic and mutant mice. Front Biosci 2003; 1: s883–902. 9. Dilman VH. Development, Aging, and Disease. A New Rationale for an Intervention Strategy. Chur, Switzerland: Harwood Academic Publishers, 1994. 10. Miller RA. Gerontology as oncology. Cancer 1991; 68:2496–501.

Age as a risk factor in multistage carcinogenesis

161

11. Kaldor JM. Day NE. Interpretation of epidemiological studies in the context of the multistage model of carcinogenesis. In: Mechanisms of Environmental Cardnogenesis, Vol 2 (Barret JC, ed). Boca Raton, FL: CRC Press, 1987:21–57. 12. Tomatis L (ed). Cancer. Causes, Occurrence and Control. Lyon: IARC Press, 1990. 13. Harvey M, Voges H, Lee EYHP et al. Mice deficient in both p53 and Rb develop tumors primarily of endocrine origin. Cancer Res 1995; 55:1146–51. 14. Birnbaum LS. Pharmacokinetic basis of age-related changes in sensitivity to toxicants. Annu Rev Pharmacol Toxicol 1991; 31:101–28. 15. Anisimov VN, Birnbaum LS, Butenko GM et al. Principlesfor Evaluating Chemical Effects on the Aged Population. Environmental Health Criteria 144. Geneva: WHO, 1993. 16. Mayersohn M. Pharmacokinetics in the elderly. Environ Health Perspect 1994; 102(Suppl 11):119–24. 17. Preston-Martin S, Pike MC, Ross RK et al. Increased cell division as a cause of human cancer. Cancer Res 1990; 50:7415–21. 18. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57–70. 19. Harris CC. Chemical and physical carcinogenesis. advances and perspectives for the 1990s. Cancer Res 1991; 51:5023s-44s. 20. Barrett JC. Mechanisms of action of known human carcinogens. In: Mechanisms of Cardnogenesis in Risk Identification (Vainio H, Magee PN, McGregor DB, McMichael AJ, eds). Lyon: IARC Press, 1992: 115–34. 21. Likhachev AJ. Effects of age on DNA repair in relation to carcinogenesis. In: Cancer and Aging (Macieira-Coelho A, Nordenskjold B, eds). Boca Raton, FL: CRC Press, 1990:97–108. 22. McDonnell TJ. Cell division versus cell death. a functional model of multistep neoplasia. Mol Carcinogen 1993; 8:209–13. 23. Evan G, Littlewood T. A matter of life and cell death. Science 1998; 281:1317–21. 24. Farber E. Programmed cell death: necrosis versus apoptosis. Mod Pathol 1994; 7:605–9. 25. Zakeri Z, Lockshin RA. Physiological cell death during development and its relationship to aging. Ann NY Acad Sci 1994; 719:212–29. 26. Hermeking H, Eick E. Mediation of c-myc-induced apoptosis by p53. Science 1994; 265:2091– 6. 27. Kinzler KW, Vogelstein B. Gatekeepers and caretakers. Nature 1997; 386:761–3. 28. Gart JJ, Krewski D, Lee PN, Tarone RE. Wahrendorf J (eds). Statistical Methods in Cancer Research. Vol III—The Design and Analysis of Long-Term Animal Experiments. Lyon: IARC Press, 1986. 29. Strehler BL. Genetic instability as the primary cause of human aging. Exp Gerontol 1986; 21:283–319. 30. Vijg J. Somatic mutations and aging. a re-evaluation. Mutat Res 2000; 447:117–35. 31. Cheng KC, Loeb LA. Genomic instability and tumor progression. mechanistic considerations. Adv Cancer Res 1993; 60:121–56. 32. Lindahl T. Instability and decay of the primary structure of DNA. Nature 1993; 362:709–15. 33. Pitot HC. The molecular biology of carcinogenesis. Cancer 1993; 72: 962–70. 34. Bishop JM. Molecular themes in oncogenesis. Cell 1991; 64:235–48. 35. Harris CC. Tumor suppressor genes, multistage carcinogenesis and molecular epidemiology. In: Mechanisms of Carcinogenesis in Risk Identification (Vainio H, Magee PN, McGregor DB. McMichael AJ, eds). Lyon: IARC Press, 1992:67–86. 36. Knudson AG. Antioncogenes and human cancer. Proc Natl Acad Sci USA 1993; 9:10914–1113. 37. Lehman TA, Harris CC. Mutational spectra of protooncogenes and tumor suppressor genes: clues in predicting cancer etiology. In: DNA Adducts. Identification and Biological Significance (Hemminki K, Dipple A, Shuker DEG et al, eds). Lyon: IARC Press, 1994:399–414. 38. Wallace SS, Van Houten B, Wah Kow Y (eds). DNA damage. Effects on DNA structure and protein recognition. Ann NY Acad Sci 1994; 726.

Comprehensive Geriatric Oncology

162

39. Holliday R. Mechanisms for the control of gene activity during development. Biol Res 1990; 65:431–71. 40. Jones PA, Buckley JD. The role of DNA methylation in cancer. Adv Cancer Res 1990; 54:1–23. 41. Catania J, Fairweather DS. DNA methylation and cellular aging. Mutat Res 1991; 256:283–93. 42. Counts JL, Goodman JI. Hypomethylation of DNA: an epigenetic mechanism involved in tumor promotion. Mol Carcinogen 1994; 11: 185–8. 43. Ono T, Uehara Y, Kurishita A et al. Biological significance of DNA methylation in the aging process. Age Aging 1993; 22:534–43. 44. Ono T, Takahashi N, Okada S. Age-associated changes in DNA methylation and mRNA level of the c-myc gene in spleen and liver of mice. Mutat Res 1989; 219:39–50. 45. Matoha HF, Cosgrove JW, Atak JR, Rapoport SI. Selective elevation of c-myc transcript levels in the liver of the aging Fischer-344 rat. Biochem Biophys Res Commun 1987; 147:1–7. 46. Olafsson B, Chardin P, Touchot N et al. Expression of the ras-related ralA, rhol2 and rab genes in adult mouse-tissues. Oncogene 1988; 3: 231–4. 47. Ono T, Tawa R, Shinya K et al. Methylation of the c-myc gene changes during aging process of mice. Biochem Biophys Res Commun 1986; 139:1299–303. 48. Novikov LB, Tlevlesov NJ, Timoshenko MG et al. Expression of proto-oncogenes in organs of adult intact rats. Exp Oncol 1989; 11: 14–17. 49. Semsei I, Ma S, Culter RG. Tissue and age specific expression of the myc proto-oncogene family throughout the life span of the C57BL/6J mouse strain. Oncogene 1989; 4:465–70. 50. Hemminki K, Dipple A, Shuker DEG et al (eds). DNA Adducts. Identification and Biological Significance. Lyon: IARC Press, 1994. 51. Dipple A. DNA adducts of chemical carcinogens. Carcinogenesis 1995; 16:437–41. 52. Park JW, Ames BN. 7-Methylguanine adducts in DNA are normally present at high levels and increase on aging. analysis by HPLC with electrochemical detection. Proc Natl Acad Sci USA 1988; 85:7467–70. 53. Randerath K, Li D, Moorthy B, Randerath E. I-compounds: endogenous DNA markers of nutritional status, ageing, tumour promotion and carcinogenesis. In: Postlabelling Methods of Detection of DNA Adducts (Phillips DH, Castegnaro M, Bartch H, eds). Lyon: IARC Press, 1993:157–65. 54. Harman DH. Free-radical theory of aging. increasing the functional life span. Ann NY Acad Sci 1994; 717:257–66. 55. Ames BN, Shigenaga MB, Hagen TM. Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci USA. 1993; 90: 7915–22. 56. Yu BP (ed). Free Radicals in Aging. Boca Raton, FL: CRC Press, 1993. 57. Shigenaga MK, Hagen TV, Ames BN. Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci USA 1994; 91: 10771–8. 58. Reiter RJ. Experimental observations related to the utility of melatonin in attenuating agerelated diseases. Adv Gerontol 1999; 3: 121–32. 59. Du MQ, Carmichael PL, Phillips DH. Induction of activated mutations in the human c-Ha-ras proto-oncogene by oxygen free radicals. Mol Carcinogen 1994; 11:170–5. 60. Fraga CG, Shigenaga MK, Park J-W et al. Oxidative damage to DNA during aging 8-hydroxy2'-deoxyguanosine in rat organ DNA and urine. Proc Natl Acad Sci USA 1990; 87:4533–7. 61. Turk PW, Laayoun A, Smith SS, Weitzman SA. DNA adduct 8-hydroxyl-2'-deoxyguanosine (8-hydroxyguanosine) affects function of human DNA methyltransferase. Carcinogenesis 1995; 16:1253–5. 62. Nair J, Barbin A, Guichard Y, Bartsch H. 1, N6-Ethenodeoxy-adenosine and 3,, N4ethenodeoxycytidine in liver DNA from human and untreated rodents detected by immunoaffinity/32P-post-labeling. Carcinogenesis 1995; 16:613–17. 63. Cerni C. Telomere, telomerase, and myc. An update. Mutat Res 2000; 462:31–47. 64. Shay JW, Wright WE, Werbin H. Loss of telomeric DNA during aging may predispose cells to cancer (review). Int J Oncol 1993; 3: 559–63.

Age as a risk factor in multistage carcinogenesis

163

65. Reddel RR. A reassessment of the telomere hypothesis of senescence. Bioessays 1998; 20:977– 84. 66. Wynford-Thomas D, Bond JA, Wyllie FS, Jones CJ. Does telomere shortening drive selection for p53 mutation in human cancer? Mol Carcinogen 1995; 12:119–23. 67. Lutz WK. Endogenous genotoxic agents and processes as a basis of spontaneous carcinogenesis. Mutat Res 1990; 238:287–95. 68. Ames BN, Gold LS. Endogenous mutagens and the causes of aging and cancer. Mutat Res 1991; 250:3–16. 69. Smith KC. Spontaneous mutagenesis. experimental, genetic and other factors. Mutat Res 1992; 277:139–62. 70. Vijg J, Gossen JA. Somatic mutations and cellular aging. Comp Biochem Physiol 1993; 104B: 429–37. 71. Anisimov VN, Gvardina OE. N-Nitrosomethylurea-induced carcinogenesis in the progeny of male rats of different ages. Mutat Res 1995; 316:139–45. 72. Berenblum I. Sequential aspects of chemical carcinogenesis. skin. In: Cancer—A Comprehensive Treatise (Becker J, ed). New York: Plenum Press, 1975:323–44. 73. Consensus Report. In: Mechanisms of Carcinogenesis in Risk Identification (Vanio H, Magee PN, McGregor D, McMichael AJ, eds). Lyon: IARC Press, 1992; 9–56. 74. Slaga TJ (ed). Mechanisms of Tumor Promotion, Vols 1–4. Boca Raton, FL: CRC Press, 1983/84. 75. Slaga TJ. Can tumor promotion be effectively inhibited? In: Models. Mechanisms and Etiology of Tumor Promotion (Borzsonyi M, Day NE, Lapis K, Yamasaki H, eds). Lyon: IARC Press, 1984:497–506. 76. Stenback F, Peto R, Shubik P. Initiation and promotion at different ages and doses in 2200 mice. III. Linear extrapolation from high doses may underestimate low-dose tumour risks. Br J Cancer 1981; 44:24–34. 77. Ebbesen P. Papilloma development on TPA treated young and senescent mouse skin. In: AgeRelated Factors in Carcinogenesis (Likhachev A, Anisimov V, Montesano R, eds). Lyon: IARC Press, 1985:167–71. 78. Ward JM. Increased susceptibility of liver of aged F.344/Ncr rats to the effects of phenobarbital on the incidence, morphology, and histochemistry of hepatocellular foci and neoplasms. J Natl Cancer Inst 1983; 71:815–23. 79. Ward JM, Lynch P, Riggs C. Rapid development of hepatocellular neoplasms in aging male C3H/HeNcr mice given phenobarbital. Cancer Lett 1988; 39:9–18. 80. Reuber MD, Glover EL. Hyperplastic and early neoplastic lesions of the liver in Buffalo strain rats of various ages given subcutaneous carbon tetrachloride. J Natl Cancer Inst 1967; 38:891– 7. 81. Schulte-Hermann R, Timmermann-Trosiener I, Schuppler J. Promotion of spontaneous preneoplastic cells in rat liver as a possible explanation of tumor production by nonmutagenic compounds. Cancer Res 1983; 43:839–44. 82. Cuttley RC, Marsman DS, Popp JA. Age-related susceptibility to the carcinogenic effect of the peroxisome proliferator WY-14,643 in rat liver. Carcinogenesis 1991; 12:469–73. 83. Kraupp-Grasl B, Huber W, Taper H, Schulte-Hermann R. Increased susceptibility of aged rats to hepatocarcinogenesis by the peroxisome proliferator nafenopin and the possible involvement of altered liver foci occurring spontaneously. Cancer Res 1991; 51:666–71. 84. Anisimov VN. Effect of age on dose-response relationship in carcinogenesis induced by single administration of AT-nitrosomethylurea in female rats. J Cancer Res Clin Oncol 1988; 114:628–35. 85. Anisimov VN. Age and dose-dependent carcinogenic effects of N-nitrosomethylurea administered intraperitoneally in a single dose to young and adult female mice. J Cancer Res Clin Oncol 1993; 119: 657–64.

Comprehensive Geriatric Oncology

164

86. Anisimov VN. Effect of aging and interval between primary and secondary treatment in carcinogenesis induced by neonatal exposure to 5-bromodeoxyuridine and subsequent administration of N-nitrosomethylurea in rats. Mutat Res 1995; 316:173–87. 87. Lee G-H, Sawada N, Mochizuki Y et al. Immortal epithelial cells of normal C3H mouse liver in culture: possible precursor populations for spontaneous hepatocellular carcinoma. Cancer Res 1989; 49:403–9. 88. Ogawa K, Onoe T, Takeuchi M. Spontaneous occurrence of y glutamyl transpeptidase-positive hepatocytic foci in 105-week-old Wistar and 72-week-old Fischer 344 male rats. J Natl Cancer Inst 1981; 67:407–12. 89. Ebbesen P. Reticulosarcoma and amyloid development in BALB/c mice inoculated with syngeneic cells from young and old donors. J Natl Cancer Inst 1971; 47:1241–5. 90. Anisimov VN. Aging and the mechanisms of carcinogenesis. some practical implications. J Exp Clin Cancer Res 1998; 17:263–8. 91. Sobue T. Yamaguchi N, Suzuki T et al. Lung cancer incidence rate for male ex-smokers according to age at cessation of smoking. Jpn J Cancer Res 1993; 84:601–7. 92. Ershler WB. Mechanisms of age-associated reduced tumor growth and spread in mice. In: Geriatric Oncology (Balducci L, Lyman GH, Ershler WB, eds). Philadelphia: Lippincott, 1992:76–85. 93. Ershler WB. Explanations for reduced tumor proliferative capacity with age. Exp Gerontol 1992; 27:551–8. 94. Miller RA. Aging and cancer—another perspective. J Gerontol 1993; 48: B8–9. 95. Yancik R, Yates JW (eds). Cancer in the Elderly. Approaches to Early Detection and Treatment. New York: Springer-Verlag, 1989. 96. Berrino F, Sant M, Verdecchia A et al (eds). Survival of Cancer Patients in Europe. EUROCARE Study. Lyon: IARC Press, 1995. 97. Anisimov VN, Zhukovskaya NV, Loktionov AS et al. Influence of host age on lung colony forming capacity of injected rat rhabdomyosarcoma cells. Cancer Lett 1988; 40:77–82. 98. Anisimov VN, Zhukovskaya NV, Loktionov AS et al. Host and donor age dependency of colony forming capacity of lung-affine rat rhabdomyosarcoma RA-2 cells. In: Abstracts of the International Conference on Tumor Micro Environment. Progression, Therapy and Prevention, Tiberias, Israel, 1995:6. 99. McCullough KD, Coleman WB, Smith GJ, Grisham JW. Age-dependent regulation of the tumorigenic potential of neoplastically transformed rat liver epithelial cells by the liver microenvironment. Cancer Res 1994; 54:3668–71. 100. Larionov LF. Cancer and Endocrine System. Leningrad: Meditsina, 1938. 101. Ohno S. Nagai Y. Genes in multiple copies as the primary cause of aging. In: Genetic Effects of Aging (Bergsma D, Harrison DE, Paul NW, eds). New York: Alan R Liss, 1978:501–14. 102. Anisimov VN. Blasomogenesis in persistent estrus rats. Vopr Onkol 1971; 8:67–75. 103. Teramoto S, Fukuchi Y, Uejima Y et al. Influences of chronic tobacco smoke inhalation on aging and oxidant-antioxidant balance in the senescent-accelerated mouse (SAM)-P/2. Exp Gerontol 1993; 28:87–95. 104. Sacher GA. Life table modification and life prolongation. In: Handbook of the Biology of Aging (Finch CE and Hayflick L, eds). New York: Van Nostrand Reinhold, 1977:582–638. 105. Alexandrov SN. Late Radiation Pathology of Mammals. Fortschritte der Onkologie, Bd 6. Berlin: Akademie-Verlag, 1982. 106. Golostchapov PV, Boitsova VP, Vorobjeva MI. Comparative Analysis of Effectiveness of Chronic External Irradiation at Different Daily Doses. Moscow: Central Research Institute Atominform, 1988. 107. Moskalev YI. Late Effects of Ionizing Irradiation. Moscow; Meditsina, 1991. 108. Beniashvili DSh, Bilanishvili VG, Menabde MZ. Low-frequency electromagnetic radiation enhances the induction of rat mammary tumors by nitrosomethyl urea. Cancer Lett 1991; 61:75–9.

Age as a risk factor in multistage carcinogenesis

165

109. Stevens RG, Wilson BW, Anderson LE. The Melatonin Hypothesis. Breast Cancer and Use of Electric Power. Columbus: Battele Press, 1997. 110. Brainard GC, Kaver R, Kheifets LI. The relationship between electromagnetic field and light exposure to melatonin and breast cancer risk. a review of the relevant literature. J Pineal Res 1999; 26:65–100. 111. Anisimov VN, Zhukova OV, Beniashvili DS et al. Effect of light deprivation and electromagnetic fields on mammary carcinogenesis in female rats. Adv Pineal Res 1994; 7:231– 6. 112. McLean J, Thansandote A, Lecueyer D et al. A 60-Hz magnetic field increases the incidence of squamous cell carcinomas in mice previously exposed to chemical carcinogens. Cancer Lett 1995; 92: 121–5. 113. Nikitina VM. Effect of modulated electromagnetic fields induced by marine radio transmitters on aging of the organism. In: Proceedings of International Conference on Shipbuilding (ISC), October 8–12, 1994, St Petersburg, 1994, Sec F: 60–6. 114. Morris SH. The genetic toxicology of 5-bromodeoxyuridine in mammalian cells. Mutat Res 1991; 258:161–88. 115. Lindahl T. DNA repair enzymes. Annu Rev Biochem 1982; 51: 61–87. 116. Davidson RL, Broeker P, Ashman CR. DNA base sequence changes and sequence specificity of bromodeoxyuridine-induced mutations in mammalian cells. Proc Natl Acad Sci USA 1988; 85:4406–10. 117. Potapenko AI. Radiation-induced shortening of life span and natural aging in D. melanogaster. Abstract of Diss Cand Biol Sci, Institute of Biophysics of the USSR Academy of Sciences, Puschino, 1982. 118. Craddock VM. Shortening of the life span caused by administration of 5-bromodeoxyuridine to neonatal rats. Chem-Biol Interact 1981; 35:139–44. 119. Likhachev AJ, Tomatis L, Margison GP. Incorporation and persistence of 5bromodeoxyuridine in newborn rat tissue DNA. Chem-Biol Interact 1983; 46:31–8. 120. Ward JM, Henneman JR, Osipova GY, Anisimov VN. Persistence of 5-bromo-2'-deoxyuridine in tissues of rats after exposure in early life. Toxicology 1991; 70:345–52. 121. Tapscott SJ, Lassar AB, Davis RL, Weintraub H. 5-Bromo-2'-deoxyuridine blocks myogenesis by extinguishing expression of MyoD1. Science 1989; 245:532–53. 122. Weghorst CM, Henneman JR, Ward JH. Dose response of hepatic and DNA synthesis rates to continuous exposure of bromodeoxyuridine (BrdU) via slow-release pellets or osmotic minipumps in male B6C3F1 mice. J Histochem Cytochem 1991; 39: 177–82. 123. Napalkov NP, Anisimov VN, Likhachev AJ, Tomatis L. 5-Bromo-deoxyuridine-induced carcinogenesis and its modification by persistent estrus syndrome, unilateral nephrectomy, and X-irradiation in rats. Cancer Res 1989; 49:318–23. 124. Anisimov VN, Osipova GY. Effect of neonatal exposure to 5-bromo-2'-deoxyuridine on life span, estrus function and tumor development in rats—an argument in favor of the mutation theory of aging? Mutat Res 1992; 275:97–110. 125. Anisimov VN, Osipova GY. Life span reduction and carcinogenesis in the progeny of rats exposed neonatally to 5-bromo-2'-deoxyuridine. Mutat Res 1993; 295:113–23. 126. Anisimov VN. The sole DNA damage induced by bromodeoxyuridine is sufficient for initiation of both aging and carcinogenesis in vivo. Ann NY Acad Sci 1994; 719:494–501. 127. Michishita E, Nakabayashi K, Suzuki T et al. 5-Bromodeoxyuridine induces senescence-like phenomena in mammalian cells regardless of cell type or species. J Biochem 1999; 125:1052–9. 128. Mikhelson VM. Diseases of DNA Repair and Their Relation with Carcinogenesis and Aging. Moscow: All-Union Institute for Medical Information Publishing, 1983. 129. Lehmann AR. Ageing. DNA repair of radiation damage and carcinogenesis. fact and fiction. In: Age-Related Factors in Carcinogenesis (Likhachev A, Anisimov V, Montesano R, eds). Lyon: IARC Press, 1985:203–14. 130. Dilman VM. Endocrinological Oncology. Leningrad: Meditsina, 1983.

Comprehensive Geriatric Oncology

166

131. Alexandrov VA. Popovich IG, Anisimov VN, Napalkov NP. Influence of hormonal disturbances on transplacental and multigeneration carcinogenesis. In: Perinatal and Multigeneration Carcinogenesis (Napalkov NP, Rice JM, Tomatis L, Yamasaki H, eds). Lyon: IARC Press, 1989:35–50. 132. Miller RA, Turke P, Chrips C et al. Age-sensitive T-cell phenotypes covary in genetically heterogenous mice and predict early death from lymphoma. J Gerontol 1994; 49:B255–62. 133. Harrison DE. Potential misinterpretations using models of accelerated aging. J Gerontol 1994; 49:B245. 134. Alexander J. Use of transgenic mice in identifying chemopreventive agents. Toxicol Lett 2000; 112/113:507–12. 135. Gulezian D, Jacobson-Kram D, McCullough CB et al. Use of transgenic animals for carcinogenicity testing. considerations and imlications for risk assessment. Toxicol Pathol 2000; 28:482–99. 136. Bartke A, Brown-Borg H, Mattison J et al. Prolonged longevity of hypopituitary mice. Exp Gerontol 2001; 36:21–8. 137. Mattison JM. Ames dwarf mice. a model for delayed aging. Adv Gerontol 2000; 4:141–6. 138. Walter CA, Grabowski DT, Street KA et al. Analysis and modulation of DNA repair in aging. Mech Ageing Dev 1997; 98:203–22. 139. Qin X, Zhang S, Matsukuma S et al. Protection against malignant progression of spontaneously developing liver tumors in transgenic mice expressing O6-methylguanine-DNA methyltransferase. Jpn J Cancer Res 2000; 91:1085–9. 140. Takeda T. Senescence-accelerated muse (SAM): a biogerontological resourse in aging research. Neurobiol Aging 1999; 20:105–10. 141. Kuro-o M, Matsumura Y, Aizawa H et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997; 390:45–51. 142. Sharkey FE, Fogh J. Incidence and pathological features of spontaneous tumors in athymic nude mice. Cancer Res 1979; 39:833–9. 143. Shisa H, Kojima A, Hiai H. Accelerating effect of nude gene heterozygocity on spontaneous AKR thymic lymphomagenesis. Jpn J Cancer Res 1986; 77:568–71. 144. Wolf E, Kahnt E, Ehrlein J. Effects of long-term elevated serum levels of growth hormone on life expectancy of mice. lessons from transgenic animal models. Mech Ageing Dev 1993; 68:71– 87. 145. Bartke A. Growth hormone and aging. Endocrine 1998; 8:103–8. 146. Asa SL, Kovacs K, Stefaneanu L et al. Pituitary mammosomatotroph adenomas develop in old mice transgenic for growth hormone-releasing hormone. Proc Soc Exp Biol Med 1990; 193: 323–5. 147. Cebalos Picot I. Transgenic mice overexpressing copper-zinc superoxide dismutase: a model for the study of radical mechanisms and aging. CR Séances Soc Biol Fil 1993; 187:308–23. 148. Alimova IN. Peculiarities of estrus cycle and dynamics of mammary tumor development in erbB-2/neu transgenic mice. In: Abstracts of the 3rd All-Russian Medico-Biological Conference of Junior Researchers ‘Human and His Health’. St Petersburg University, 2000:6–8. 149. Moroy T, Fischer PE, Lee G et al. High frequency of myelomonocytic tumors in aging E-mu L-myc transgenic mice. J Exp Med 1992; 175:313–22. 150. Miskin R, Masos T, Yahav S et al. αMUPA mice. a transgenic model for increased life span. Neurobiol Aging 1999; 20:555–64. 151. Coschigano KT, Clemmons D, Bellush LL, Kopchick JJ. Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. Endocrinology 2000; 141:2608–13. 152. Van Steeg H, Klein H, Beems RB, van Kreijl CF. Use of DNA repair-deficient XPA transgenic mice in short-term carcinogenicity testing. Toxicol Pathol 1998; 26:742–9. 153. Masutani M, Nozaki T, Nakamoto K et al. The reponse of Parp knockout mice against DNA damaging agents. Mutat Res 2000; 462:159–66.

Age as a risk factor in multistage carcinogenesis

167

154. Vogel H, Lim DS, Karsenty G et al. Deletion of Ku86 causes early onset of senescence in mice. Proc Natl Acad Sci USA 1999; 96: 10770–5. 155. Gu Y, Seidi KJ, Rathbun GA et al. Growth retardation and leakey SCID phenotype of Ku70deficient mice. Immunity 1997; 7: 653–65. 156. Migliaccio E, Giorgio M, Mele S et al. The p66shr adaptor protein controls oxidative stress response and life span in mammals. Nature 1999; 402:309–13. 157. Barlow C, Hirotsune S, Paylor R et al. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 1996; 86:159–71. 158. Donehower LA, Harvey M, Vogel H et al. Effects of genetic backgroun on tumorigenesis in p53-deficient mice. Mol Carcinogen 1995; 14:16–22. 159. Temme A, Buchmann A, Gabriel HD et al. High incidence of spontaneous and chemically induced liver tumors in mice deficient for connexin32. Curr Biol 1997; 7:713–16. 160. Rudolph KL, Chang S, Lee HW et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 1999; 96: 701–12. 161. Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature 1998; 396:643–9. 162. Campisi J. Aging and cancer. the doube-edged sword of replicative senescence. J Am Geriatr Soc 1997; 45:482–8. 163. Campisi J. Cancer, aging and cellular senescene. In Vitro 2000; 14: 183–8. 164. Holliday R. Somatic mutatons and aging. Mutat Res 2000; 463: 173–8. 165. Crowley C, Curtis HJ. The development of somatic mutations in mice with age. Proc Natl Acad Sci USA 1963; 49:625–8. 166. Sato S, Taketomi M, Nakajima M et al. Effect of aging on spontaneous micronucleus frequencies in peripheral blood of nine mouse strains. Mutat Res 1995; 338:51–7. 167. Brown-Borg HM, Rakoczy SG. Catalase expression in delayed and premature aging mouse models. Exp Gerontol 2000; 35:199–212. 168. Hosokawa M, Fujisawa H, Ax S et al. Age-associated DNA damage is accelerated in the senescence-accelerated mice. Mech Ageing Dev 2000; 118:61–70. 169. Allay E, Veigl M, Gerson SL. Mice over-expressing human O6-alkylguanine-DNA alkyltransferase selectively reduce O6-methylguanine mediated carcinogenic mutations to threshold levels after N-methyl-N-nitrosourea. Oncogene 1999; 18:3783–7. 170. Glassner BJ, Weeda G, Allan JM et al. DNA repair methyl-transferase (Mgmt) knockout mice are sensitive to the lethal effects of chemotherapeutic alkylating agents. Mutagenesis 1999; 14:339–47. 171. Nishino H, Knoll A, Buettner VL et al. p53 wild-type and p53 nullizygous Big Blue transgenic mice have similar frequencies and patterns of observed mutation in liver, spleen and brain. Oncogene 1995; 11:263–70. 172. Buettner VL, Nishino H, Haavik J et al. Spontaneous mutation frequencies and spectra in p53+/+ and p53−/− mice: a test of the ‘guardian of the genome’ hypothesis in th Big Blue transgenic mouse mutation detection system. Mutat Res 1997; 379. 13–20. 173. Jacks T, Remington L,Williams BO et al. Tumor spectrum analysis in p53-mutant mice. Curr Biol 1994; 4:1–7. 174. Hursting SD, Perkins SN, Haies DC et al. Chemoprevention of spontaneous tumorigenesis in p53-knockout mice. Cancer Res 1995; 55:3949–53. 175. Atardi LD, Jacks T. The role of p53 in tumour suppression: lessons from mouse models. Cell Mol Life Sci 1999; 55:48–63. 176. Van Steeg H, Mullenders LHF, Vijg J. Mutagenesis and carcinogenesis in nucleotide excision repair-deficient XPA knock out mice. Mutat Res 2000; 450:167–80. 177. Dolle MET, Giese H, Hopkins CL et al. Rapid accumulation of genome rearrangements in liverbut not in brain of old mice. Nat Genet 1997; 17:431–4. 178. Dolle MET, Snyder WK, Gossen JA et al. Distinct spectra of somatic mutations accumulated with age in mouse heart and small intestine. Proc Natl Acad Sci USA 2000; 97:8403–8.

Comprehensive Geriatric Oncology

168

179. Ono T, Ikehata H, Nakamura S et al. Age-associated increase of spontaneous mutant frequency and molecular nature of mutation in newborn and old lacZ-transgenic mouse. Mutat Res 2000; 447: 165–77. 180. Stuart GR, Oda Y, de Boer JG, Glickman BW. Mutation frequency and specificity with age in liver, bladder and brain of Lacl transgenic mice. Genetics 2000; 154:1291–300. 181. DePinho RA. The age of cancer. Nature 2000; 408:248–54. 182. Wright WE, Shay JW. Telomere dynamics in cancer progression and prevention. fundamental differences in human and mouse telomere biology. Nat Med 2000; 6:849–51. 183. Vainio H, Magee P, McGregor D, McMichael AJ (eds). Mechanisms of Carcinogenesis in Risk Identification. Lyon: IARC Press, 1992. 184. Emanuel LM, Obukhova LK. Types of experimental delay in aging patterns. Exp Gerontol 1975; 13:25–9. 185. Frolkis VY, Muradian KhK. Life Span Prolongation. Boca Raton, FL: CRC Press, 1992. 186. Harman D. Extending functional life span. Exp Gerontol 1998; 33: 95–112. 187. Obukhova LK. Chemical geroprotectors and a problem of life extension. Adv Chem (Moscow) 1975; 44:1914–25. 188. Lipman RD. The prolongation of life. a comparison of antioxidants and geroprotectors versus superoxide in human mitochondria. J Gerontol 1981; 36:550–7. 189. Zs-Nagy I, Harman D, Kitani K (eds). Pharmacology of aging process. Methods of assessment and potential interventions. Ann NY Acad Sci 1994; 717. 190. Ebrahim S, Kalache AK (eds). Epidemiology in Old Age. London: BMJ Publishing, 1996. 191. Rudman D, Feller AG, Nagraj HS. Effect of human growth hormone in men over 60 years old. N Engl J Med 1990; 323:1–6. 192. Vance ML. Growth hormone for the elderly? N Engl J Med 1990; 323:52–4. 193. Khansari DN. Gustad T. Effects of long-term, low-dose growth hormone therapy on immune function and life expectancy of mice. Mech Ageing Dev 1991; 57:87–100. 194. Moon HD, Simpson ME, Lee CH, Evans HM. Neoplasms in rats treated with pituitary growth hormone. III. reproductive organs. Cancer Res 1950; 10:549–56. 195. Weindruch R, Gravenstein S. Cancer and aging. In: New Frontiers in Cancer Causation (Iversen OH, ed). Washington, DC: Taylor & Francis, 1993:321–32. 196. Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science 1996; 273:59–63. 197. Dempsey JL, Pfeiffer M, Morley AA. Effect of dietary restriction on in vivo somatic mutation in mice. Mutat Res 1993; 291:141–8. 198. Stuart GR, Oda Y, de Boer JG, Glickman BW. No change in spontaneous mutation frquency or specificity in dietary restricted mice. Carcinogenesis 2000; 21:317–19. 199. Reiter RJ. Reactive oxygen species, DNA damage, and carcinogenesis. intervetnion with melatonin. In: The Pineal Gland and Cancer. Neuroimmunoendocrine Mechanisms in Malignancy (Bartsch C, Bartsch H, Blask DE et al, eds). Berlin: Springer-Verlag, 2001:443–55. 200. Vijalaxmi, Meltz ML, Reiter RJ, Herman TS Melatonin and protection from genetic damage in blood and bone marrow: whole-body irradiation studies in mice. J Pineal Res 1999; 27:221– 5. 201. Ubeda A, Trillo MA, House DE, Blackman CF. Melatoninenhanced junctional transfer in normal C3H/lOT1/2 cells. Cancer Lett 1995; 91:241–5. 202. Anisimov VN, Khavinson VKh, Morozov VG. Twenty years of study on effects of pineal peptide preparation: epithalamin in experimental gerontology and oncology. Ann NY Acad Sci 1994; 719:483–93. 203. Anisimov VN, Arutjunyan AV, Khavinson VKh. Effect of pineal peptide preparation epithalamin on free radical processes in animals and humans. Neuroendocr Lett 2001; 22:9–18. 204. Thatcher AR, Kannisto V, Vaupel JW. The Force of Mortality at Ages 80 to 120. Odense: Odense University Press, 1998.

Age as a risk factor in multistage carcinogenesis

169

205. Stenbeck M, Rosen M, Sparen P. Causes of increasing cancer prevaence in Sweden. Lancet 1999; 354:1093–4. 206. Moolgavkar S, Krewski D, Zeise L et al (eds). Quantitative Estimation and Prediction of Human Cancer Risk. Lyon: IARC Press, 1999. 207. Anisimov VN, Soloviev MN. Evolution of Concepts in Gerontology. St Petersburg: Aesculap, 1999. 208. Khavinson VKh, Morozov VG, Anisimov VN. Experimental studies of the pineal gland preparation epithalamin. In: The Pineal Gland and Cancer. Neuroimmunoendocrine Mechanisms in Malignancy (Bartsch C, Bartsch H, Blask DE et al, eds). Berlin: SpringerVerlag, 2001:294–306. 209. Mylnikov SV, Lybimova NE. Effect of pineal peptides on motrality and antioxidant capacity in Drosophila melanogaster. Adv Gerontol 2000; 4:84–7. 210. Khavinson VKh, Izmaylov DM, Obukhova LK, Malinin W. Effect of Epitalon on the lifespan increase in Drosophila melanogaster. Mech Ageing Dev 2000; 120:141–9. 211. Anisimov VN, Khavinson VKh, Mikhalski AI, Yashin AI. Effect of synthetic thymic and pineal peptides on biomarkers of ageing, survival and spontaneous tumour incidence in female CBA mice. Mech Ageing Dev 2001; 122:41–68. 212. Ukraintseva SV. Individual age-related changes and mortality in population. Adv Gerontol 2000; 4:21–8. 213. Lee CK, Klopp RC, Weindruch R, Prolla TA. Gene expression profile of aging and its retardation by caloric restriction. Science 1999; 285:1390–3. 214. Lee CK, Weindruch R, Prolla TA. Gene-expression profile of the ageing brain in mice. Nat Genet 2000; 25:294–7. 215. Anisimov VN. Life span extension and cancer risks: myths and reality. Exp Gerontol 2001; 36:1101–36. 216. Anisimov VN. Priorities in fundamental gerontology. Adv Gerontol 2003; 12:9–27. 217. Bauer ES. Cancer as a biological problem. In: Modern Problems of Theoretical Medicine, Vol 1 (Jackson RE, ed). Moscow: State Publishing House for Biological and Medical Literature, 1936: 37–45.

9 Growth factors, oncogenes, and aging J Alberto Fernandez-Pol Introduction One of the main topics of this book is the prevention of the aging process and the rational treatment of cancer in the elderly patient. The prevention and treatment of cancer in the elderly requires a detailed understanding of the aging process, which involves a myriad of agents, including (but not limited to) growth factors, protooncogenes, tumor suppressor genes, and specific enzymes involved in the repair of cellular damage.1–9 The complexity of this subject is clearly indicated by the discovery of numerous growth factors, hundreds of oncogenes, and a unique group of tumor suppressor genes in recent decades. Moreover, hundreds of enzymes involved in molecular, cellular, and systemic changes during the lifespan of the organism are influenced by environment and genetics.10 The physiologic decline of an organism and the presence of disease result from molecular degradation of homeostatic systems,10–12 and these systems are controlled by classical hormones and growth factors.13 This decline is a consequence of the suboptimal functioning of systems that have evolved to protect the cells, but that in the process of decay cause further damage (Figure 9.1). For example, the utilization of energy by mitochondria is much more efficient in young people than in the elderly, and creates an opportunity for stochastic damage as the systems age.10 On the other hand, young cells have significant capacity to resist environmental stress such as that produce by viruses, bacteria, and toxic substances.10,14 The key to understanding aging and cancer is to define the molecular events that control cell growth and cell death.1–10,15–21 Key among these targets is the capacity of the cell to correct molecular damage to its genetic material. The deleterious consequences of DNA damage in mammalian systems—including mutation, cancer, lethality, and some aspects of aging—will be examined in this chapter. Most physical and chemical carcinogens interact primarily with DNA, and the aging cell lacks the capacity to correct the damage in time to avoid decline.10 Fortunately, mammalian organisms are diploid, and this provides them with the capacity to buffer and correct genetic damage. Further environmental challenges to cell growth include the development of modified proteins by either direct chemical modification or gene expression.10,11 For example, when proteins degrade and crosslink, somatic mutations accumulate, and the capacity of the cellular machinery to deal with the folding pathways and protein partnerships is exceeded as the organism ages.11,12 The aims of this chapter are fourfold. First, some key concepts in the field of cancer and aging, such as growth factor-induced cell proliferation in malignant and senescent cells, will be elucidated. Second, the complexity of these concepts will be shown, thereby

Growth factors, oncogenes, and aging

171

demonstrating that simplicity and anticipation of findings are not possible in this area of research. Third, a gene product, called MPS-1 (MPS/S27, metallopanstimulin), which is involved in growth factor-induced responses, in carcinogenic ribotoxic responses, and in the aging process, will be reviewed. Moreover, the experimental use of MPS-1 ribosomal protein and heat-resistant extremophilic

Figure 9.1 Genomic and mitochondrial DNA integrity is continuously challenged by endogenous and exogenous agents and by intrinsic chemical instability. To ensure genetic stability, evolution has led to an intricate network of complementary DNA repair systems. Genomic, mitochondrial, and ribosomal integrity are essential for cellular homeostasis. Cancer and aging result from failure of these systems. proteins in the diagnosis of oncogenic processes will be summarized. Finally, some insight into pharmacologic approaches to the control of metalloproteins involved in carcinogenesis and aging will be presented. None of the findings reviewed here could be anticipated, because of the complexity of the factors involved in the molecular and

Comprehensive Geriatric Oncology

172

cellular systems active in oncogenesis and aging, such as growth factors, oncogenes, tumor suppressor genes, and apoptosis. To the extent to which this chapter succeeds in clarifying some aspects of the complexity of this field, it should discourage the formulation of oversimplified hypothesis of oncogenic and aging processes in vivo, including those of the author. An example presented in this review that offers a remarkable illustration of the extreme complexity of the oncogenic process in vivo concerns the expression of the MPS-1 ribosomal protein in human melanoma. Molecular biology of growth factors, oncogenes, and tumor suppressor genes The cancer phenotype consists of several distinct characteristics, such as indefinite proliferative lifespan, anchor-age-independent growth, low growth factor requirements, neovascularization, invasion, and metastasis.1–9,13,15,23–26 A common characteristic of tumor cells is the constant overexpression of glycolytic and glutaminolytic enzymes, which results in altered carbohydrate metabolism.27,28 In addition, cancerous cells can synthesize their own growth factors, leading to cell proliferation that is independent of the otherwise carefully regulated supply of growth factors and growth-related hormones.1–8,13,22–24 Moreover, growth factors are instrumental in the invasive characteristics of cancer cells.26 For example, vascular endothelial growth factor (VEGF) activates the proliferation of endothelial cells, resulting in the creation of new blood vessels.26 Most interestingly, growth factors can also activate matrix metalloproteinases (MMPs), which are able to degrade the extracellular matrix.29,30 Remarkably, one of the prominent features of MMPs is that many of their genes are inducible by growth factors, cytokines, carcinogenic agents (e.g. phorbol esters), chemotherapeutic agents (actin stress fiber-disrupting drugs), radiation, and oncogenic cellular transformation.29 MMP gene expression may also be downregulated by transforming growth factors, retinoic acids, and glucocorticoids.29 Thus, MMPs are instrumental in the invasive process and metastatic disease, and are susceptible to pharmacologic control.29,30 The development of potent synthetic inhibitors of MMPs had led to clinical trials to treat patients with cancer.30 As used in this review, ‘growth factors’ refers to proteins and peptides that stimulate or promote cell division (Figure 9.2). Such growth factors are produced by virtually all types of tumors, and their involvement in cancer has been documented during the last three decades in numerous scientific and medical articles.10,13,22–24,31

Growth factors, oncogenes, and aging

173

Figure 9.2 Growth factors and growth factor receptors activate signal transduction, which in turn regulates transcription. Damage to several of these genes can result in oncogenesis. Growth factor independence and autonomous growth of cancer cells are due to the constitutive expression of growth factors, their membrane receptors, or intracellular signal pathways, ultimately leading to induction of DNA synthesis and cell division (Figure 9.2).7,8,13 The constitutively expressed growth factors, which function as transforming proteins in the neoplastic cell, may be encoded by oncogenes, or alternatively their expression may be under the control of oncogenes.1–7 A large number of oncogenes have been identified, each encoding a specific protein that is involved in certain specific types of cancer.1–3,7,8 For example, the c-myc oncogene and its protein are involved in breast and colon carcinomas,7,8 while the c-erbB-2 (HER2/neu) oncogene and its protein are involved in breast and ovarian carcinomas.25 More recently, the approximate number of functional genes for each human organ has been determined by methods of genomics and proteomics. It is reasonable to predict that a significant number of these new genes have oncogenic and tumor suppressor potential. Numerous tumor suppressor genes have been identified. These genes have various functions.3,4 Although a number of tumor suppressors function in defined pathways of

Comprehensive Geriatric Oncology

174

cell cycle regulation or DNA repair, others have functions indirectly related to cell cycle or DNA-repair control.32 Table 9.1 illustrates a selected group of

Table 9.1 Tumor suppressor genes Gene

Familial syndrome

Spontaneous cancers with mutated gene

Mechanism of action

p53

Li-Fraumeni syndrome

Present in 50% of all cancers

Response to DNA damage (transcription factor, zincfinger protein, apoptosis)

BRCA1

Familial breast and ovarian cancer

Ovarian carcinoma

DNA repair of oxidative damage

BRCA2

Familial male and female breast and pancreatic carcinoma

Pancreatic carcinoma

DNA repair of oxidative DNA damage

hMLH1, Hereditary polyposis colorectal

Colon, gastric, and endometrial

DNA mismatch repair

hMSH2 carcinoma

carcinomas

p16

Familial melanoma and pancreatic carcinoma

Melanoma, glioblastoma, and pancreatic carcinoma

Cell cycle regulation (cyclin-dependent kinase inhibitor)

Rb1

Familial retinoblastoma

Retinoblastoma, melanoma, osteosarcoma, and breast, prostate, and lung carcinomas

Cell cycle regulation

tumor suppressor genes involved in cell cycle regulation and DNA repair.8 Other tumor suppressor genes, such as those involved in neurofibromatosis, von Hippel-Lindau syndrome, WAGR syndrome, Gorlin syndrome, Cowden syndrome, and familial adenomatous polyposis, which are instrumental in neuroblastoma, renal carcinoma, multiple carcinomas, Wilms’ tumor, skin cancer, and colon carcinoma, represent restriction points in many different cellular pathways.8 Many oncogenes enable continuous cell proliferation by either encoding growth factor proteins or inducing the expression of these proteins, which are secreted by the cells.7,8,13 The secreted proteins can interact with and stimulate growth-mediating receptors on the surfaces of the same cells that secreted the proteins. This self-stimulating property of cancerous cells has been termed ‘autocrine secretion’.13,22,24 The result of this inappropriate secretion of growth factors is the activation of a cascade of enzymatic reactions (Figure 9.2) that result in cell proliferation, neovascularization, and metastatic disease. There are peculiar types of autocrine growth factors, produced by various normal and cancerous cells, that possess both growth-stimulatory and growth-inhibitory activities in the same molecule.24,33–36 The growth response to these bifunctional growth factors is largely dependent on cell type and culture conditions.13 For example, transforming growth factor β1 (TGF-β1), a 25 kDa disulfidelinked homodimer, is mitogenic for many fibroblastic cell lines but growth-inhibitory for diverse epithelial cell types, including

Growth factors, oncogenes, and aging

175

lung, breast, and prostate carcinomas.13 One conspicuous attribute of TGF-β1 is that it affects the expression of series of genes and oncogenes to either negatively or positively control their expression.13,33,35 There are growth factors and oncogenes produced by viruses that illustrate the complexity of the growth-regulatory mechanism and the oncogenic process in vivo.8,37,38 For example, the complex smallpox virus, which has recently acquired new notoriety because of its potential use in bioterrorism, contains a gene that encodes soluble epidermal growth factor (EGF) protein, which promotes cell proliferation and is detected in all poxvirus genera.37 Furthermore, the family of poxviruses produces interleukin-1β receptor (IL-1βR) which blocks IL-1β cellular defense activity.37 Tumor necrosis factor (TNF) is also produced by poxviruses, and contributes to virulence in the form of apoptosis.37 All of these poxvirus virokines and viroreceptor gene products contribute to pathogenesis in the form of production of granulomatous proliferative lesions, and benign tumors as in the case of myxomatosis in rabbits.37 It has also been reported that the Tat protein of the human immunodeficiency virus (HIV), a viral regulatory gene product, possesses growth-stimulatory activity in certain cell types.39,40 Oncogenic proteins of human papillomaviruses, such as the E6 and E7 zinc-finger proteins, are also able to immortalize normal cells in vivo and in vitro.14,37,41–43 These oncogenic proteins are involved in human cancers, such as carcinoma of the uterine cervix.14,41 There is strong preclinical evidence that the blockade of growth factor receptors can arrest the growth of cancer.13,44,45 For example, inhibition of EGF receptor (EGFR) tyrosine kinase is a concept that has been translated into successful clinical trials.44 Activation of EGFR results in cell growth, proliferation, and angiogenesis.13,23,26 The majority of epithelial malignancies express this receptor to some extent.13 The effects of EGFR activation can be counteracted by blocking its intrinsic tyrosine kinase activity, which is localized on the intracellular domain of the receptor.13 Numerous studies have shown that monoclonal antibodies13,45 that bind to the extracellular domain of EGFR, such as 2D1 monoclonal and cetuximab, and drugs that selectively block EGFR tyrosine kinase activity directly such as anilinoquinazoline compounds, can abolish EGF/TGF-α activation of EGFR.13,44,45 Neutralization of EGFR by both monoclonals and drugs can be achieved in patients with minimal toxicity, indicating that chemotherapeutic control of the EGFR pathway is a relevant approach to the control of cancer in the elderly population. Molecular basis of aging and cancer The lifespans of animals are genetically controlled, and new data exist to support common mechanisms to control the maximum number of times a cell can divide (i.e. the number of cell divisions before the cell reaches senescence).10,12,46 A fundamental characteristic of normal cells is their limited ability to proliferate in culture.46 Invariably, after an initial mitotic period in culture, normal cells from humans and most other species suffer a gradual decline in their ability to proliferate. Eventually, the decline becomes irreversible. This progression towards a lower activity state has been termed ‘cellular senescence’.46 Cellular senescence has been studied most often in cultures of human fibroblasts (e.g. WI-38 cells).46 Numerous studies have indicated that cellular senescence

Comprehensive Geriatric Oncology

176

in culture reflects aging in vivo.46 More recent studies have suggested that senescent fibroblasts are unable to proliferate, at least in part, because of selective repression of genes involved in transcriptional activity, such as a protooncogene designated c-fos.10,46,47 Cancer in humans and animals results from a multistep process that is described in experimental model systems as initiation, promotion, conversion, and progression.6,8 Each step in the process represents the selection of cells that have acquired the ability to surmount extra- and intracellular growth-regulatory signals.13 The cytogenetic evidence of multiple chromosome abnormalities in most tumor cells and the progressive aberrant chromosome structures that can be observed during tumor progression are also evidence for a multistep process.10,48 Since the tumorigenic process occurs rarely,51 multiple levels of control must be operative to prevent the emergence of such cells in metazoan organisms. The common cancers of the adult, including colon, lung, prostate, and breast, develop by stepwise accumulation of mutations affecting both oncogenes and tumor suppressor genes.8,48–50 These mutations accumulate gradually over time, and extensive genetic changes are necessary to produce a highly malignant cell.10,51 For example, benign adenomas of the colon usually have a single gene change.8,48 As they progress toward malignancy, they acquire three or four more gene alterations. These multiple changes may occur in a specific order. However, it is very likely that it is the number of changes rather than their precise sequence that is important for cancer development.48 Thus, the non-specific cellular changes as the cell ages continue to contribute to shift the balance of control from tumor suppressor genes to oncogenes. There are overlapping mechanisms that may be common to both cancer and aging. The loss of efficient DNA-repair capacity is a major factor in both cancer progression and the aging process.5,6,12 One model for aging proposes that it is the result of accumulation of damage in the DNA genome, with resulting loss of function of critical genes.12 It has been proposed that during the aging process, robust DNA-repair events become less active or inefficient, resulting in the accumulation of damaged DNA, and eventually in death.10,12 One unifying concept simply states that that failure to repair DNA damage in proto-oncogenes or tumor suppressor genes causes loss of growth control and cancer.10 However, if the accumulation of DNA damage does not involve these growth-regulatory genes, this simply leads to cell death or senescence. Under certain conditions, some endogenous cellular processes are intrinsically mutagenic, and may be significant factors in the origin of some human tumors.10,12 This contribution is probably substantial for cancers with no known risk factors and for cancers in which the incidence is age-dependent. Many reactions that damage DNA and contribute to spontaneous mutagenesis have been identified.10,12 DNA damage by these agents occurs at a significant frequency, which, as the organism ages, may exceed the capacity of the cell to repair itself.10,12 There is considerable evidence that free radicals play a role in the carcinogenic process.10,12 Damage to DNA from free radicals occurs at sufficiently high frequency to be considered a source of spontaneous mutations of both mitochondrial and nuclear genomes (Figure 9.1). Various by-products of oxygen metabolism include the superoxide radical ion, the hydroxyl radical, hydrogen peroxide, and products of lipid peroxidation. Superoxide and other radicals are known to cause DNA damage, and alterations in DNA bases possibly induced by radicals have been shown to increase in old animals.10 To

Growth factors, oncogenes, and aging

177

counteract these deleterious effects, there are both enzymatic and non-enzymatic systems available to defend the cell. The enzymes involved include superoxide dismutases (SOD), catalases, and peroxidases.10,52 Superoxide can also be formed by the reaction with redoxcyclin drugs such as paraquat.52 The selective toxicity of paraquat towards virustransformed cells and other cancers cells correlates with decreased activity of SOD in malignant cells.52 Nitric oxide (NO˙) is another reactive species (with a half-life of ~6 s) that acts endogenously as a vasodilator (endothelial-derived relaxing factor, EDRF).53,54 Members of the non-enzymatic defense system include the antioxidants β-carotene, vitamin A, uric acid, glutathione, homocysteine, coenzyme Q10, and vitamin E, which presumably contribute to longevity.10 Thousands of plant-derived chemicals have the ability to scavenge free radicals. Flavonoids and phytoestrogens are the most well known. Thus, radicals and lipid peroxidation are present in both aging and cancer, and suggest an overlap in mechanisms that lead to both conditions. In summary, when these antioxidant systems fail, cellular damage is produced in various forms, leading to aging, cancer, or other diseases. Molecular biology of zinc- and iron-finger proteins: aging and carcinogenesis Of particular interest for this review are the ‘zinc-finger’ metal-ion-binding proteins.14,55– In the past several years, a series of discoveries revealed that many proteins contain metal ions, particularly zinc ions (Zn2+), that play fundamental roles in stabilizing specific protein conformations.14,55,58 Many of these metalloproteins are involved in nucleic acid binding, gene regulation,14,55 and enzymatic activity.14,55,56 In addition, numerous ribosomal proteins such as MPS-1 possess zinc-finger-like motifs (see Figures 9.13 and 9.14 below).14 The primary finding in this field came from analysis of the sequence of the protein transcription factor III (TFIIIA) from Xenopus laevis.55 This sequence contains nine tandem imperfect repeats that have the consensus sequence (Phe, Tyr)-X-Cys-X2,4-CysX3-Phe-X5-Leu-X2-His-X3,4-His-X2–6, where X represents a non-conserved two- to sixamino-acid residue.55,56 This sequence contains two cysteines and two histidines that form a complex with a single metal ion, particularly Zn2+.55,56 This structural domain was termed a ‘zinc finger’.55,57 The zinc-finger domains function as the nucleic acid-binding regions of these regulatory molecules, which are involved in the control of gene transcription.14,55–58 Subsequently, zinc-finger motifs have been identified in numerous eukaryotic and viral proteins with transcriptional regulatory activity.14,55–58 Transition metal ions at physiological concentrations, such as iron, cobalt, and copper, are essential elements for biological functions; however, at higher levels they are toxic.10,14 This is particularly true for iron.14 Elevated levels of iron contribute to carcinogenesis in several ways: first, iron has the capacity to generate highly reactive free radicals, which damage DNA; second, there is an increased iron requirement by rapidly proliferating transformed cells for DNA replication (ribonucleotide reductase) and energy production by mitochondria.10 Recent studies have offered new insight into the mechanisms and potential for damage to DNA by transition 58

Comprehensive Geriatric Oncology

178

Figure 9.3 A hypothetical model of the DNA-binding domain of an ironfinger hormone receptor protein bound to DNA as a dimer. The α-helices of the first iron finger of each subunit (perpendicular cylinders) are positioned in consecutive major grooves on one face of the DNA double helix. The second iron finger (horizontal cylinders) of each subunit is involved in dimer formation. In the presence of chemical agents (ascorbate+hydrogen peroxide

Growth factors, oncogenes, and aging

179

(H2O2)), ultraviolet (UV) light, viruses, etc, the iron in the iron-finger protein generates free radicals (hydroxyl, HO˙). The free radicals degrade DNA genetic regulatory response elements. DNA degradation may lead to carcinogenesis and aging. Adapted from: Hard T et al. Science 1990; 249:157; Branden C, Tooze J. Introduction to Protein Structure. New York: Garland, 1991; Conte D et al. J Biol Chem 1996; 271:5125. metals, particularly iron and copper.10 These new insights result from the discovery that transcriptional regulatory proteins that interact with DNA (DNA-binding proteins), which normally bind zinc (zinc-finger domains) but can substitute zinc by other transition metals present in the cell at abnormal concentrations, may be involved in the degradation of DNA genetic regulatory response elements, leading to carcinogenesis and aging (Figure 9.3).10,14 Transition-metal ions, particularly copper(II) ions (Cu2+), complexes containing iron(III) ions (Fe3+), and complexes containing both Cu2+ and Fe3+, can dissociate and replace the zinc ion from the zinc fingers of important regulatory proteins (Figure 9.3).14,59 For example, zinc-finger-containing hormone receptor proteins for testosterone, progesterone, etc., can replace zinc by iron and may generate free radicals that damage DNA in specific regulatory regions and potentially induce tumors in prostate, uterus, etc., respectively (Figure 9.3).10,14,59,60 Thus, classical hormones13 can modulate iron-finger receptor proteins, which suggests that these hormones potentiate the destructive actions of free radicals, mediated by abnormal iron-finger receptor proteins, on regulatory regions of DNA (Figure 9.3). Indeed, it may be feasible to maintain zinc-finger proteins in an undamaged zinc-containing form by using a combination of specific chemopreventive agents such as specific iron chelators and radical scavengers that, respectively, interfere with the formation of aberrant iron-finger proteins and free radicals.14 Molecular biology of MPS-1 ribosomal protein: a zinc-finger protein involved in ribotoxic responses to carcinogens Biotechnological advances such as differential hybridization of growth factor-induced cDNA libraries have allowed us to identify genes associated with neoplastic growth and subsequently to develop isotopic and non-isotopic methods for measuring the protein products of these genes in tissues and biological fluids (Figures 9.4–9.10; Tables 9.2 and 9.3). The biochemical and biolog-

Comprehensive Geriatric Oncology

180

Figure 9.4 Flow chart delineating the main steps in the methodologies utilized to isolate the MPS-1 gene, synthesize the recombinant (r) MPS-1 protein(s), and produce anti-rMPS-1 antibodies. The clinical applications of

Growth factors, oncogenes, and aging

181

the MPS tests to detect MPS-N (the N terminal of MPS-1) and MPS-N-like proteins in biological fluids and tissues are also outlined.

Figure 9.5 Construction and screening of the cDNA library from which the MPS-1 sequence was isolated.

Comprehensive Geriatric Oncology

182

(a) Human carcinoma cells were treated with transforming growth factor β (TGF-β), in the presence of EGF, and their mRNAs were converted into cDNA. The various cDNAs were inserted into cloning plasmids, which were then used to transform Escherichia coli cells to generate a library of numerous different cDNA sequences, from which the MPS-1 sequence was isolated by differential hybridization. (b) The ± differential hybridization method. The cDNA library contained in E. coli cells was plated and triplicated using nitrocellulose filters lifts. Two filters were screened using two different sets of mRNA probes; one set (message +) was derived from mRNA from carcinoma cells that had been treated with TGF-β, and one set (message −) was derived from control cells that had not been treated with TGF-β. E. coli colonies containing cDNA that hybridized with the mRNA from treated cells, but did not hybridize with the mRNA from untreated cells, were identified, isolated, and cloned. Those colonies were further analyzed, and one clonal colony contained a sequence that was later designated as the MPS-1 cDNA sequence. The third of the triplicate filter lifts was stored as a master to preserve the colonies in the same spatial arrangement as the processed filters.

Growth factors, oncogenes, and aging

183

Figure 9.6 Cloning of the human MPS-1 (ST1H2) sequence into the baculovirus transfer vector pJVETL to construct the recombinant expression vector pJVETL-ST1H2/P17, which expressed two proteins: (i) the endogenous form of MPS-1, and (ii) an additional protein that contained 17 additional amino acid residues at the N terminus.

Comprehensive Geriatric Oncology

184

Figure 9.7 MPS-1 mRNA level in various human carcinomas: 0, ovarian carcinoma; C, carcinoma of the uterine cervix; E, endometrial carcinoma; VM, vulvar melanoma. The widely different levels of MPS-1 mRNA correlate with the pathological degree of malignancy and growth rate of the tumors. Ovarian carcinomas (samples 1–3) and carcinoma of the cervix (samples 4–6) were histologically well differentiated; endometrial carcinomas (samples 7 and 8) were highly invasive to myometrium. Sample 9 corresponds to a very fast-growing malignant melanoma; the patient underwent vulvectomy at the time of sample

Growth factors, oncogenes, and aging

185

collection, and died 3 weeks later of widespread metastatic disease. ical characteristics of one such gene, denoted MPS-1, which was isolated by differential hybridization (Figure 9.5), are summarized in Tables 9.2 and 9.4–9.7 and Figure 9.11.61,62 The nucleotide sequence and the deduced amino acid sequence of the MPS-1 protein are shown in Figure 9.12, and its structure is illustrated in Figures 9.13 and 9.14. The MPS-1 sequence has a zinc-finger motif (Figure 9.15), and it shows a significant homology to several transcriptionally active proteins, including viral zinc-finger proteins (GenBank database). It should be noted that the MPS-1 protein has a zinc-finger-like domain with four cysteines (Figures 9.13 and 9.15). Proteins with this motif generally bind to DNA as dimers (Table 9.5). How these motifs participate in binding to RNA is not known. As used herein, ‘metallopanstimulin’ (MPS) is defined to include synthetic or naturally occurring proteins that have the following properties: (i) they have at least one zinc-finger domain; (ii) they are amphipathic (sufficiently soluble in both water and lipids to allow them to penetrate lipid membranes while remaining soluble in aqueous fluid) (Figure 9.16); (iii) they are released or secreted from cancerous cells; (iv) they penetrate into the nucleus, where

Figure 9.8 MPS-1 mRNA expression in mice embryonic epithelia. Mice embryos were 10 days old and were purchased from Novagene (Madison, WI). In situ hybridization was done using a biotinylated cDNA MPS-1

Comprehensive Geriatric Oncology

186

probe. (a, c) Parasagittal section showing the skin over the optic vesicle and optic nerve. (b, d) Transverse section of the neural tube. (a, b) Biotinylated MPS-1 cDNA probe. (c, d) Control: no MPS-1 cDNA probe. Magnification: (a, c) 200×; (b, d) 100×. Note that (i) the MPS-1 cDNA probe strongly labels the epithelia (skin) of the embryo (a: arrows) and (ii) it also labels the neural crest (N, arrows), (D, dorsal position), and ventral ganglia (open arrows); this latter observation is of interest since melanomas that are neural-crestderived showed strong MPS-1 mRNA expression, as shown elsewhere in this application. These results show that the MPS-1 sequence is present in greater abundance in cells derived from the ectodermal layer than in those derived from endodermal or mesodermal layers.

Growth factors, oncogenes, and aging

187

Figure 9.9 In situ hybridization with a biotinylated DNA MPS-1 probe reveals that the MPS-1 mRNA is limited to the cytoplasm of cancerous cells and no staining is observed in the stroma. The pathologic tissue specimen corresponds to patient 2J with ovarian carcinoma metastatic to omentum. Darkly stained cells are both positive for MPS-1 mRNA and malignant. Tissues were subjected to a standard in situ hybridization procedure. Magnification×100.

Comprehensive Geriatric Oncology

188

Figure 9.10 The expression of MPS-1 in melanocytic lesions. (a) Benign melanocytic lesion: melanocytic nevus, compound type. The patient is a 3year-old White girl with changing congenital nevus. Section shows nevus cell nests within the epidermis and dermis. ‘Dropping off’ is seen at the dermal-epidemal junction. (b)

Growth factors, oncogenes, and aging

189

Malignant melanocytic lesion: malignant melanoma, superficial spreading type. The patient is a 65year-old White man with a shoulder lesion. The section shows a proliferation of atypical melanocytes in the dermis and epidermis. In areas, there is clear cell nesting as well as small basaloid cells consistent with intralesional transformation. Sections (a) and (b) were processed identically for immunohistochemistry with antiMPS-1 ntibodies.

Figure 9.11 Percentage distribution of MPS-N (the N terminus of MPS-1). The MPS-N ranges 1 to 5 correspond to those shown in Table 9.3. White,

Comprehensive Geriatric Oncology

190

healthy subjects; gray, active cancerous disease; black, nonmalignant diseases. The numbers of patients for each group are shown in the inset.

Figure 9.12 Nucleotide sequence of the 329 bp fragment of the plasmid ST1H2-pcDNA-II, containing the exon coding for the 84 amino acids of human MPS-1 and the 5′ and 3′ flanking regions. The deduced amino acid sequence is shown in one-letter code. The translational initiation site ATG starts at nucleotide position 21 and the TAA termination signal starts at nucleotide 273. The underlined amino acid residues in regions 2–17, 41–55, and 67–84 correspond to three synthetic peptides designated A1, A2, and A3, respectively, that were utilized for antibody production. The numbers in each line refer to the nucleotide (upper) and amino acid (lower) positions. The methionine at position 21 constitutes the N terminus.

Growth factors, oncogenes, and aging

191

Table 9.2 Detection of MPS-1 mRNA and protein in human tissues Type of tissue

No. of samples: mRNAa/proteinb

Organ of origin

Carcinomas and sarcomas Carcinoma

52+++/+++

Vulva, cervix, ovary, endometrium, colon, lung, bladder, liver, metastatic

Squamous cell carcinoma

35+++/+++

Vulva, cervix, esophagus, lung

Adenocarcinoma

25++/++

Cervix, ovary, endometrium, colon, prostate

Carcinoma in situ

9++/++

Vulva

Serous carcinoma

5+/+

Ovary

Papillary serous carcinoma

5++/++

Endometrium

Sarcoma

4++/++

Ovary, endometrium, metastasis

Melanoma

2>+++/+++

Vulva, metastasis

Verrucous carcinoma

1++/++

Vulva

Retroperitoneal liposarcoma

1+++/+++

Retroperitoneal

Mucinous carcinoma

1+/+

Ovary

Leiomyosarcoma

1++/++

Ovary

Papillary carcinoma

1++/++

Ovary

Papillary adenocarcinoma

1++/++

Endometrium

Adenosquamous carcinoma

1++/++

Endometrium

Clear cell carcinoma

1++/++

Endometrium

Mixed mesodermal carcinoma

1+/+

Endometrium

Mixed müllerian tumor

1+/+

Endometrium

Ductal carcinoma

3+++/+++

Breast

Inflammatory carcinoma

1>+++/+++

Breast

1−/−

Vulvar skin

Benign lesions Lichen sclerosus

Comprehensive Geriatric Oncology

192

atrophicus Benign cysts

10ND/−

Ovary, breast

Granuloma

1ND/+

Lung

Leiomyoma

2ND/−

Uterus

1ND/−

Ovary

63−/−

Cervix, ovary, endometrium, myometrium, vagina, peritoneum, fallopian tubes, breast, rectal muscle, skin, small intestine, lymph node

Fibroma c

Normal tissues

a

The MPS-1 mRNA was detected using a biotinylated single-stranded antisense DNA probe. The MPS-1 protein was detected by immunohistochemical staining using anti-peptide A antibodies. Signals: −, negative; +, weakly positive; ++, positive; +++, strongly positive; ND, not done. The staining recorded refers to the that of the cancer cells, since the stroma cells were not significantly stained. As can be seen, there was an excellent correlation between MPS-1 mRNA and protein expression. c Although normal tissues are listed as ‘−’, they showed staining (+ to +++) only in areas of normal cell proliferation. Notes: (i) Vulvar melanoma and breast inflammatory carcinoma had the highest levels of MPS-1 mRNA and protein detected; by northern blot analysis, the MPS-1 mRNA levels in these tissues were >80-fold normal levels. (ii) Lichen sclerosus atrophicus, a rare condition characterized by extremely low proliferation rates, was negative for MPS-1 mRNA and protein in the usual areas of cell multiplication. These observations are highlighted in italic. b

they bind to specific sequences of DNA, identified as cyclic adenosine monophosphate (cAMP) response elements (CREs).62 Thus, MPS-1 proteins are zinc-finger ribosomal proteins that can be shown experimentally to have a number of different functions.14,61–63 An important characteristic of the MPS-1 gene is that it has been shown to be transcribed into mRNA at abnormally high levels in a wide variety of cancerous cells (Tables 9.2, 9.6, and 9.7).61–63 In addition, in a number of tumors studied to date, the quantity of MPS-1 mRNA present in the cells is a useful indicator of the aggressive-ness and potential lethality of the malignancy (Figure 9.7; Table 9.2). Thus, the MPS-1 protein offers a method of detecting and diagnosing a broad variety of cancers, as well as a method of assessing the level and aggressiveness of the treatment that will be required to combat the spread of a tumor in a specific patient (Figure 9.17). It is of interest to mention here that embryologic studies in mice have shown that the MPS-1 sequence is present in greater abundance in cells derived from the ectodermal layer than in those derived from endodermal or mesodermal layers (Figure 9.8). These results suggest

Table 9.3 Distribution of MPS values (total number of patients 632) Percentage with MPS values (ng/ml) of: No. <7.0

7.0–10

10.01–20

20.01–50

>50.01

Growth factors, oncogenes, and aging

193

Healthy subjects Women (19–64 years)

20

70

20

10

0

0

Men (21–55 years)

20

65

10

25

0

0

Men (50–88 years)

107

62

20

18

0

0

Total

147

64

18

17

0

0

Prostate

126

1

<1

11

48

38

Bladder

6

0

0

0

33

66

Testicular

1

0

0

0

0

100

Esophageal

3

0

0

33

66

0

Pancreatic

1

0

0

0

0

100

Hepatoma

2

0

0

0

50

50

Colorectal

27

0

0

7

44

48

27

0

0

11

26

63

6

0

0

0

66

33

Primary neoplasms

1

0

0

0

0

100

Neuroendocrine origin

6

0

0

17

17

66

Leukemia and lymphoma

7

0

0

0

43

57

12

0

0

0

58

42

225

<1

<1

9

45

44

Benign prostatic hypertrophy

37

30

16

38

13

3

Hepatitis B or C

18

83

5

11

0

0

4

100

0

0

0

0

Other

201

58

21

20

1

0

Total

260

56

19

21

3

<1

Cancerous diseases, active Genitourinary tract:

Gastrointestinal tract:

Lung cancer: Epithelial malignancies Head and neck region: Epithelial malignancies Central nervous system:

a

Other malignancies Total

Non-malignant diseases

Liver cirrhosis

Premalignant disease

Comprehensive Geriatric Oncology

Colorectal polyps

4

0

194

0

0

75

25

a

Include cancer of unknown origins, squamous cell carcinomas, etc.

Table 9.4 Summary of MPS-1 gene expression features Experiments

Results

Salient featuresa (known or proposed)

Northern blot

0.4 kb mRNA

High levels in cancer cells

Western blot

10 kDa protein

High levels in cancer cells

Phosphorylation

Phosphoprotein

Required for action

Dimerization

Forms dimers

Required for function (not known)

Gel shift

Binds cAMP response element Role in gene regulation (not (CRE) known)

UV light activation

UV stimulates MPS-1 gene expression

Involved in DNA repair (not known)

In situ hybridization in mice embryos

Localizes in areas of cell proliferation

Role in embryogenesis

a Proposed features are based on indirect evidence, and thus they are the subject of further investigation.

Figure 9.13 Schematic representation of the MPS-1 protein, showing the

Growth factors, oncogenes, and aging

195

coordination of the zinc atom to cysteine residues. Table 9.5 Comparison of the zinc-finger structure, DNA interaction, and trans-acting activity of the MPS-1 protein with other zinc-finger proteinsa Finger typeb

Binds DNA in vitro

Transacting

Organism

GAL4 (PPRI/ARGRII/ LAC9/qa-1f)

C6

+

+

Yeast

MPS-1 (ST1H2)

C4

+

+ (?)

Human/rat/ mouse

E1A

C4

−

+

Adenovirus

Steroid hormone receptor superfamily

C4+C5

+

+

Human/rat/ mouse/ chicken

a DNA-binding activity is documented by Fernandez-Pol et al.62 Trans-acting activity was demonstrated in preliminary CAT assay analysis of COS-1 and PC-12 cell extracts, which indicated enhancement of transcriptional activity induced by the MPS-1 protein (data not shown). The cells were cotransfected with the expression/activator (pMEP4-MPS-1) and reporter (pCRE-CAT) plasmids using the calcium phosphate method. b c4=C-X2-C-X13-C-X2-C or C-X2-C-X15-C-X2-C c5=C-X5-C-X9-C-X2-C-X4-C c6=C-X2-C-X6-C-X6-C-X2-C-X6-C

that the MPS-1 sequence may be a marker for ectodermally derived malignancies. Therefore, the embryologic studies also suggest that the MPS-1 cDNA and polypeptide sequences may provide a useful and widely applicable method of detecting the presence of a cancerous or precancerous condition in patients suspected of having numerous different types of cancer, regardless of which specific type is involved.

Table 9.6 Presence of MPS-1 mRNA in cultured human malignant cell lines Cell type

Cell line

Breast carcinoma

MDA-MA-468, MDA-MB-231, BT-20

Prostate carcinoma

DU-145, PC-3

Melanoma

SK-MEL-28, RPMI-7951

Colon adenocarcinoma

LoVo

Lung carcinoma

A-549

Vulvar carcinoma

A-431

Fibrosarcoma

HT-1080

Comprehensive Geriatric Oncology

Neuroblastoma

LAN-5

Squamous cell carcinoma of skin

SCC-15

196

Table 9.7 Presence of MPS-1 mRNA in human hematologic malignancies MPS-1 mRNAa Type of malignancy

Negative

Positive

Chronic lymphocytic leukemia

0

3

Chronic myelogenous leukemia

0

2

Multiple myeloma

0

3

Lymphoma

0

3

Melanoma

1

0

Small cell lung carcinoma

1

0

Colon carcinoma

2

0

Presence of malignant cells in peripheral blood:

Absence of malignant cells in peripheral blood (control):

a

White blood cells were tested by northern blot analysis with an MPS-1 probe.

Growth factors, oncogenes, and aging

197

Figure 9.14 Molecular model of a zinc-finger protein. This backbone model corresponds to the sequence of MPS-1. The atom represented by the dark circle is zinc, which is coordinately bound to four cysteine residues. The model was generated by a Silicon Valley computer with molecular modeling programs.

Comprehensive Geriatric Oncology

198

Figure 9.15 Nucleotide sequence and deduced amino acid sequence of the region of ST1H2 cDNA coding for MPS-1. The deduced amino acid sequence is shown in the three-letter code. The amino acid sequence for the zinc-finger domain of MPS-1 is boxed in the zinc-binding regions and underlined in the connecting region. Numbers above each line refer to the nucleotide position. The termination codon (TAA) is indicated by three stars.

Growth factors, oncogenes, and aging

199

Figure 9.16 Hydropathy profile of the MPS-1 8.4 kDa protein. A positive value on the vertical axis indicates that the corresponding residue is hydrophobic; a negative value indicates hydrophilicity. The residue window size used was 6; the curve was generated by DNASIS (Hitachi).

Figure 9.17 Schematic representation of some of the biological characteristics of MPS-1 protein.

Comprehensive Geriatric Oncology

200

MPS-1 here refers to immunoreactive MPS-1 and MPS-1-like proteins detected by anti-rMPS-1 antibodies in biological fluids. (a) In normal proliferating cells, MPS-1 is produced, and it is released in detectable amounts into the extracellular space. (b) In benign tumors, MPS-1 is produced at higher levels than in proliferating normal cells, and it is released in significant amounts into the extracellular space. (c) In malignant tumors, MPS-1 is produced at much higher levels than in proliferating normal cells or benign tumors, and it is secreted/released to the extracellular space in abundant quantities. (d) In aging cells, the synthesis of MPS-1 is greatly reduced or absent, and thus MPS-1 is undetectable in extracellular fluids. In addition, the widely different levels of MPS-1 mRNA or protein in various different tumors correlated well with the pathologic degree of malignancy and growth rate of those tumors (Figure 9.7; Table 9.2). Therefore, the diagnostic methods presented elsewhere in this chapter can provide very useful and quickly available information on how aggressively a cancerous or precancerous condition in a patient should be treated using chemotherapy, radiation therapy, or surgery. Numerous experiments with human tissue culture cells and human pathologic tissue specimens have demonstrated that MPS-1 mRNA and protein are expressed in normal cells to a much lesser degree than in premalignant or malignant tumor cells, and they are present at very low levels in senescent cells compared with young healthy cells

Growth factors, oncogenes, and aging

201

Figure 9.18 Time course showing the changes in MPS-1 mRNA levels after the addition of fetal calf serum (FCS) to human WI-38 diploid fibroblasts at

Comprehensive Geriatric Oncology

202

early passage (young) and at the extreme of their proliferative lifespan (senescence). (a) WI-38 cells were used at early passage, when the cells had undergone fewer than 20 population doublings (PD) and over 75% were capable of DNA synthesis, and at late passage (senescent; over 27 PDs), when less than 20% of the cells were capable of DNA synthesis, as determined by monoclonal anti-5bromo-2′-deoxyuridine (BrdU) antibodies to detect BrdU incorporation in DNA (Cell Proliferation kit, Amersham, Arlington Heights, Illinois). WI-38 cells at early (19 and 20 PDs: A and B, respectively) and late passage (27 and 28 PDs: C and D, respectively) were plated at 1.25×106 cells per 100 mm dish in DME/F-12 plus 10% calf serum for 48 h. After rinsing with serum-free medium, the cells were maintained for an additional 24 h in synthetic serumfree DME/F12+H medium. Subsequently, serum-deprived (control, time=0) or 5% serumstimulated (15 min, 1 h, and 3 h) earlyand late-passage cells were analyzed for the abundance of MPS-1 mRNA. Aliquots of total RNA (20 µg per lane) were fractionated on agarose gels and transferred to a nylon membrane. The transcripts were detected by hybridization with a 32P-labeled MPS-1 cDNA probe and subsequent autoradiography. (b) The resulting autoradiogram was quantified by densitometric scanning and the relative

Growth factors, oncogenes, and aging

203

abundance of the hybridization signal for each time point was plotted: open circles, 19 PDs; filled circles, 20 PDs; open triangles, 27 PDs; filled triangles, 28 PDs. (Tables 9.2, 9.6, and 9.7; Figures 9.7, 9.9, 9.10, and 9.18). In vitro experimental results indicate that senescent human WI-38 fibroblasts express MPS-1 mRNA at lower levels than in their respective early-passage cultures (Figure 9.18). Senescent cells also show striking, irreversible decreases in the expression of MPS-1 mRNA; this is manifested by the loss of MPS-1 mRNA inducibility by fetal calf serum and other growth factors (e.g. EGF and TGF-α), which have been shown to induce MPS-1 mRNA in young human WI-38 fibroblasts (Figure 9.18). This loss results at least in part from a reduction in the production of the MPS-1 protein. Thus, reduction in MPS1 production is associated with senescence, and it may be one of the factors contributing to cellular aging. These results suggest that it may be possible to restore senescent cells to a replication-competent state by utilization of MPS-1 protein as an anti-aging factor, in combination with other critical factors that are involved in the aging process. It is interesting to note here that the rate at which a cell produces protein, and thus the number of ribosomal units that are required, is linked closely to the rate of cell growth.9,64 For example, a change in growth conditions leads rapidly to an increase or decrease in the rate of synthesis of all ribosomal units.9,64 The mechanism of this coordinated regulation is due to the properties of ribosomal proteins related to their ability to act as translational repressors of their own synthesis.9,64 These universal properties of ribosomal proteins related to cell growth may make some of them—in particular those that might be released into the extracellular fluids by neoplastic cells, during the process of oncogenesis,1–7,13,14 necrosis,18 or apoptosis,16,18–20—ideal for use as serum tumor markers (Table 9.3; and see Figure 9.23 below). In fact, when the MPS-1 protein is artificially overproduced by transformed cells, such as baculovirus-transformed cells (Figure 9.6), it is released from the cells into the extracellular fluids.62 It should not be surprising that ribosomal proteins such as MPS-1 can be released from cancer cells into the extracellular fluids. Several mechanisms may explain this release into extracellular fluids, such as intrinsic chemical properties of MPS-1 (e.g. its amphipathic properties (Figure 9.16), which allow the molecule to transverse cell membranes), necrosis, or possibly apoptosis.16,18–20 Even insoluble nuclear matrix proteins can be released from apoptotic cells in a soluble form, and they can be detected in serum from cancer patients.17,65 It has been demonstrated that the MPS-1 protein is overproduced in cancer cells.14,61–63 It is conceivable that overproduction of MPS-1 by malignant cells may be part of the ribotoxic cellular response to carcinogenic agents (Figure 9.19),66 as will be discussed in more detail in the next section. In summary, as is the case with numerous proteins that are overproduced in many diseases, pathologic effects of

Comprehensive Geriatric Oncology

204

Figure 9.19 The ribotoxic stress response. Ribosomal proteins are involved in DNA-damage processing. The involvement of MPS-1 in mRNA

Growth factors, oncogenes, and aging

205

degradation triggered by genotoxic stress is shown. MPS-1 is activated in response to signals generated by a variety of genotoxic stresses, such as UV radiation and carcinogenic agents. The intact MPS-1 pathway helps to maintain genomic integrity by eliminating defective mRNA. Intact ribosomes are essential mediators of the ribotoxic stress response. protein overproduction will eventually result that may be quite independent and unpredictable from the normal function of the protein. Zinc-finger ribosomal proteins, ribotoxic responses, and carcinogenesis The ribotoxic stress response, which is conserved between prokaryotes and eukaryotes, is a cellular reaction to cytotoxic interference with the function of the 3′ end of the large (23S/28S) ribosomal RNA.66 In mammalian cells, the ribotoxic stress response involves activation of protein kinases and transcriptional induction of genes such as c-fos and cjun.66 Active ribosomes are essential mediators of the ribotoxic stress response (Figure 9.19).66 Cellular signaling cascades in response to UV light and carcinogenic agents may be generated in the ribosome, and possibly triggered by damage to ribosomal RNA.66–69 There are many reports indicating a connection between overexpression of genes encoding some ribosomal proteins and cancer.14,62,70–78 Furthermore, a number of ribosomal proteins have additional functions separate from their role in the ribosome and in protein synthesis.62,72–76,78 Recentevidence for extraribosomal functions of ribosomal proteins is beginning to emerge in the field of oncogenesis.14 Zinc-fmger motifs are characteristics of numerous ribosomal proteins, allowing them to bind to nucleic acids.14,72 This binding ability offers a potential mechanism for ribosomal proteins to participate in both transcriptional and translational mechanisms and potentially interfere with them. For example, the rat ribosomal protein S3a is identical to the product of the rat Fte-1 gene, which encodes the v-fos transformation effector.73 S3a is involved in the initiation of protein synthesis, and is also related to proteins involved in the regulation of growth and the cell cycle,73 rat ribosomal protein L10 is homologous to the Jun-binding protein and to a putative Wilms’ tumor suppressor.14,78 The yeast protein Rrp7p, which is homologous to MPS-1, is required for correct assembly of pre-rRNA in the preribosomal particle.51 The genes identified were RPS27A and RPS27B, which are duplicated genes that encode a protein with 70% homology to the rat ribosomal protein S27.51 Cells with either RPS27 gene deleted are viable, but the double delation is non-viable, showing that both genes are expressed and that the rpS27 protein is essential.51 The proteins are required for correct assembly of rpS27 into the

Comprehensive Geriatric Oncology

206

preribosomal particle, with inhibition of pre-rRNA processing appearing as a consequence of this defect.51 Revenkova and co-workers68,69 have shown the involvement of ribosomal protein S27 (MPS-1 present in plants) in mRNA degradation triggered by genotoxic stress in the model plant Arabidopsis thaliana. Deletion of MPS-1 in plants is accompanied by formation of tumors instead of auxiliary roots on exposure to UV light or chemical carcinogens.69 Taken together, these findings of ribosomal proteins with oncogenic, tumor supressor, or cell cycle functions suggest extraribosomal functions of certain ribosomal proteins related to oncogenesis.14,72 Prokaryotes and eukaryotes express a number of heat-shock proteins (Hsps) in response to various forms of stress—heat shock, heavy metals, hormones, and viral infections (Figure 9.20).14 These Hsps, which are zinc-finger proteins, act as intracellular detectors that recognize misfolded proteins.11,14,79,80 The stress response may lead to apoptosis (see Figure 9.25 below), and is also involved in cancer and in aging.10,12,14,79,80 One of the most interesting proteins involved in the response to viral infection is DnaJ, an Hsp that functions in the control of iintracellular protein folding. DnaJ contains two CCCC zinc fingers, defined by the ‘J domain’, which plays an essential role in stimulation of the ATPase activity of Hsp70 (DnaK, an ~70 kDa Hsp induced by numerous environmental stresses).14 The results reviewed here and elsewhere10,14 suggest that there may be a relationship between the ribotoxic response (Figure 9.19), the stress response (Figure 9.20), and carcinogenesis and aging.10,66,69,79,80 Hsp70 plays a protective role in inflammation and infection, and has a regulatory role in cytokine biosynthesis. Hsp70 exists in cells in equilibrium between its free state (in the cytoplasm) and its bound state, protecting proteins in the nucleolus, interacting with ribosomal proteins either to refold some of the unfolded ribosomal proteins or to solubilize the denatured ribosomal proteins to facilitate their use and increase their turnover rate.14,79,80 Expression of MPS-1 mRNA and protein in human cancer MPS-1 cDNA was used to generate DNA and RNA probes to detect MPS-1 mRNA (Figure 9.4).61–63 Furthermore, recombinant (r) MPS-1 protein and chemical derivatives were used to generate polyclonal anti-MPS-1 antibodies (Figure 9.4).62,63 Both the DNA probes and the anti-MPS-1 antibodies were used to detect MPS-1 mRNA and MPS proteins, respectively, in various types of cultured cells and pathologic tissue specimens (Figure 9.4).61–63 Table 9.6 indicates the presence of MPS-1 mRNA in exponentially growing cultured human malignant cell lines. Tissue culture experiments have demonstrated that the level of MPS-1 mRNA was severalfold greater (from 3- to 15-fold) in human malignant cell lines than in normal human WI-38 diploid fibroblasts under the same experimental conditions.61,62 Furthermore, experiments with pathologic tissue specimens demonstrated that the MPS-1 gene is expressed at high levels in numerous human cancers such as prostate, breast, brain, and lung cancer, and particularly melanomas (Table 9.2). In contrast, the MPS-1 gene is expressed at low levels in

Growth factors, oncogenes, and aging

207

Figure 9.20 The cellular stress response. This response is triggered by numerous physiologic and pathologic factors, and is involved in carcinogenesis and aging. The diagram indicates a relationship between the stress response and the ribotoxic response. DnaJ is a zinc-finger heatshock protein involved in inflammation. normal tissues (Table 9.2). Table 9.7 indicates the presence of MPS-1 mRNA in the peripheral blood of human patients with hematologic malignancies. MPS-1 mRNA was detected using a biotinylated single-stranded antisense DNA probe (Figure 9.9). MPS-1 protein was detected by immunohistochemical staining using antipeptide A antibodies (Figure 9.10); the MPS-1 peptide sequences used for antibody production are underlined in Figure 9.12. As can be seen from Table 9.2, there is an excellent correlation between MPS-1 mRNA and protein expression. The results of numerous immunohistochemistry experiments indicated that the MPS-1 antigen is a ubiquitous tumor marker that may be useful in the detection, prognosis, and management of various types of neoplastic conditions. An illustrative example of the use

Comprehensive Geriatric Oncology

208

of MPS-1 in the study of human melanocytic lesions is presented in the following section. MPS-1 as a marker to study melanocytic lesions at the immunohistologic level Although the detection and management of all forms of cancer is desirable, the detection of malignant melanoma is particularly challenging to the clinician. Often benign lesions are difficult to distinguish from malignant lesions. It is imperative, however, that malignant melanoma be detected early and reliably to improve survival rates. Immunohistochemical studies have been conducted to examine the expression of MPS-1 protein in various types of benign and malignant melanocytic lesions.77 Protein antigen, detected with anti-MPS-1 antibodies, has been found in both benign and malignant melanocytic lesions. In benign lesions (Figure 9.10a), the staining is weak and in a gradient—the most superficial cells with nesting growth patterns are positive, particularly those within the epidermis. The stain intensity decreases for melanocytes located deeper in the dermis. In practice, only type A melanocytes stain positively, while types B and C are negative. Recurrent melanocytic nevi have also been studied.77 MPS-1 is nearly negative in the original untreated nevi. In recurrent lesions, the regenerating epidermal and dermal melanocytic components are intensely and evenly stained. These findings are very similar to those seen in melanomas. These changes are an example of intense activation of the newly formed melanocyte population, and not a sign of malignant transformation. It is of interest that scar tissue generates large amounts of growth factors.77 Thus, growth factors may be responsible for both the activation of melanocytic cells and the intense expression of MPS-1 observed on biopsy. It will be appreciated that the histologic features of these recurrent nevi are indistinguishable from those of melanomas—a phenomenon that often confounds the diagnostician. The correct diagnosis is made by reviewing the original melanocytic nevus. In melanomas (Figure 9.10b), the staining patterns are more complex.77 While some melanomas stain evenly positive, others have remarkably variable expression of MPS-1. This seems to correlate, to some extent, with intralesional transformation (Figure 9.10b).77 The variability is so pronounced that some cells stain intensely positive in nests of cells staining moderately positive (Figure 9.10b). The scattered melanocytes migrating to the upper layers of the epidermis are usually intensely positive. Curiously, melanoma metastatic to lymph nodes shows only faint positivity in the limited sampling studied.77 A single example of melanoma metastatic to the skin was evenly and intensely positive in spite of its seemingly well-differentiated, almost nevoid appearance.77 No gradient staining was present, as it should have been in the case of a benign nevus.77 Macrophages in and around the area are intensely positive, with a coarse, granular cytoplasmic pattern.77 Macrophages present in less intensely stained areas have less MPS-1 content than those located in strongly stained areas. This is particularly so in nevi in which macrophages are rare or non-existent (Figure 9.10a). This finding tends to correlate with the near absence of apoptosis in nevi. On the other hand, the presence of MPS-1 in macrophages of melanomas (Figure 9.10b) suggests direct phagocytosis of

Growth factors, oncogenes, and aging

209

melanoma cell debris following apoptosis—a common phenomenon.77 Some melanocytes in melanomas show individual cells with similar patterns, supporting the concept of phagocytosis by melanoma cells.77 As the above discussion indicates, MPS-1 is a useful marker for melanocytic lesions at the immunohistologic level, providing important clues to the biological nature of melanocytic tumors not obtainable by other methods.77 MPS-H antigen(s) as a ubiquitous tumor marker for early detection, prognosis, and management of benign and malignant oncogenic processes Over the last quarter of a century or so, serum tumor markers have been studied intensively.81 Numerous circulating antigens have been proposed as universal or organspecific tumor markers for diagnosis, localization, and assessment of treatment.81 In the studies summarized in this chapter, MPS-H (‘H’ denoting ‘heating’, see below) as a ‘universal or broad spectrum’ tumor maker has been defined as antigens related to MPS-1 sequences and found in abnormal concentrations in the blood of a large number of patients (>80%) suffering from various forms of benign and malignant neoplastic processes.82 The results evaluated here demonstrate that MPS-H and MPS-H-like proteins are heat-resistant antigens that may be useful in the early detection, prognosis, and management of various types of malignant neoplastic conditions.31,82–84 As used in this chapter, ‘MPS-H’ refers to heat-generated immunoreactive serum proteins that are used as pragmatic tumor markers. These proteins are generated in the serum of cancer patients after denaturation by controlled heat treatment. Since they are created by heating under extreme denaturing conditions, they will be also be referred to as serum extremophilic MPS-H antigens. It has been shown above that the MPS-1 DNA sequence and the protein can be used in diagnostic methods such as detection of malignant cells associated with several types of tumors. The development of a sensitive and specific radioimmunoassay (RIA) for MPS-N (the N terminus of the MPS-1 protein), using recombinant MPS-1 proteins (Figure 9.6)82 and synthetic peptide technology,85 has made it possible to detect the very low concentrations of MPS-N and MPS-H in human blood and other body fluids (Figure 9.11; Table 9.3).82,83 Thus, the MPS-N RIA provides a method for determining the presence of certain types of abnormal proliferative conditions and/or active oncogenic processes in patients (Figure 9.11; Table 9.3).82 A preliminary clinical study including 632 individuals separated into healthy subjects, active cancerous diseases, non-malignant diseases, and premalignant diseases has provided important information about the use of the MPS-H test in the detection of various types of cancer (Figure 9.11; Table 9.3).82 The data from the clinical study are shown in Table 9.3 and also illustrated graphically in Figure 9.11. In general, the MPS-H test was found to be experimentally useful in (i) detection of primary cancerous disease in previously undiagnosed individuals and (ii) detection of cancer recurrence in previously diagnosed and treated patients. Since the MPS-H assay measures proteins common to various forms of cancer, including MPS-H and MPS-H-like proteins in human serum, it is clearly not useful for determining tumor localization.

Comprehensive Geriatric Oncology

210

The MPS-H test may have significant importance in the detection of a number of undiagnosed common malignancies. As shown in Table 9.3, increased MPS-H levels have been detected with high frequency (>80% of cases) in many common cancers, including prostate, colorectal, lung, and neuroendocrine cancers, as well as leukemias. Moreover, in patients with these cancers, MPS-H testing may have important value in monitoring metastatic or persistently active cancer, following chemotherapy, surgery, or radiotherapy. A persistent elevation in circulating MPS-H levels following treatment or an increase in an otherwise lower level is indicative of recurrent or residual cancer and poor response to therapy (see Figure 9.23 below).82 A declining MPS-H value is generally indicative of a good response to treatment and a favorable prognosis (Figure 9.21; and see Figure 9.24 below). Serum MPS-H can also be elevated in active non-malignant tumorigenic processes such as benign prostatic hypertrophy (BPH; Table 9.3). It is conceivable that, in a number of cases of BPH, MPS-H detects early cancer of the prostate, present in a field of neoplastic cells that was not detected by other means. Of course, it is also possible that MPS-H antigens are released by BPH cells that have not suffered malignant transformation. Inflammatory conditions of the prostate, liver, intestine and colon were negative for MPS-H (Table 9.3). Finally, it is interesting to note here that four cases of premalignant colorectal polyps have tested positive for MPS-H antigen, suggesting that early diagnosis of premalignant proliferative conditions by measurement of MPS-H antigen in the serum may be feasible (Table 9.3). Taken together, these results indicate that the MPS-H test, which measures a unique serum antigen(s) common to a variety of oncogenic processes, provides the following clinically useful information: (i) first and foremost, the MPS-H test narrows down the uncertainty zone concerning the presence or absence of an oncogenic process; (ii) the MPS-H test may be useful in signalling cases where further clinical investigation of oncogenic processes by a physician is needed; (iii) thus, the MPS-H test is an indicator of potential clinical problems in the area of oncogenesis.82 We have used the MPS-H tumor marker test, which detects MPS-1 and MPS-1-like proteins, to determine the relationship between MPS-H serum levels and clinical status of patients at risk for head and neck squamous cell carcinomas (HNSCC).83,86 In this study, 151 patients were prospectively enrolled from a university head and neck oncology clinic. Participants were both newly diagnosed and follow-up HNSCC patients. Two control groups, including 25 healthy individuals and 64 actively smoking individuals, were studied for comparison. A total of 848 serum samples (736 cases, 48 healthy controls, and 64 smoking controls) collected over a 24-month period were analyzed by the MPS-H RIA. Healthy control and smoking control groups had average MPS-H values of 10 ±4.3 ng/ml and 12.75±8.8 ng/ml, respectively (p= 0.0001) (Figure 9.22). Mean MPS-H levels did not vary significantly with AJCC stage (p=0.74) in cancer patients. Using the results of 188 positron emission tomography (PET) scans in a subset of 68 HNSCC patients as an indicator for presences of disease, the area under the receiver operating characteristic (ROC) curve was 0.66 (p =0.001), suggesting moderate predictive value. The results of PET scans were also correlated with two thresholds for a positive MPS-H test: (i) MPS-H≥35 ng/ml and (ii) 20 ng/ml ≥MPS-H ≥35 ng/ml. Figures 9.23 and 9.24 illustrate two longitudinal case scenarios demonstrating the MPS-H levels

Growth factors, oncogenes, and aging

211

and their response to various forms of antineoplastic treatment, as well as life with and death from untreatable disease. The authors concluded that

Figure 9.21 Monitoring serum levels of MPS-N antigen after successful therapy of a patient with prostate carcinoma. Note the faster decline in serum MPS-N levels in comparison with the slower decrease in serum prostate-specific antigen (PSA) levels. MPS-H proteins are elevated in patients with HNSCC (Figure 9.22), and that MPS-H appears to be a promising marker of presence of disease and response to treatment in HNSCC patients (Figures 9.23 and 9.24).83,86 The MPS-H antigen(s) present in the blood does not meet some of the criteria for rating a protein as a perfect tumor marker (Table 9.8). Evidently, the MPS-H antigen(s) is a non-specific tumor marker, since it is present in healthy subjects and it is produced by both benign and malignant tumors (Figure 9.12). However, the MPS-H antigen(s) is sensitive (it is present in early stages; and frequently present in late stages), it can be used as a guide to management (the concentration reflects prognosis and correlates with therapeutic resection), and, analytically, the immunoassay is quantitative and sensitive. Finally, it is conceivable that the MPS-H tumor marker may be useful to detect numerous types of malignancies in early stages, thereby reducing mortality, and thereby the enormous expenditures associated with the treatment of advanced cancer.

Comprehensive Geriatric Oncology

212

Pharmacologic disruption of the activity of metalloproteins involved in carcinogenesis and angiogenesis There are numerous drugs that affect gene expression, including hormones, growth factors, and specific chemicals.13,14 There are essential viral and cellular zinc- and ironcontaining metalloproteins that are targets for novel antiviral and anticancer agents.14 One can infer that the

Figure 9.22 Mean serum MPS-H level for a non-age-matched control group (n=51) and patients with head and neck squamous cell carcinoma (HNSCC) (n=151, all stages and sites within the head and neck). The mean of healthy controls is 10.2 ng/ml, that of screening controls is 12.8 ng/ml, and that of HNSCC patients is 39.5 ng/ml (p<0.0001). development of a variety of drugs that control or neutralize metalloproteins such as zincfinger proteins may lead to a new therapeutic approach directed at controlling carcinogenesis.14 New insights concerning apoptosis, metalloproteins, and novel anticancer agents will be briefly reviewed here (Figure 9.25). It has been shown that intracellular zinc, copper, and/or iron chelation induce apoptosis in virally infected cells and spontaneously transformed cancer cells, perhaps by

Growth factors, oncogenes, and aging

213

inhibiting both cellular and viral metalloproteins that play critical roles in cellular and viral survival (Figure 9.25).14,21,87–89 It has been shown that cancer cells are more

Figure 9.23 This patient with HNSCC was without evidence of disease from surgery through radiation therapy (XRT) (draws 1–5). The patient suffered a recurrence of clinical disease following radiation therapy (draws 6–8), which progressed until death. susceptible to decreases in intracellular zinc or iron concentrations, which in turn results in apoptosis (Figure 9.25).14,87–89 intracellular pools of chelatable Fe2+ and Zn2+ play critical roles in apoptosis, possibly by modulating the activity of Fe2+/3+- and Zn2+containing proteins such as ribonucleotide reductase and zinc-finger proteins, respectively, which are essential for the maintenance of cellular and viral structure and function, and which are highly active in virally transformed cells and cancer cells.14,90,91 Picolinic acid (pyridine-2-carboxylic acid), a naturally occurring product of tryptophan catabolism, is a biological response modifier, endowed with a variety of effects

Comprehensive Geriatric Oncology

214

Figure 9.24 This patient with HNSCC was followed for 24 months without evidence of recurrence on physical examination, endoscopies, or PET. Table 9.8 Rating a protein as a tumor marker Specificity •

Absent in healthy subjects

•

Exclusively produced by malignant tumors

Sensitivity •

Present in early stage

•

Present frequently in late stage

Management guide •

Concentration reflects prognosis

•

Concentration correlates with therapeutic resection

Analytical •

Quantitative and sensitive assay

Confirmatory reports •

Worldwide acceptance

Growth factors, oncogenes, and aging

215

on transition-metal ion traffic, the cell cycle, viral and bacterial growth, and host immune responses (Figure 9.25). Furthermore, picolinic acid exerts antitumor effects in vivo.14 It is also an immune-response modifier capable of inducing a variety of cytokines, including interferons, tumor necrosis factor, and interleukins.98,99 In animal model systems, picolinic acid has demonstrated antiviral, antitumor, and immune-modulatory activities.14,89 In addition, inactive macrophages are activated in response to picolinic acid, which may be a mechanism for the elimination of both viruses and cancer cells.14,54,64,89,98–103 It is conceivable that the differential effects of picolinic acid are due to its interactions with cellular and/or viral proteins that depend on transition-metal ions for their functions and that these proteins are produced at greater levels in virally infected cells and cancer cells than in normal adult cells.14 The cellular target metalloproteins may be ribosomal proteins, heat-shock proteins, or enzymes such as ribonucleotide reductase.14 The chemical disruption of such proteins by agents such as picolinic acid and other chelators may result in the induction of apoptosis in both virus-infected cells and cancer cells (Figure 9.25).14,89 At present, there are ongoing clinical trials using copper chelators, with the aim of inhibiting angiogenesis in tumors.26,30,104–108 Penicillamine, which binds copper by its sulfhydryl group and decreases neovascularization, is in phase II clinical trials for glioblastoma.107 Tetrathiomolybdate binds copper tightly through its thiol groups and thus prevents copper from becoming available to the tumor.14,107 This agent is in phase I/II clinical trials for advanced metastatic cancer.107 Finally, captopril, an antihypertensive agent, chelates copper and zinc, and is in phase I/II clinical trials.107 These drugs have been shown to alter the properties of distinctive zinc-, copper-, and iron-containing proteins.14,107 The ability to control the activities of specific metalloproteins may lead to the development of therapies for a broad range of human and animal diseases, including drugs to treat viral infections and cancer.14

Comprehensive Geriatric Oncology

216

Figure 9.25 Modulation of growth (1), maturation (2), apoptosis (3), and aging (4) by intracellular fluctuations of zinc or the presence of zinc chelators such as picolinic acid. Conclusions and future prospects Cellular senescence is defined as the loss of proliferative capacity of cultured cells, and results in inability of the cell population to increase in cell number after a number of divisions. In this sense, senescence is the opposite of cancer, and may be suspected to include the inactivation of proto-oncogenes and activation of tumor suppressor genes. The patterns of gene expression in senescent cells, younger quiescent cells, and growing cells have been compared, and the results indicate that senescent fibroblasts are unable to proliferate because of selective repression of numerous proto-oncogenes at the level of gene transcription. These results strengthen the hypothesis that aging is an active terminal differentiation process that involves proto-oncogene inactivation. It is conceivable that senescence-related genes may have inhibitory activity on DNA synthesis and cell growth, and thus may be related or identical to tumor suppressor genes. Future molecular biological studies will most likely identify specific senescence-related genes that might be used for the clinical control of human cancer.

Growth factors, oncogenes, and aging

217

The unexpected role of ribosomal proteins in DNA-damage processing has now been shown. Ultraviolet radiation and numerous toxic agents, including carcinogens, trigger ribotoxic stress responses in animals and plants, indicating that these pathways are evolutionarily conserved to permit the existence of prokaryotic and eukaryotic life forms on this planet. The ribotoxic stress response, which is conserved between prokaryotes and eukaryotes, is a cellular reaction to cytotoxic interference with the function of the 3' end of large (23S/28S) ribosomal RNA. In mammalian cells, the ribotoxic stress response involves the activation of protein kinases and the transcriptional induction of specific genes. Active ribosomes are essential mediators of the ribotoxic stress response, and experimental evidence indicates that this response is involved in aging and carcinogenesis. The rate at which a cell produces protein and thus the number of ribosomal units that are required is linked closely to the rate of cell growth. Cancer cells can somehow subvert this system, with consequent overproduction of ribosomal proteins. Many different human cancers overexpress the MPS-1 (S27 ribosomal) gene, as demonstrated by numerous different assays. Both MPS-1 mRNA and protein are present in abnormally high concentrations in a wide variety of cancer cells. They thus provide a method for detecting and diagnosing malignancy in many type of tumors. Assays using labeled DNA or RNA probes and antibodies that bind to MPS-1 mRNA and protein, respectively, have allowed clear discrimination between cancerous and non-cancerous cells. Further analysis of this system promises to yield useful information both for understanding malignant transformation and for the use of MPS-1 and MPS-1-like antigens to aid in the early detection of cancer. Drugs developed from studies of the disruption of metalloproteins by specific chelating agents may show strong activity against cancer cells in vitro, and may also be safe and effective when administered in vivo.14,107 Thus, these drugs may be of possible use in the elderly population for certain types of cancers with no alternative treatment. The results reviewed here suggests strongly that some of the pharmacologic agents that disrupt metalloproteins are significant for further pharmaceutical development. Very recently, there have been some new developments in the areas of cancer detection109 and drug development.110 Acknowledgements Some of the work reviewed here was supported in part by the DVA Medical Center Research Funds from 1980 to 1999. The work in the area of drug development was supported by Metalloproteomics, Inc. of Chesterfield, MO, USA. The author thanks Eilleen Collins, Medical Illustrations Service, DVA Medical Center, for the preparation of some of the figures. This review would not have been possible without the research work of Dennis J Klos, chemist, Paul D Hamilton, molecular biologist, and Vera M Schuette, research technician. The research contributions of Patricia Huygens, Visiting Professor from the University of Buenos Aires, Argentina, are acknowledged. The contribution of Maria E Fernandez-Pol, computer specialist, in patient data analysis is appreciated. Sebastian Fernandez-Pol generated significant experimental data for this review in the area of drug development, metalloproteins, and anticancer agents. The

Comprehensive Geriatric Oncology

218

author thanks his collaborators for providing materials for this review: gastrointestinal cancer, Daniel Ganger, MD, Rush Presbyterian-St Luke’s Medical Center, Chicago, IL; gynecologic cancer, Francisco P Xynos, MD, St Louis University, St Louis, MO; and melanocytic lesions, Daniel Santa Cruz, St Johns’ Mercy Medical Center, St Louis, MO. References 1. Bishop JM. The molecular genetics of cancer. Science 1987; 235: 305–11. 2. Land H, Parada LF, Weinberg RA. Cellular oncogenes and multistep carcinogenesis. Science 1983; 222:771–8. 3. Weinberg RA. Oncogenes, antioncogenes, and the molecular bases of multistep carcinogenesis. Cancer Res 1989; 49:3713–21. 4. Klein G. The approaching era of the tumor suppressor genes. Science 1987; 238:1539–45. 5. Nowell PC. The clonal evolution of tumor cell populations. Science 1976; 194:23–8. 6. Weinstein IB. The origins of human cancer: molecular mechanisms of carcinogenesis and their implications for cancer prevention and treatment. Cancer Res 1988; 48:4135–43. 7. Cooper GM. Oncogenes, 2nd edn. Boston: Jones and Bartlett, 1995. 8. Brugge J, Brugge T, Curran E et al (eds). Origins of Human Cancer: A Comprehensive Review. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 1991. 9. Watson JD, Hopkins NH, Roberts JN et al. Molecular Biology of the Gene, 4th edn. Menlo Park, CA: Benjamin-Cummings, 1988:494–6. 10. Fernandez-Pol JA, Douglas MG. Molecular interactions of cancer and age. Hematol Oncol Clin North Am 2000; 14:25–44. 11. Alberts B. The cell as a collection of protein machines: preparing the next generation of molecular biologists. Cell 1998; 92:291–4. 12. Saul RL, Gee P, Ames BN. Free radicals, DNA damage, and aging. In: Modern Biological Theories of Aging (Warner HR, Sprott RL, Butler RN, Schneider EL, eds). New York: Raven Press, 1987:113–29. 13. Fernandez-Pol, JA. Modulation of EGF receptor protooncogene expression by growth factors and hormones in human breast carcinoma cells. CRC Crit Rev Oncogen 1991; 2:173–85. 14. Fernandez-Pol JA, Hamilton PD, Klos DJ. Essential viral and cellular zinc and iron containing metalloproteins as targets for novel antiviral and anticancer agents: implications for prevention and therapy of viral diseases and cancer. Anticancer Res 2001; 21:931–58. 15. Saltiel AR. Signal transduction pathways as drug targets. Sci Am Sci Med 1995; 2:58–67. 16. Tomei LD, Cope O (eds). Apoptosis II: The Molecular Basis of Apopto-sis in Disease. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 1994. 17. Miller TE, Beausang LA, Meneghini M, Lidgard G. Cell death and nuclear matrix proteins. In: Apoptosis II: The Molecular Basis of Apoptosis in Disease (Tomei LD, Cope O, eds). Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 1994:357–76. 18. Majno G, Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol 1995; 146:3–15. 19. Hetts SW. To die or not to die: an overview of apoptosis and its role in disease. JAMA 1998; 279:300–7. 20. Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science 1995; 267:1456–62. 21. Fernandez-Pol JA. Regulation of apoptosis by viruses and zinc chelators antiviral agents: implications for prevention and therapy of viral diseases and cancer. In: The Third National AIDS Malignancy Conference, Bethesda, MD, May 26–27, 1999. 22. Goustin AS, Leof EB, Shipley GD, Moses HL. Growth factors and cancer. Cancer Res 1986; 46:1015–29.

Growth factors, oncogenes, and aging

219

23. Carpenter G. Receptors for epidermal growth factor and other polypeptide mitogens. Annu Rev Biochem 1987; 56:881–914. 24. Sporn MB, Roberts AB, Wakefield LM, de Crombrugghe B. Some recent advances in the chemistry and biology of transforming growth factor-β. J Cell Biol 1987; 105:1039–45. 25. Slamon DJ, Godolphin W, Jones LA et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989; 244:707–12. 26. D’Amore PA, Ng YS, Darland DC. Angiogenesis. Sci Am Med 1999; 6:44–53. 27. Mazurek S, Boschek CB, Eigenbrodt E. The role of phosphometabolites in cell proliferation, energy metabolism, and tumor therapy. J Bioenerget Biomembranes 1997; 29:315–30. 28. Pearline RV, Lin Y-Z, Shen KJ et al. Alterations in enzymatic functions in hepatocytes and hepatocellular carcinomas from Rastransduced livers resemble the effects of insulin. Hepatology 1996; 24: 838–48. 29. Nagase H, Woessner JF. Matrix metalloproteinases. J Biol Chem 1999; 274:21491–4. 30. Lush RM, Rudek MA, Figg WD. Review of three new agents that target angiogenesis, matrix metalloproteinases, and cyclin-dependent kinases. Cancer Control 1999; 6:459–65. 31. Mide SM, Huygens P, Bozzini CE, Fernandez-Pol JA. Effects of human recombinant erythropoietin on differentiation and distribution of erythroid progenitor cells on murine medullary and splenic erythropoiesis during hypoxia and posthypoxia. In Vivo 2001; 15: 125– 32. 32. Cowen LC, Avrutskaya AV, Latour AM et al. BRCA1 required for transcription-coupled repair of oxidative DNA damage. Science 1998; 281:1009–12. 33. Fernandez-Pol, JA, Klos DJ, Hamilton PD, Talkad VD. Modulation of epidermal growth factor receptor gene expression by transforming growth factor-β in a human breast carcinoma cell line. Cancer Res 1987; 47:4260–5. 34. Fernandez-Pol JA, Hamilton PD, Klos DJ. Transcriptional regulation of proto-oncogene expression by epidermal growth factor, transforming growth factor β–1, and triiodothyronine in MDA-468 cells. J Biol Chem 1989; 264:4151–6. 35. Fernandez-Pol, JA, Klos DJ, Hamilton PD. Modulation of transforming growth factor ocdependent expression of epidermal growth factor receptor gene by transforming growth factor β, triiodothyronine, and retinoic acid. J Cell Biochem 1989; 41:159–70. 36. Fernandez-Pol JA, Talkad VD, Klos DJ, Hamilton PD. Suppression of the EGF-dependent induction of c-myc proto-oncogene expression by transforming growth factor β in a human breast carcinoma cell line. Biochem Biophys Res Commun 1987; 144:1197–205. 37. Collier L, Balows A, Sussman M (eds). Topley & Wilson: Microbiology and Microbial Infections—Virology, 9th edn. London: Arnold, 1998. 38. Bais C, Santomasso, Coso O et al. G-protein-coupled receptor of Kaposi’s sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature 1998; 391:86–89. 39. Ensoli B, Barillari G, Salahuddin SZ et al. Tat protein of HIV-1 stimulates growth of cells derived from Kaposi’s sarcoma lesions of AIDS patients. Nature 1990; 345:84–6. 40. Frankel AD, Pabo CO. Cellular uptake of the tat protein from human immunodeficiency virus. Cell 1988; 55:1189–93. 41. Howley PM. The role of papillomaviruses in human cancer. Important Adv Oncol 1987; 1:55– 73. 42. Chinami M, Inoue M, Masunaga K et al. Nucleic acid binding by zinc finger-like motif of human papillomavirus type 16 E7 oncoprotein. J Virol Meth 1996; 59:173–6. 43. Alani RM, Munger K. Human papillomaviruses. Sci Am Sci Med 1998; 5:28–35. 44. Kris MG, Miller VA. Inhibition of epidermal growth factor receptor tyrosine kinase: a concept now in the clinic. In: American Society of Clinical Oncology Educational Book (Perry MC, ed). American Society of Clinical Oncology, 2001:435–40. 45. Fernandez-Pol JA. Epidermal growth factor receptor of A431 cells: characterization of a monoclonal anti-receptor antibody non-competitive agonist of EGF action. J Biol Chem 1985; 260:5003–11.

Comprehensive Geriatric Oncology

220

46. Seshadri T, Campisi J. Repression of c-fos transcription and an altered genetic program in senescent human fibroblasts. Science 1990; 247:205–9. 47. Johnson PF, McKnight SL. Eukaryotic transcriptional regulatory proteins. Annu Rev Biochem 1989; 58:799–839. 48. Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature 1998; 369:643–9. 49. Agarwal ML, Taylor WR, Chernov MV et al. The p53 network. J Biol Chem 1998; 273:2–4. 50. Sekowski JW, Malkas LH, Schnaper L et al. Human breast cancer cells contain error-prone DNA replication apparatus. Cancer Res 1998; 58:3259–63. 51. Baudin-Baillieu A, Tollervey D, Cullin C, Lacroute F. Functional analysis of Rrp7p, an essential yeast protein involved in pre-rRNA processing and ribosome assembly. Mol Cell Biol 1998; 17:5023–32. 52. Fernandez-Pol JA, Klos DJ, Hamilton PD. Correlation between the loss of the transformed phenotype and an increase in superoxide dismutase activity in a revertant subclone of sarcoma virus-infected mammalian cells. Cancer Res 1982; 42:609–17. 53. Melillo G. A hypoxia-responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoter. J Exp Med 1995; 182:1683–93. 54. Melillo G, Cox GW, Biragyn A et al. Regulation of nitric-oxide synthase mRNA expression by interferon-γ and picolinic acid. J Biol Chem 1994; 269:8128–33. 55. Berg JM. Metal-binding domains in nucleic acid-binding and gene regulatory proteins. Prog Inorg Chem 1989; 37:143–90. 56. Berg JM. Zinc fingers and other metal-binding domains. J Biol Chem 1990; 265:6513–16. 57. Evans RM, Hollenberg SM. Zinc fingers; gilt by association. Cell 1988; 52:1–3. 58. Berg JM. Zinc finger domains: hypothesis and current knowledge. Annu Rev Biophys Biophys Chem 1990; 19:405–21. 59. Fernandez-Pol JA. Oxidative DNA damage mediated by hormone and growth factor regulated iron finger proteins: implications for prevention of cancer and aging. Ann Oncol 1998; 9:33–4. 60. Conte D, Narindrasorasak S, Sarkar B. In vivo and in vitro iron-replaced zinc finger generates free radicals and causes DNA damage. J Biol Chem 1996; 271:5125–30. 61. Fernandez-Pol JA, Klos DJ, Hamilton PD. A growth factor-inducible gene encodes a novel nuclear protein with zinc-finger structure. J Biol Chem 1993; 268:21198–204. 62. Fernandez-Pol JA, Klos DJ, Hamilton PD. Metallopanstimulin gene product produced in a baculovirus expression system is a nuclear phosphoprotein that binds to DNA. Cell Growth Diff 1994; 5:811–25. 63. Xynos FP, Klos DJ, Hamilton PD et al. Expression of metallopanstimulin in condylomata acuminata of the female anogenital region induced by papilloma virus. Anticancer Res 1994; 4:773–86. 64. Varesio L, Radzioch D, Bottazzi B, Gusella GL. Ribosomal RNA metabolism in macrophages. Curr Top Micorbiol Immunol 1992; 181: 209–35. 65. Miller TE, Beausang LA, Winchell LF, Lidgard GP. Detection of nuclear matrix proteins in serum from cancer patients. Cancer Res 1992; 52:422–7. 66. Iordanov MS, Pribnow D, Magun JL et al. Ultraviolet radiation triggers the ribotoxic stress response in mammalian cells. J Biol Chem 1998; 273:15794–803. 67. Kim J, Chubatsu LS, Admon A et al. Implication of mammalian ribosomal protein S3 in the processing of DNA damage. J Biol Chem 1995; 270:13620–9. 68. Masson JE, King PJ, Paszkowski J. Mutants of Arabidopsis thaliana hypersensitive to DNAdamaging treatments. Genetics 1997; 146: 401–7. 69. Revenkova E, Masson J, Koncz C et al. Involvement of Arabidopsis thaliana ribosomal protein S27 in mRNA degradation triggered by genotoxic stress. EMBO J 1999; 18:101–10. 70. Chan Y-L, Suzuki K, Olvera J, Wool IG. Zinc finger-like motifs in rat ribosomal proteins S27 and S29. Nucl Acids Res 1993; 21:649–55.

Growth factors, oncogenes, and aging

221

71. Thomas G, Novak-Hofer I, Martin-Perez J et al. EGF-mediated phosphorylation of 40S ribosomal protein S6 in Swiss mouse 3T3 cells. In: Cancer Cells 3/Growth Factors and Transformation. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 1985: 33–9. 72. Wool IG. Extraribosomal functions of ribosomal proteins. In: Ribosomal RNA and Group I Introns (Green R, Schroeder R, eds). Austin, TX: Landes Biosciences, 1997:153–78. 73. Chan Y-L, Olvera J, Paz V, Wool IG. The primary structures of rat ribosomal proteins S3a (the v-fos transformation effector) and of S3b. Biochem Biophys Res Commun 1996; 228:141–7. 74. Chan Y-L, Diaz J-J, Denoroy L et al. The primary structure of rat ribosomal protein L10: relationship to a Jun-binding protein and to a putative Wilms’ tumor suppressor. Biochem Biophys Res Commun 1996; 225:952–6. 75. Wool IG. Extraribosomal functions of ribosomal proteins. Trends Biochem Sci 1996; 21:165. 76. Fernandez-Pol JA, Fletcher JW, Hamilton PD, Klos DJ. Expression of metallopanstimulin and oncogenesis in human prostatic carcinoma. Anticancer Res 1997; 17:1519–30. 77. Santa Cruz DJ, Hamilton PD, Klos DJ, Fernandez-Pol JA. Differential expression of metallopanstimulin/S27 ribosomal protein in melanocytic lesions of the skin. J Cutan Pathol 1997; 24:533–42. 78. Vaarala M, Porvari KS, Kyllonen AP et al. Several genes encoding ribosomal proteins are overexpressed in prostate-cancer cell lines: confirmation of L7a and L37 over-expression in prostate cancer tissue samples. Int J Cancer 1998; 78:27–32. 79. Bukau B, Horwich AL. The Hsp70 and Hsp60 chaperone machines. Cell 1998; 92:351–66. 80. Samali A, Cotter TG. Heat shock proteins increase resistance to apoptosis. Exp Cell Res 1996; 223:163–70. 81. Schwartz, MK Cancer markers. In: Cancer: Prindples and Practice of Oncology, 4th edn (DeVita VT Jr, Hellman S, Rosenberg SA, eds). Philadelphia: JB Lippincott, 1993:531–42. 82. Fernandez-Pol JA. Metallopanstimulin as a novel tumor marker in sera of patients with various types of common cancers: implications for prevention and therapy. Anticancer Res 1996; 16:2177–86. 83. Stack BC Jr, Dalsaso TA, Lee C Jr et al. Overexpression of MPS antigens by squamous cell carcinomas of the head and neck: immunohistochemical and serological correlation with FDG positron emission tomography. Anticancer Res 1999; 19:5503–10. 84. Ganger RG, Hamilton PD, Klos DJ, Jakate S, McChesney L, and Fernandez-Pol JA. Differential expression of metallopanstimulin/S27 ribosomal protein in hepatic regeneration and neoplasia. Cancer Detect Prev 2001; 25:241–6. 85. Grant GA (ed). Synthetic Peptides. New York: WH Freeman, 1992. 86. Stack Jr BC, Hollenbeack CS, Lee C et al. Metallopanstimulin as a marker for head and neck cancer. Submitted. 87. Ogata S, Takeuchi M, Okumura K, Taguchi H. Apoptosis induced by niacin-related compounds in HL-60 cells. Biosci Biotechnol Biochem 1998; 62:2351–6. 88. Taguchi H. Vitamins and apoptosis—induction of apoptosis in human cancer cells by nicotinic acid-related compounds. Nippon Rinsho—Jpn J Clin Med 1999; 57:2319–24. 89. Fernandez-Pol JA, Klos DJ, Hamilton PD. Antiviral, cytotoxic and apoptotic activities of picolinic acid on human immunodeficiency virus-1 and human herpes simplex virus-2 infected cells. Anticancer Res 2001; 21:1–4. 90. Lammers M, Follmann H. The ribonucleotide reductases—a unique group of metalloenzymes essential for cell proliferation. Struct Bonding 1983; 54:27–91. 91. Lien EJ. Ribonucleotide reductase inhibitors as anticancer and antiviral agents. Prog Drug Res 1987; 31:101–26. 92. Fernandez-Pol JA, Bono VH Jr, Johnson GS. Control of growth by picolinic acid: Differential response of normal and transformed cells. Proc Natl Acad Sci USA 1977; 74:2889–93. 93. Fernandez-Pol JA, Klos DJ, Hamilton PD. Cytotoxic activity of fusaric acid on human adenocarcinoma cells in tissue culture. Anticancer Res 1993; 13:57–64.

Comprehensive Geriatric Oncology

222

94. Fernandez-Pol JA, Johnson GS. Selective toxicity induced by picolinic acid in simian virus 40transformed cells in tissue culture. Cancer Res 1977; 37:4276–9. 95. Fernandez-Pol JA. Isolation and characterization of a siderophore-like growth factor from mutants of SV40-transformed cells adapted to picolinic acid. Cell 1978; 14:489–99. 96. Collins JJ, Adler CR, Fernandez-Pol JA et al. Transient growth inhibition of Escherichia coli K-12 by ion chelators: ‘in vivo’ inhibition of ribonucleic acid synthesis. J Bacteriol 1979; 138:923–32. 97. Johnson GS, Fernandez-Pol JA. NRK cells synchronized in G1 by picolinic acid are supersensitive to prostaglandin E1 stimulation. FEBS Lett 1977; 74:201–4. 98. Melillo G, Bosco MC, Musso T, Varesio L. Immunobiology of picolinic acid. Adv Exp Med Biol 1996; 398:135–41. 99. Ruffmann R, Welker RD, Saito T et al. In vivo activation of macrophages but not natural killer cells by picolinic acid (PLA). J Immunopharmacol 1984; 6:291–304. 100. Ruffman R, Schlick E, Chirigos MA et al. Antiproliferative activity of picolinic acid due to macrophage activation. Drugs Exp Clin Res 1987; 13:607–14. 101. Blasi E, Radzioch D, Varesio L. Inhibition of retroviral mRNA expression in the murine macrophage cell line GG2EE by biologic response modifiers. J Immunol 1988; 141:2153–7. 102. Melillo G, Cox GW, Radzioch D, Varesio L. Picolinic acid, a catabolite of L-tryptophan is a costimulus for the induction of reactive nitrogen intermediate production in murine macrophages. J Immunol 1993; 150:4031–40. 103. Bosco MC, Rapisarda A, Massazza S et al. The tryptophan catabolite picolinic acid selectively induces the chemokines macrophage inflammatory protein-1α and -1β in macrophages. J Immunol 2000; 164:3283–91. 104. Yoshida D, Ikeda Y, Nakazawa S. Copper chelation inhibits tumor angiogenesis in the experimental 9L gliosarcoma model. Neurosurgery 1995; 37:287–92. 105. Carter SK. Clinical strategy for the development of angiogenesis inhibitors. Oncologist 2000; 5(Suppl 1): 51–4. 106. Rosen L. Antiangiogenic strategies and agents in clinical trials. Oncologist 2000; 5(Suppl 1): 20–7. 107. Brem S. Agiogenesis and cancer control: from concept to therapeutic trial. Cancer Control 1999; 6:436–58. 108. Fernandez-Pol JA. Essential viral and cellular zinc finger proteins as targets for novel widespectrum antiviral, anticancer, and antiangiogenesis agents. Adv Gerontol (Russ Acad Sci) 2000; 5:21 (Abst 28). 109. Fernandez-Pol JA. Proteomics, genomics and immuno-mass spectroscopy: detection of earlystage human breast cancer by serum protein analysis. Cancer Genom Proteom 2004; 1: in press. 110. Fernandez-Pol JA, Fernandez-Pol S. Pharmacological agents and methods of treatment that inactivate pathogenic prokaryotic and eukaryotic cells and viruses by attaching highly conserved domains in structural metalloprotein and metalloenzyme targets. US Patent Application US 2003/0225155, December 4, 2003, issued May, 2004, pp 1–48.

10 Proliferative senescence and cancer Judith Campisi Cancer, tumor suppression, and aging Complex organisms such as mammals are composed of two fundamentally different types of somatic cells: postmitotic cells and mitotic or mitotically competent cells. Postmitotic cells are those that have irreversibly lost the ability to proliferate (‘proliferation’ is used here interchangeably with ‘growth’). Mitotic cells, in contrast, are those that can divide when there is a physiological need. Postmitotic cells include mature neurons, skeletal and cardiac muscle cells, and differentiated adipocytes. Mitotic cells include the epithelial and stromal cells that comprise organs such as the skin, liver, breast, prostate, etc., the lymphocytes and precursor cells of the hematopoietic system, and support cells such as the glial cells of the

Figure 10.1 Organization of complex organisms and susceptibility to agerelated diseases. The composition of complex organisms can be divided

Comprehensive Geriatric Oncology

224

very simply into extracellular and cellular components, each of which undergo age-dependent changes. Cellular components may be either postmitotic or mitotic. The primary age-related pathologies of postmitotic tissues are degenerative. In contrast, mitotic tissues are subject to hyperproliferative disorders, including cancer. nervous system. One of the most striking differences between tissues composed mostly of postmitotic cells and those composed mostly of mitotic cells is the type of pathology to which each becomes increasingly susceptible with advancing age. Because postmitotic cells cannot be replaced by the proliferation of neighboring postmitotic cells, postmitotic tissues are particularly vulnerable to degeneration. Mitotic tissues, on the other hand, are particularly vulnerable to hyperproliferation, which can lead to cancer (Figure 10.1). Mitotically competent cells afford organisms the luxury of renewing and repairing tissues—clearly an advantage for organisms such as mammals, which have relatively long lifespans. However, cell division puts the genome at risk for acquiring and fixing mutations. Cell division also puts the genome at risk for loss of epigenetic control of gene expression. Either of these events, in turn, can put adult organisms at risk for developing cancer. Indeed, cancer poses a major threat to the longevity of complex organisms with renewable tissues, including humans.1,2 Because mitotically competent cells are at risk for oncogenic transformation, complex organisms had to evolve mechanisms to suppress the development of malignant tumors.3– 8 These mechanisms have been termed tumor suppressor (or anticancer) mechanisms. Although tumor suppressor mechanisms are obviously imperfect, they are in fact very effective at preventing cancer in young adults. It is only in older adults that cancer is a major cause of mortality.1,2 This chapter will deal with some current thoughts on the cell biology of cancer and tumor suppression in mammalian organisms, and how these processes may be related to aging. Cancer incidence and the rate of aging Age is the largest single risk factor for the development of cancer among mammalian species. In both humans and mice, for example, cancer incidence (although not necessarily cancer mortality) increases with sharply exponential kinetics beginning at about the midpoint of the lifespan.1,2,9 Of particular interest, the development of cancer scales with lifespan. That is, the rate at which cancer increases is proportional to the rate of aging.10,11 Thus, mice begin to develop cancer at significant rates after about a year and a half of age—or nearly halfway through their lifespan. Moreover, caloric restriction, which extends the lifespan of mice by 30–40%, proportionally retards the rate at which

Proliferative senescence and cancer

225

cancer develops. On the other hand, humans begin to develop cancer after 50–60 years, or halfway through their lifespan. Of course, many age-related pathologies scale with lifespan, but not necessarily all pathology. Some age-related diseases—Alzheimer’s disease, for example—do not develop at all in some short-lived mammals such as mice. Very little is known about the mechanisms that link the rate of aging with the incidence of cancer among mammalian species. Whatever the basis for this relationship, the malignancies of childhood and young adults are relatively rare, and the majority of cancers that develop in mammals arise in mid-life.1,2,9–11 It has been cogently argued11 that in order to thoroughly understand how and why spontaneous cancers arise in mammals, it will be necessary to understand the molecular and cellular basis of aging, particularly the mechanisms that determine species-specific aging rates. Age-related cancers Most age-related cancers arise from epithelial cells, producing carcinomas of epithelial tissues. This is particularly true among humans, and there are now a variety of good mouse models for human epithelial cancers.1,2,11–14 The most prevalent mid- and late-life cancers in humans are carcinomas of the breast, colon, lung, and prostate, but carcinomas of other epithelial tissues also arise. Humans (and mice) also develop hematological malignancies, gliomas, sarcomas, and other non-epithelial cancers with increasing age. However, overall, these tumors tend to be more common among children and young adults than they are in older adults. Why does cancer increase with age, and why are epithelial cells particularly susceptible to age-related carcinogenesis? Answers to these questions are still incomplete. However, there is increasing evidence that epithelial cells are particularly sensitive to changes in their microenvironment. The tissue microenvironment is a critical regulator of the growth and function of epithelial cells,15–17 and the structure and integrity of tissues certainly undergo a variety of age-related changes.1,18,19 The relationship between the tissue environment and age-related tumorigenesis is discussed in greater detail below. Interestingly, although the incidence of epithelial and other tumors rises almost relentlessly with age, the malignant characteristics of tumors tend to change with age. Specifically, malignant tumors tend to grow more slowly, and be less aggressive, in very old, compared with old or middle-aged, individuals.2 One factor that may reduce the malignancy of tumors in very old individuals is the ability of the tissue to undergo angiogenesis. Angiogenesis refers to the formation of new blood vessels. It is an important attribute of malignant tumors, which cannot grow beyond 1–2 mm in size without the nutrients provided by an adequate blood supply.13,20,21 In both mice and humans, the ability of tissues to generate a vigorous angiogenic reaction in response to tumor-derived signals declines with age.18,22,23 Requirements for malignant tumorigenesis Cancer arises from individual cells in a multistep process that culminates in malignant growth and progression. Age-related carcinomas, like all cancers, require a minimum

Comprehensive Geriatric Oncology

226

number of changes in potential cancer cells.21 These changes often (but not always) arise as a consequence of mutations, the acquisition of which is often accelerated by the development of genomic instability. In brief, the cellular changes required for malignant tumorigenesis are: (1) loss of normal growth control (acquisition of self- sufficient positive growth signals, and loss of sensitivity to growth-inhibitory signals); (2) resistance to programmed cell death (apoptosis); (3) acquisition of an extended or indefinite replicative lifespan; (4) ability to initiate and sustain angiogenesis; (5) ability to invade the surrounding tissue (invasiveness); (6) ability to survive in, and colonize, an ectopic environment (metastasis). A discussion of each of these changes can be found in a review by Hanahan and Weinberg21 and references therein. Here, two factors that are particularly important for the initiation and progression of epithelial cancers (mutations and the tissue environment) are discussed, with an emphasis on how tumor suppression mechanisms and aging affects these factors. Mutations and cancer Mutations are critical for the initiation and progression of all cancers, including agerelated carcinomas.24 Somatic mutations arise continually throughout the lifespan. They occur primarily as a consequence of DNA damage caused by both exogenous and endogenous sources, as well as errors in DNA replication or repair. Many mutations are phenotypically silent—that is, they have little or no impact on cellular behavior or function and hence little or no consequence for the organism. However, some mutations can lead to phenotypic changes that contribute to oncogenic transformation. Potential cancer-causing mutations tend to activate oncogenes or inactivate tumor suppressor genes, and confer on cells the properties that are needed for malignant growth and progression. The realization that mutations are paramount for malignant tumorigenesis has lead to the genetic paradigm for the development of cancer. At least initially, this paradigm stipulated that a relatively small number of specific, often sequentially acquired, genetic changes were required for malignant transformation.24 Consequently, it was generally thought that cancer incidence increases with age because it takes time for cells to accumulate the requisite number of mutations needed for malignant growth. There are several reasons to suspect that this idea, while certainly not invalid, is an oversimplification. • It is now clear that somatic mutations accumulate throughout life, beginning at very early ages. Moreover, potentially oncogenic mutations are present in young adults and in apparently normal tissues. This has been demonstrated in both mice and humans.25– 28 These findings suggest that mutations alone may not be sufficient to drive fullblown malignancy. • Malignant tumors rarely harbor only a few specific mutations.5 Rather, they often harbor literally dozens of mutations, including many chromosomal deletions,

Proliferative senescence and cancer

227

amplifications, and gross rearrangements.29 These findings suggest that most malignant tumors are genomically unstable, and that the resulting mutator phenotype drives the rapid acquisition of the mutations needed for malignant progression.30,31 However, genomic instability is frequently evident well before tumors exhibit malignant characteristics. Thus, for example, the normal tissue that is adjacent to breast cancer often shows loss of heterozygosity.25 In addition, relatively nonaggressive breast tumors, such as ductal carcinoma in situ, can harbor most of the gross chromosomal abnormalities that are present in highly aggressive and potentially lethal tumors, such as metastatic breast cancer.32 Likewise, multiple chromosomal aberrations are apparent at the earliest stages of cervical cancer, and the early- and late-stage cancers are remarkably similar with respect to gross mutational load.33 Thus, many tumors appear to require more than mutations per se in order to progress to fullblown malignancy. • Finally, as will be discussed further below, there is increasing evidence that malignant tumorigenesis requires a permissive tissue for progression. Moreover, the cellular microenvironment can be a powerful suppressor of malignant phenotypes, even in the face of severe mutational loads.34–41 These complexities notwithstanding, there is little doubt that mutations are among the critical events that drive malignant transformation and progression. Needless to say, it does indeed take time to accumulate the requisite number of mutations, even if this cannot fully explain the exponential rise in cancer. What else, then, is important for the development of late-life cancers, and why do epithelial cells appear to be particularly vulnerable to malignant transformation in aging mammals? One reason for the age-related rise in carcinomas may be that the oncogenic transformation of epithelial cells appears to require fewer genetic changes compared with the genetic changes required to transform cells from other lineages (e.g. mesenchymal cells such as fibroblasts). Thus, upon expression of the oncogenic SV40 virus large T antigen, human mammary epithelial cells are much more susceptible to immortalization (acquisition of an unlimited growth potential) than human mammary fibroblasts.42 Likewise, expression of the human papillomavirus oncoproteins E6 and E7 immortalizes human epithelial cells from a variety of tissues, but these proteins do not immortalize human fibroblasts.43,44 As noted above, replicative immortality is an important, if not critical, step in the development of cancer.21,45 Epithelial cells may be particularly susceptible to this step. A second reason for the preponderance of carcinomas among age-related cancers is that epithelial cells may be more prone to developing genomic instability than other cell types. For example, cultured human breast epithelial cells, but not fibroblasts, have an unusually high incidence of chromosomal aberrations as they approach the end of their replicative lifespan (replicative senescence, discussed below).46 A third possibility is that the proper growth and differentiation of epithelial cells are especially sensitive to control by the tissue microenvironment, which, as discussed below, can change with age.

Comprehensive Geriatric Oncology

228

Tissue microenvironment, cancer, and aging It is now well established that certain tumor-derived cells fail to produce malignant cancers when they are transplanted to some normal animal tissues, but not others. Likewise, some tumor-derived cells fail to form malignant cancers when they are subject to manipulations that mimic a suppressive microenvironment.18,34–36,38,40,41,47,48 This phenomenon—the suppression of malignant phenotypes by the normal tissue microenvironment—is perhaps most dramatically illustrated by the behavior of teratocarcinoma stem cells in vivo.34 When transplanted into some tissues, these undifferentiated totipotent or pluripotent stem cells form malignant germ cell tumors. However, when the same cells are transplanted into murine blastocysts, they often become integrated into the embryo, where they undergo normal differentiation and contribute to the formation of many normal tissues in the resulting chimeric mice.34 The malignant phenotype of many tumor cells can be suppressed by manipulating their microenvironment. For example, the oncogenic potential of cells transformed by the Rous sarcoma virus can be suppressed by an embryonic extracellular matrix and milieu.36 On a more molecular level, the malignant growth of human bladder cancer cells can be suppressed by the expression of an epithelial cell-adhesion molecule.47 Similarly, certain anti-integrin antibodies can revert the malignant growth and aberrant differentiation of some human breast cancer cells.48 If some normal microenvironments can suppress malignant tumorigenesis, it stands to reason that some abnormal tissue environments can promote malignant tumorigenesis.39– 41 Indeed, there is increasing evidence that this is the case. For example, ectopic expression of a stromal-degrading matrix metalloproteinase (stromelysin-1) in the mammary glands of mice causes premalignant changes in the tissue, and eventually malignant conversion of the resident breast epithelial cells.49 Likewise, ionizing radiation alters the structure and cytokine profile of the mouse mammary gland stroma, and the irradiated stroma, but not the unirradiated stroma, has been shown to promote tumor formation by implanted preneoplastic breast epithelial cells.50 Of particular interest are the undifferentiated tumors that formed when hepatocarcinoma cells were transplanted into the livers of rats. In young animals, these tumors eventually regressed because the surrounding normal tissue suppressed the growth of the tumor cells and induced them to differentiate.38 In old animals, however, the same cells formed malignant tumors that continued to grow progressively and did not regress.38 These findings suggest that, whereas the young tissue is capable of suppressing the malignant growth of the tumor cells, the old tissue is either deficient in this ability or is a more permissive environment for the development of malignant tumors. Taken together, these and other findings strongly suggest that the tissue microenvironment can be a powerful suppressor—or promoter—of malignant phenotypes caused by oncogenic mutations. Moreover, they suggest that aging changes the tissue milieu, such that it is less able to suppress the growth and progression of malignant cells. What types of processes might bring about the changes in tissue structure and milieu that occur during aging? The answer to this question is not completely known, and is undoubtedly complex. Tissues change with aging owing to chemical alterations in the

Proliferative senescence and cancer

229

extracellular matrix (e.g. non-enzymatic glycation), alterations in the proportions or types of cells that occupy the tissue (e.g. infiltration of inflammatory immune cells), and/or functional alterations in the resident cells. An example of this last type of alteration is the process of cellular senescence, a cellular response to damage and stress, as discussed below. The hypothesis that senescent cells may contribute to the aging phenotypes of at least some tissues emerged more than four decades ago. The hypothesis is still only a working model for how aging and cancer may be related. However, it has slowly gained modest experimental support and has also provided new perspectives on why cancer incidence may be so strongly linked to aging. Causes of cellular senescence Cellular senescence was first described as the process that limits the proliferation of normal human cells in culture.51 This seminal study, and subsequent studies, carefully documented the fact that normal human cell cultures doubled only a finite number of times before all cells in the culture irreversibly ceased division. The number of doublings ranged from a few to more than 80, and depended on the cell type, the age and genotype of the donor, and the history of the tissue. This phenomenon was termed replicative senescence. At the end of their replicative lifespan, senescent human cells remained viable and continued to metabolize RNA and protein. However, they had arrested growth with a G1 DNA content, and could not be stimulated to initiate DNA replication in response to physiological mitogens (reviewed by StanulisPraeger,52 Cristofalo and Pignolo,53 and Campisi et al54). We now know that a prime cause of the replicative senescence of human cells is progressive telomere shortening (reviewed by Chiu and Harley,55 Campisi et al,56 and Shay and Wright57). Telomeres are the repetitive DNA sequence and associated proteins that cap the ends of linear chromosomes.58 Without telomeres, chromosome ends are indistinguishable from DNA double-strand breaks, and are therefore subject to degradation and/or fusion by cellular repair systems. Thus, telomeres are essential structures, and are required for the stability of genomes with linear chromosomes. However, owing to the biochemistry of DNA replication, with each round of DNA replication, 50–200 bp at the 3' end of each telomere cannot be replicated.59 This cell cycle-dependent erosion of the telomeres has been termed the end-replication problem. As a result of the end-replication problem, telomeres shorten progressively with cell division. When human telomeres reach an average length of approximately 4–6 kb— before the telomeric cap has completely eroded—cells receive a signal (the nature of which is not well understood) to cease division. Thus, repeated cell division and the accompanying telomere erosion causes the eventual irreversible arrest of cell proliferation—replicative senescence.8,56,60 Recent findings suggest that telomere shortening leads to a disruption of the capped telomeric structure, and that cells actually respond to a disrupted and dysfunctional telomeric structure, rather than telomere length per se.61,62 Whatever the case, the senescence response prevents the proliferation of cells with critically short telomeres, thereby avoiding the risk of losing genetic information and/or developing genomic instability.

Comprehensive Geriatric Oncology

230

Germline precursors, early embryonic cells, and the majority of cancer cells avoid the end-replication problem by expressing telomerase, a reverse transcriptase that can add telomeric DNA repeats to chromosome ends de novo.63,64 Most somatic mammalian cells (especially human cells) do not express telomerase, or express it only transiently or at suboptimal levels.65 In addition, telomerase is subject to both positive and negative regulation by a variety of proteins, as well as the telomeric structure itself.66 A small but significant minority of cancer cells maintain their telomeres by a telomerase-independent recombinational mechanism,67 but this mechanism does not appear to operate in normal somatic cells. Thus, the germline, early embryonic cells and most cancer cells proliferate indefinitely, without telomere loss and without triggering the replicative senescence response, owing in large measure to the presence of telomerase.68,69

Figure 10.2 Inducers of cellular senescence. The senescence response entails an irreversible arrest of cell proliferation, and adoption of a characteristic (senescent) phenotype (see text for details). Cellular senescence can be induced by cell division (replicative senescence), which is caused by short, dysfunctional telomeres. Cellular senescence can also be induced by changes in chromatin,

Proliferative senescence and cancer

231

DNA damage, oncogene expression and stressful mitogenic signals. In recent years, it has become clear that replicative senescence is a specific example of a much more widespread cellular response, which we now term cellular senescence. Thus, dysfunctional telomeres are but one of a growing number of stimuli that can induce a senescence growth arrest (Figure 10.2). The agents that induce cellular senescence have one overarching characteristic in common: they all have the potential to cause or contribute to oncogenic transformation. In addition to undergoing senescence in response to telomere dysfunction, most normal cells arrest growth with a senescent phenotype when they experience moderately high levels of DNA damage, induced, for example, by ionizing radiation or oxidants.70–72 Likewise, normal mammalian cells undergo a senescence arrest when treated with agents, or suffer mutations, that disrupt heterochromatin.73,74 Loss of heterochromatin is known to activate the expression of silenced genes, and is frequently seen in cancer.75,76 Finally, normal cells senesce when they experience strong mitogenic signals, such as those delivered by certain oncogenes or overexpression of certain proteins that are involved in transducing positive growth signals (Figure 10.2).77–81 Cellular senescence and tumor suppression Several lines of evidence suggest that cellular senescence, or the senescence response, is a powerful mechanism for suppressing the development of cancer in mammals.7,82 First, many cell types from many mammalian species have been shown to senesce in response to telomere dysfunction, DNA damage, chromatin perturbations, or potentially oncogenic stimuli. As noted above, all these inducers have the potential to cause oncogenic transformation. Second, cancer-causing stimuli, such as dysfunctional telomeres or oncogenes, tend to transform cells only after they have acquired mutations that abrogate the senescence response. What types of mutations prevent cellular senescence? The most critical are those that inactivate p53 and/or pRb function. p53 and pRb lie at the heart of the two most important tumor suppressor pathways in mammals, and both pathways are crucial for establishing and maintaining the senescent phenotype.7,83–85 Thus, the senescence response is, very likely, a failsafe mechanism to prevent the growth of potentially oncogenic cells, rendering them incapable of proliferation and hence tumorigenesis. Two additional lines of evidence support this idea. First, most (if not all) malignant tumors eventually acquire cells that can proliferate indefinitely, and, in many cases, are refractory to other senescence-inducing signals.21,45,82 Second, there are now several mouse models in which cells fail to senesce in response to multiple stimuli; inevitably, these mice die prematurely of cancer.86–91 Taken together, current findings strongly suggest that cellular senescence is a powerful (albeit imperfect) tumor suppression mechanism in mammals. As such, it ensures longevity by suppressing the development of cancer—at least in young organisms.

Comprehensive Geriatric Oncology

232

Cellular senescence and aging In apparent contradiction to the idea that cellular senescence suppresses tumorigenesis, senescent cells have also been proposed to contribute to age-related pathology.54,57,92–94 As discussed below, the apparent paradox between the proposed beneficial and detrimental effects of senescent cells can be resolved by understanding their phenotype and the evolution of aging. There is increasing evidence that senescent cells accumulate in aging tissues and at sites of age-related pathology. In some cases, these studies entail the ex vivo culture of cells from donors of varying ages or from tissues with or without age-related pathology. For example, cells cultured from venous ulcers have been shown to have a reduced replicative lifespan and increased proportion of cells expressing a senescence marker (a senescence-associated β-galactosidase,97 SA-βgal), compared with cells cultured from unaffected areas or individuals.98 In other cases, SA-βgal was used to infer the presence of senescent cells in mammalian tissues. SA-βgal-positive cells were shown to increase with age in human and monkey skin,97,99 monkey retina,100 human liver,101 and rat kidney.102 SA-βgal-positive cells also accumulated in benign hyperplastic lesions in human prostate103 and atherosclerotic lesions in human aorta.104 Both of these conditions increase markedly with age. Similarly, SA-βgal-positive cells accumulated in rabbit carotid arteries after repeated denudation by balloon catheters,105 which increases the risk of atherosclerosis. Interestingly, in human aortas, average telomere lengths decreased with age, and were shorter at sites of turbulent blood flow (which are at higher risk for developing atherosclerosis).106 Thus, senescent cells may play a role in initiating atherosclerosis. Consistent with this idea, endothelial cells that simultaneously express SA-βgal and lack thymosin-β-10 (an independent marker of senescent endothelial cells) were found at the margins of atherosclerotic lesions in human aortas.104 These findings are, of course, simply correlations at present. However, they lend support to the idea that senescent cells accumulate with age and may contribute to agerelated pathology. The Senescent phenotype How might senescent cells contribute to aging phenotypes? In order to answer this question, it is important to

Proliferative senescence and cancer

233

Figure 10.3 The phenotype of senescent cells. Cellular senescence entails phenotypic changes including an irreversible arrest of cell proliferation, resistance to certain apoptotic signals (some cell types), and selective changes in differentiated functions, including the secretion of factors that can disrupt tissue integrity. understand that the senescence response entails much more than a simple arrest of cell proliferation. Rather, it appears to entail a reprogramming of the pattern of gene expression. That is, cellular senescence entails many changes in gene expression, only some of which are obviously important for growth arrest. As a consequence of these changes in gene expression, senescent cells acquire two (in some cases three) characteristics that, together, define the senescent phenotype (Figure 10.3). These characteristics are (i) an irreversible arrest of cell proliferation; (ii) in some cell types, resistance to signals that cause apoptotic cell death; and (iii) selected changes in differentiated cell functions (reviewed by StanulisPraeger,52 Cristofalo and Pignolo,53 and Campisi et al54). Among the phenotypic changes associated with cellular senescence, the changes in cell function may be especially pertinent to the development of aging phenotypes. Some senescence-associated functional changes are common to most, if not all, cell types. These changes include an increase in nuclear and cytoplasmic volume, an increase lysosome biogenesis, and decreases in the rates of protein synthesis and degradation (reviewed by Stanulis-Praeger,52 Cristofalo and Pignolo,53 and Campisi et al54). In

Comprehensive Geriatric Oncology

234

addition, most senescent cells express SA-βgal.97 The origin and function of this enzyme are not known, but a simple histochemical stain can detect it, and, as discussed above, it has been a useful marker for the senescent phenotype in culture and in intact tissues. Senescent cells also display changes in the expression or regulation of cell typespecific genes. For example, senes- cent human adrenocortical epithelial cells selectively lose the ability to induce 17α-hydroxylase, a key enzyme in cortisol biosynthesis.107 Senescent dermal fibroblasts, on the other hand, show a marked increase in the expression of interstitial collagenase,108 stromelysin-1,109 and epidermal growth factor (EGF)-like growth factors such as heregulin.110 Senescent fibroblasts and endothelial cells also upregulate expression of interleukin-1α, a proinflammatory cytokine,111 and senescent endothelial cells downregulate expression of thymosin-β-10.104 It is particularly interesting, and may be important, that many of the genes that are overexpressed by senescent cells encode secreted factors. Cellular senescence and aging phenotypes We have proposed that senescent cells might slowly accumulate with age. Furthermore, as they accumulate, their phenotype—particularly the factors that they secrete—might disrupt local tissue integrity and thus contribute to age-related pathology.95,112 Senescent cells may accumulate with age owing to many factors. These factors can include replicative exhaustion (and subsequent telomere dysfunction),57,113,114 and DNA damage from endogenous (e.g. mitochondrial oxidation) or exogenous (e.g. ionizing radiation) sources.115,116 They can also include loss of heterochromatin (owing to replication, repair or inherent instability),117–119 or mutational or epigenetic activation of cell proliferation pathways.10,26–28,78,80,81 Likewise, the deleterious effects of senescent cells may be mediated by multiple factors, owing to the complexity of the senescent phenotype. These factors can include cellular resistance to apoptosis (which would allow the cells to accumulate). They most likely also include secretion of degradative enzymes (which would destroy the local tissue architecture, particularly the stroma), inflammatory cytokines (which would cause local oxidative damage to the tissue), and growth factors (which would stimulate the proliferation of susceptible neighboring cells). Cellular senescence and evolutionary antagonistic pleiotropy How can it be that cellular senescence, which clearly benefits organisms early in life (by suppressing cancer), might also be deleterious to organisms, albeit later in life (by contributing to aging phenotypes)? In order to answer this question, it is important to understand current evolutionary hypotheses of aging. Aging is thought to be a consequence of the declining force of natural selection with age. One predicted outcome of this decline is that some processes that were selected to maintain the health and fitness of young organisms can have unselected, deleterious effects in old organisms (reviewed by Kirkwood and Austad120). This idea has been termed antagonistic pleiotropy. We have proposed that cellular senescence may be an example of antagonistic pleiotropy.

Proliferative senescence and cancer

235

As discussed above, there is strong evidence to suggest that the senescence response evolved to prevent the development of cancer in organisms with mitotically competent cells, such as mammals. In this regard, the senescence growth arrest may be the selected trait. This trait prevents potential cancer cells from proliferating. That is, in order for tumorigenesis to occur, cells must first acquire mutations that abrogate the senescence response. Thus, the senescence response suppresses tumorigenesis because it imposes a barrier that cells must overcome in order to undergo oncogenic transformation. Indeed, for the most part, mammals are protected from cancer for the portion of their lifespan during which they are at their peak of reproductive fitness, which is near the maximal lifespan of organisms in the natural environments in which most of their evolution occurred (an estimated 30–40 years or so for humans). However, in organisms that survive substantially longer—most humans living today in the protected environments of developed countries (and mice housed under laboratory conditions)—the deleterious effects of senescent cells may become apparent at advanced ages. In this regard, the functional changes associated with the senescent phenotype may be the unselected traits, which escaped natural selection. The result of these unselected traits may be certain aging phenotypes or age-related diseases, particularly in mitotically competent tissues. Cellular senescence and cancer Given the hypothesis that senescent cells may contribute to age-related pathology, might they also contribute to the development of age-related cancer? Might senescent cells disrupt the suppressive tissue microenvironment that prevents the expression of malignant phenotypes by mutant (preneoplastic or neoplastic) cells? There is some evidence to suggest that this might be the case. For example, radiation induces a senescence mammary gland stroma has been shown to promote the response in stromal fibroblasts,70,72 and an irradiated malignant progression of transplanted tumor cells.50 Although the irradiated mammary stroma was not examined for senescent cells, it is possible that its ability to promote tumorigenesis is due to cellular senescence induced by the radiation. More direct evidence for this idea has been obtained by examining human liver for the presence of senescent cells as function of age, chronic cell turnover owing to infection by hepatitis C virus, and hepatocellular carcinoma. Senescent (SAβgal-positive) cells increased with age, and also were present in greater quantities in the livers of individuals with chronic hepatitis. Moreover, senescent cells were present in areas surrounding the liver cancers that developed in infected individuals.101 We have tested the idea that senescent cells, particularly senescent stromal fibroblasts, can promote the expression of malignant phenotypes by neighboring epithelial cells.121 Our initial experiments used a simple cell culture system: lawns of presenescent or replicatively senescent human fibroblasts in serum-free medium, onto which a small number of epithelial cells were seeded. We used normal or mutant (preneoplastic or neoplastic) epithelial cells from human skin, or mouse or human mammary gland. We followed cell proliferation by expressing green fluorescent protein in the epithelial cells and quantifying green fluorescence. Alternatively, we stained the co-cultures with a fluorescent DNA-intercalating dye that preferentially stains the more compact epithelial nuclei, and used image analysis to quantify the intensely fluorescent epithelial nuclei.

Comprehensive Geriatric Oncology

236

Whatever the method, senescent fibroblasts, much more than presenescent fibroblasts, stimulated the growth of preneoplastic (immortalized but not tumorigenic) and neoplastic (tumor-derived) epithelial cells. Variations on this experiment provided three important clues about the significance and nature of the ability of senescent cells to stimulate epithelial cell proliferation. First, although preneoplastic or frankly neoplastic epithelial cells responded to senescent fibroblasts, normal epithelial cells did not. Thus, normal human keratinocytes or normal mammary epithelial cells had no growth advantage on lawns of senescent, compared with presenescent, fibroblasts. Second, the stimulatory effect of senescent fibroblasts was independent of the senescence inducer. Thus, fibroblasts induced to senescence by replicative exhaustion, oxidative DNA damage or oncogenic Ras all stimulated preneoplastic epithelial cell growth. Third, much of the growth stimulation caused by senescent fibroblasts was attributable to the factors that they secreted. Thus, growth stimulation was seen even when preneoplastic epithelial cells were separated from senescent fibroblasts by a porous membrane that permitted the passage of diffusible molecules, but not cells. Likewise, preneoplastic epithelial cells grew preferentially on the insoluble extracellular matrix deposited by senescent fibroblasts, compared with the matrix deposited by presenescent fibroblasts.121 Finally, we tested the ability of senescent fibroblasts to stimulate epithelial cell growth in vivo. First, we injected preneoplastic epithelial cells with presenescent or senescent human fibroblasts into immunocompromised mice. None of the epithelial cells formed tumors when injected alone. Preneoplastic mouse mammary epithelial cells did not form tumors in the presence of presenescent fibroblasts, but formed large lethal tumors in the presence of

Figure 10.4 Model for synergy between the accumulation of mutations and senescent cells to explain the exponential rise in cancer incidence

Proliferative senescence and cancer

237

with age. In young tissues, potentially oncogenic mutant cells and senescent cells are relatively rare, but both accumulate with age. Early in life, the oncogenic potential of the mutant cells is suppressed by the young tissue environment. Late in life, the integrity and suppressive effects of the tissue decline, owing in part to the degradative enzymes, cytokines, and growth factors that are secreted by senescent cells. With age, there is an increasingly greater probability that an oncogenic mutation has occurred in a cell that is near a senescent cell and its surrounding permissive tissue environment. senescent fibroblasts. Preneoplastic human keratinocytes formed small tumors in the presence of presenescent fibroblasts, most of which eventually regressed. In the presence of senescent fibroblasts, however, these cells formed larger, more aggressive tumors. In the case of human breast cancer cells, senescent fibroblasts markedly stimulated the rate at which they formed large, lethal tumors.121 Taken together, these findings suggest that senescent cells (particularly senescent stromal cells) can stimulate the hyperproliferation and malignant progression of preneoplastic and neoplastic epithelial cells, both in culture and in vivo. As such, these findings support the idea that cellular senescence is an example of antagonistic pleiotropy—protecting complex organisms from cancer early in life, but promoting cancer later in life. The results also suggest, as a working model, a more comprehensive explanation for the exponential rise in cancer incidence that is seen with age (Figure 10.4). According to this model, mutations and senescent cells accumulate throughout life. In young tissues, both mutant cells and senescent cells are relatively rare. With age, however, both types of cells accumulate. At all ages, at least some of the mutations that accumulate are oncogenic. However, early in life, the oncogenic potential of the mutant cells is held in check by the (young) suppressive tissue environment. Later in life, as senescent cells accumulate, the integrity and suppressive effects of the tissue decline. This decline is proposed to result in part from the degradative enzymes, cytokines, and growth factors that are secreted by senescent cells, which create a tissue environment that is permissive for the expression of malignant phenotypes. With age, there is an increasingly greater probability that an oncogenic mutation has occurred in a cell that is in close proximity to a senescent cell and its surrounding permissive tissue environment. Thus, we propose that the age-related rise in cancer is due to the synergistic accumulation

Comprehensive Geriatric Oncology

238

of both mutations and senescent cells. Obviously, additional experiments are needed in order to determine whether and to what extent this model is accurate. Acknowledgements I thank the many past and present laboratory members who contributed to the ideas and data discussed in this chapter for their hard work and challenging discussions. I also thank our many colleagues for sharing reagents and ideas, and the National Institute on Aging, the California and Department of Defense Breast Cancer Research Programs, the Department of Energy, and the Ellison Medical Foundation for primary research support. References 1. DePinho RA. The age of cancer. Nature 2000; 408:248–54. 2. Balducci L, Beghe C. Cancer and age in the USA. Crit Rev Oncol Hematol 2001; 37:137–45. 3. Weinberg RA. Tumor suppressor genes. Science 1991; 254:1138–46. 4. Reed JC. Mechanisms of apoptosis in avoidance of cancer. Curr Opin Oncol 1999; 11:68–75. 5. Knudson AG. Chasing the cancer demon. Annu Rev Genet 2000; 34: 1–19. 6. Macleod K. Tumor suppressor genes. Curr Opin Genet Dev 2000; 10: 81–93. 7. Campisi J. Cellular senescence as a tumor-suppressor mechanism. Trends Cell Biol 2001; 11:27– 31. 8. Wright WE, Shay JW. Cellular senescence as a tumor-protection mechanism: the essential role of counting. Curr Opin Genet Dev 2001; 11:98–103. 9. Balducci L, Lyman G. Cancer in the elderly. Epidemiologic and clinical implications. Clin Geriatr Med 1997; 13:1–14. 10. Martin GM. Somatic mutagenesis and antimutagenesis in aging research. Mutat Res 1966; 350:35–41. 11. Miller RA. Gerontology as oncology: research on aging as a key to the understanding of cancer. Cancer 1991; 68:2496–501. 12. Artandi SE, Chang S, Lee SL et al. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 2000; 406:641–5. 13. Compagni A, Christofori G. Recent advances in research on multistage tumorigenesis. Br J Cancer 2000; 83:1–5. 14. Wu X, Pandolfi P. Mouse models for multistep tumorigenesis. Trends Cell Biol 2001; 11:2–9. 15. Donjacour AA, Cunha GR. Stromal regulation of epithelial function. Cancer Treat Res 1991; 53:335–64. 16. Adams JC, Watt FM. Regulation of development and differentiation by the extracellular matrix. Development 1993; 117:1183–98. 17. Roskelley CD, Bissell MJ. Dynamic reciprocity revisited: a continuous bidirectional flow of information between cells and the extracellular matrix regulates mammary epithelial cell function. Biochem Cell Biol 1995; 73:391–7. 18. McCullough D, Coleman WB, Smith GJ, Grisham JW. Age-dependent induction of hepatic tumor regression by the tissue microenvironment after transplantation of neoplastically transformed rat liver epithelial cells into the liver. Cancer Res 1997; 57:1807–13. 19. Campisi J. Cancer aging and cellular senescence. In Vivo 2000; 14: 183–8. 20. Zetter BR. Angiogenesis and tumor metastasis. Annu Rev Med 1998; 49:407–24. 21. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57–70.

Proliferative senescence and cancer

239

22. Pili R, Guo Y, Chang J et al. Altered angiogenesis underlying age-dependent changes in tumor growth. J Natl Cancer Inst 1994; 86:1303–14. 23. Marinho A, Soares R, Ferro JML, Schmitt FC. Angiogenesis in breast cancer is related to age but not to other prognostic parameters. Pathol Res Pract 1997; 193:267–73. 24. Bishop J. Cancer: the rise of the genetic paradigm. Genes Dev 1995; 9:1309–15. 25. Deng G, Lu Y, Zlotnikov G et al. Loss of heterozygosity in normal tissue adjacent to breast carcinomas. Science 1996; 274:2057–9. 26. Jonason AS, Kunala S, Price GT et al. Frequent clones of p53-mutated keratinocytes in normal human skin. Proc Natl Acad Sci USA 1996; 93:14025–9. 27. Dolle, ME, Giese H, Hopkins CL et al. Rapid accumulation of genome rearrangements in liver but not in brain of old mice. Nat Genet 1997; 17:431–4. 28. Dolle ME, Snyder WK, Gossen JA et al. Distinct spectra of somatic mutations accumulated with age in mouse heart and small intestine. Proc Natl Acad Sci USA 2000; 97:8403–8. 29. Gray JW, Collins C. Genome changes and gene expression in human solid tumors. Carcinogenesis 2000; 21:443–52. 30. Loeb LA. Cancer cells exhibit a mutator phenotype. Adv Cancer Res 1998; 72:25–56. 31. Cahill DP, Kinzler KW, Vogelstein B, Lengauer C. Genetic instability and Darwinian selection in tumours. Trends Cell Biol 1999; 9: M57–M60. 32. Aubele M, Mattis A, Zitzelsberger H et al. Extensive ductal carcinoma in situ with small foci of invasive ductal carcinoma: evidence of genetic resemblance by CGH. Int J Cancer 2000; 85:82– 6. 33. Umayahara K, Numa F, Suchiro Y et al. Comparative genomic hybridization detects genetic alterations during early stages of cervical cancer progression. Genes Chromosomes Cancer 2002; 33:98–102. 34. Ilmensee K. Reversion of malignancy and normalized differentiation of teratocarcinoma cells in chimeric mice. Basic Life Sci 1978; 12: 3–25. 35. Sachs L. The cellular and molecular environment in leukemia. Blood Cells 1993; 19:709–26. 36. Boudreau N, Reddy ST, Stoker AW et al. The embryonic environment and extracellular matrix suppress oncogenic transformation by Rous sarcoma virus in chick embryos. Mol Cell Diff 1995; 3:261–74. 37. Ronnov-Jessen L, Petersen OW, Bissell MJ. Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. Physiol Rev 1996; 76:69–125. 38. McCullough KD, Coleman WB, Ricketts SL et al. Plasticity of the neoplastic phenotype in vivo is regulated by epigenetic factors. Proc Natl Acad Sci USA 1998; 95:15333–8. 39. van den Hoof A. Stromal involvement in malignant growth. Adv Cancer Res 1998; 50:159–96. 40. Park CC, Bissell MJ, Barcellos-Hoff MH. The influence of the microenvironment on the malignant phenotype. Mol Med Today 2000; 6:324–9. 41. Liotta LA, Kohn EC. The microenvironment of the tumour-host interface. Nature 2001; 411:375–9. 42. Shay JW, Van Der Haegen BA, Ying Y, Wright WE. The frequency of immortalization of human fibroblasts and mammary epithelial cells transfected with SV40 large T-antigen. Exp Cell Res 1993; 209: 45–52. 43. Shay JW, Wright WE, Brasiskyte D, Van der Haegen BA. E6 of human papillomavirus type 16 can overcome the M1 stage of immortalization in human mammary epithelial cells but not in human fibroblasts. Oncogene 1993; 8:1407–13. 44. McDougall JK. Immortalization and transformation of human cells by human papillomavirus. Curr Top Microbiol Immunol 1994; 186:101–19. 45. Yeager TR, DeVries S, Jarrard DF et al. Overcoming cellular senescence in human cancer pathogenesis. Genes Dev 1998; 12:163–74. 46. Romanov SR, Kozakiewicz BK, Holst CR et al. Normal human mammary epithelial cells spontaneously escape senescence and acquire genomic changes. Nature 2001; 409:633–7.

Comprehensive Geriatric Oncology

240

47. Kleinerman DI, Dinney CP, Zhang WW et al. Suppression of human bladder cancer growth by increased expression of C-CAM1 gene in an orthotopic model. Cancer Res 1996; 56:3431–5. 48. Weaver VM, Petersen OW, Wang F et al. Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies. J Cell Biol 1997; 137:231–45. 49. Sternlicht MD, Lochter A, Sympson CJ et al. The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell 1999; 98:137–46. 50. Barcellos-Hoff MH, Ravani SA. Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells. Cancer Res 2000; 60:1254–60. 51. Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 1965; 37:614–36. 52. Stanulis-Praeger B. Cellular senescence revisited: a review. Mech Aging Dev 1987; 38:1–48. 53. Cristofalo VJ, Pignolo RJ. Replicative senescence of human fibroblast-like cells in culture. Physiol Rev 1993; 73:617–38. 54. Campisi J, Dimri GP, Hara E. Control of replicative senescence. In: Handbook of the Biology of Aging (Schneider E, Rowe J, eds). New York: Academic Press, 1996:121–49. 55. Chiu CP, Harley CB. Replicative senescence and cell immortality: The role of telomeres and telomerase. Proc Soc Exp Biol Med 1997; 214:99–106. 56. Campisi J, Kim S, Lim C, Rubio M. Cellular senescence cancer and aging: the telomere connection. Exp Gerontol 2001; 36:1619–37. 57. Shay JW, Wright WE. Telomeres and telomerase: implications for cancer and aging. Radiat Res 2001; 155:188–93. 58. Blackburn E. Structure and function of telomeres. Nature 1991; 350: 569–73. 59. Levy MZ, Allsopp RC, Futcher AB et al. Telomere end-replication problem and cell aging. J Mol Biol 1992; 225:951–60. 60. Harley CB, Futcher AB, Greider CW. Telomeres shorten during aging of human fibroblasts. Nature 1990; 345:458–60. 61. Blackburn EH. Telomere states and cell fates. Nature 2000; 408:53–6. 62. de Lange T. Telomere capping—one strand fits all. Science 2001; 292: 1075–6. 63. Lingner J, Cech TR. Telomerase and chromosome end maintenance. Curr Opin Genet Dev 1998; 8:226–32. 64. Collins K. Mammalian telomeres and telomerase. Curr Opin Cell Biol 2000; 12:378–83. 65. Weng NP, Hodes RJ. The role of telomerase expression and telomere length maintenance in human and mouse. J Clin Immunol 2000; 20:257–67. 66. Nugent CI, Lundblad V. The telomerase reverse transcriptase: components and regulation. Genes Dev 1998; 12:1073–85. 67. Reddel RR. The role of senescence and immortalization in carcinogenesis. Carcinogenesis 2000; 21:477–84. 68. Kim NW, Piatyszek MA, Prowse KR et al. Specific association of human telomerase activity with immortal cells and cancer. Science 1994; 266:2011–15. 69. Wright WE, Piatyszek MA, Rainey WE et al. Telomerase activity in human germline and embryonic tissues and cells. Dev Genet 1996; 18:173–9. 70. DiLeonardo A, Linke SP, Clarkin K, Wahl GM. DNA damage triggers a prolonged p53dependent Gl arrest and long-term induction of Cipl in normal human fibroblasts. Genes Dev 1994; 8:2540–51. 71. Chen Q, Fischer A, Reagan JD et al. Oxidative DNA damage and senescence of human diploid fibroblast cells. Proc Natl Acad Sci USA 1995; 92:4337–41. 72. Robles SJ, Adami GR. Agents that cause DNA double strand breaks lead to p16INK4a enrichment and the premature senescence of normal fibroblasts. Oncogene 1998; 16:1113–23. 73. Ogryzko W, Hirai TH, Russanova VR et al. Human fibroblast commitment to a senescence-like state in response to histone deacetylase inhibitors is cell cycle dependent. Mol Cell Biol 1996; 16:5210–18.

Proliferative senescence and cancer

241

74. Bertram MJ, Berube NG, Hang-Swanson X et al. Identification of a gene that reverses the immortal phenotype of a subset of cells and is a member of a novel family of transcription factor-like genes. Mol Cell Biol 1999; 19:1479–85. 75. Cairns B. Emerging roles for chromatin remodeling in cancer biology. Trends Cell Biol 2001; 11:15–21. 76. Wade PA. Transcriptional control at regulatory checkpoints by histone deacetylases: molecular connections between cancer and chromatin. Hum Mol Genet 2001; 18:693–8. 77. Ridley AJ, Paterson HF, Noble M, Land H. Ras-mediated cell cycle arrest is altered by nuclear oncogenes to induce Schwann cell transformation. EMBO J 1988; 7:1635–45. 78. Serrano M, Lin AW, McCurrach ME et al. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 1997; 88:593–602. 79. Sewing A, Wiseman B, Lloyd AC, Land H. High-intensity Raf signal causes cell cycle arrest mediated by p21/Cip1. Mol Cell Biol 1997; 17: 5588–97. 80. Zhu J, Woods D, McMahon M, Bishop JM. Senescence of human fibroblasts induced by oncogenic raf. Genes Dev 1998; 12:2997–3007. 81. Dimri GP, Itahana K, Acosta M, Campisi J. Regulation of a senescence checkpoint response by the E2F1 transcription factor and p14/ARF tumor suppressor. Mol Cell Biol 2000; 20:273–85. 82. Sager R. Senescence as a mode of tumor suppression. Environ Health Persp 1991; 93:59–62. 83. Bringold F, Serrano M. Tumor suppressors and oncogenes in cellular senescence. Exp Gerontol 2000; 35:317–29. 84. Lundberg AS, Hahn WC, Gupta P, Weinberg RA. Genes involved in senescence and immortalization. Curr Opin Cell Biol 2000; 12:705–9. 85. Itahana K, Dimri G, Campisi J. Regulation of cellular senescence by p53. Eur J Biochem 2001; 268:2784–91. 86. Donehower LA, Harvey M, Slagke BL et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumors. Nature 1992; 356:215–21. 87. Harvey M, Sands AT, Weiss RS et al. In vitro growth characteristics of embryo fibroblasts isolated from p53-deficient mice. Oncogene 1993; 8:2457–67. 88. Serrano M, Lee H, Chin L et al. Role of the INK4A locus in tumor suppression and cell mortality. Cell 1996; 85:27–37. 89. Ghebranious N, Donehower LA. Mouse models in tumor suppression. Oncogene 1998; 17:3385–400. 90. de Boer J, Hoeijmakers J. Cancer from the outside, aging from the inside: mouse models to study the consequences of defective nucleotide excision repair. Biochimie 1999; 81:127–37. 91. Artandi SE, DePinho RA. Mice without telomerase: What can they teach us about human cancer? Nat Med 2000; 6:852–5. 92. Hayflick L. Human cells and aging. Sci Am 1968; 218:32–7. 93. Smith JR, Pereira-Smith OM. Replicative senescence: implications for in vivo aging and tumor suppression. Science 1996; 273:63–7. 94. Campisi J. From cells to organisms: Can we learn about aging from cells in culture? Exp Gerontol 2001; 36:607–18. 95. Campisi J. Aging and cancer: the double-edged sword of replicative senescence. J Am Geriatr Soc 1997; 45:1–6. 96. Rinehart CA, Torti VR. Aging and cancer: the role of stromal interactions with epithelial cells. Mol Carcinogen 1997; 18:187–92. 97. Dimri GP, Lee X, Basile G et al. A novel biomarker identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 1995; 92:9363–7. 98. Stanley A, Osler T. Senescence and the healing rates of venous ulcers. J Vasc Surg 2001; 33:1206–11. 99. Pendergrass WR, Lane MA, Bodkin NL et al. Cellular proliferation potential during aging and caloric restriction in rhesus monkeys (Macaca mulatta). J Cell Physiol 1999; 180:123–30.

Comprehensive Geriatric Oncology

242

100. Mishima K, Handa JT, Aotaki-Keen A et al. Senescence-associated β-galactosidase histochemistry for the primate eye. Invest Ophthalmol Vis Sci 1999; 40:1590–3. 101. Paradis V, Youssef N, Dargere D et al. Replicative senescence in normal liver chronic hepatitis C, and hepatocellular carcinomas. Hum Pathol 2001; 32:327–32. 102. Ding G, Franki N, Kapasi AA et al. Tubular cell senescence and expression of TGF-β1 and p21WAF1/CIP1 in tubulointerstitial fibrosis of aging rats. Exp Mol Pathol 2001; 70:43–53. 103. Choi J, Shendrik I, Peacocke M et al. Expression of senescence-associated β-galactosidase in enlarged prostates from men with benign prostatic hyperplasia. Urology 2000; 56:160–6. 104. Vasile E, Tomita Y, Brown LF et al. Differential expression of thymosin β–10 by early passage and senescent vascular endothelium is modulated by VPF/VEGF: evidence for senescent endothelial cells in vivo at sites of atherosclerosis. FASEB J 2001; 15: 458–66. 105. Fenton M, Barker S, Kurz DJ, Erusalimsky JD. Cellular senescence after single and repeated balloon catheter denudations of rabbit carotid arteries. Arteriosder Thromb Vasc Biol 2001; 21:220–6. 106. Chang E, Harley CB. Telomere length and replicative aging in human vascular tissues. Proc Natl Acad Sci USA 1995; 92:11190–4. 107. Hornsby PJ, Hancock JP, Vo TP et al. Loss of expression of a differentiated function gene steroid 17α-hydroxylase as adrenocortical cells senesce in culture. Proc Natl Acad Sci USA 1987; 84:1580–4. 108. West MD, Pereira-Smith OM, Smith JR. Replicative senescence of human skin fibroblasts correlates with a loss of regulation and overexpression of collagenase activity. Exp Cell Res 1989; 184: 138–47. 109. Millis AJT, Hoyle M, McCue HM, Martini H. Differential expression of metalloproteinase and tissue inhibitor of metalloproteinase genes in diploid human fibroblasts. Exp Cell Res 1992; 201:373–9. 110. Linskens MHK, Feng J, Andrews WH et al. Cataloging altered gene expression in young and senescent cells using enhanced differential display. Nucleic Acids Res 1995; 23:3244–51. 111. Maier JAM, Voulalas P, Roeder D, Maciag T. Extension of the life-span of human endothelial cells by an interleukin-1α antisense oligomer. Science 1990; 249:1570–4. 112. Campisi J. Replicative senescence: an old lives tale? Cell 1996; 84: 497–500. 113. Harley CB. Human ageing and telomeres. Ciba Found Symp 1997; 211:129–39. 114. Hodes RJ. Telomere length aging and somatic cell turnover. J Exp Med 1999; 190:153–6. 115. Barnett YA, Barnett CR, Von Zglinicki T. DNA damage and telomere length in human T cells. J Anti-Aging Med 2000; 3:383–8. 116. Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature 2000; 408:239–47. 117. Howard BH. Replicative senescence: considerations relating to the stability of heterochromatin domains. Exp Gerontol 1996; 31: 281–93. 118. Villeponteau B. The heterochromatin loss model of aging. Exp Gerontol 1997; 32:383–94. 119. Kitano H, Imai S. The two-process model of cellular aging. Exp Gerontol 1998; 33:393–419. 120. Kirkwood TB, Austad SN. Why do we age? Nature 2000; 408: 233–8. 121. Krtolica A, Parrinello S, Lockett S et al. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci USA 2001; 98:12072– 7.

11 Apoptosis, chemotherapy, and aging David E Fisher Historical The formal recognition that apoptotic death was a distinct entity that differed from other modes of cell death was made in 1972 by a group of British pathologists studying the appearance of a variety of tissue types under a variety of growth/exposure conditions. Their striking observation was that, rather than all dying cells appearing uniform, certain cells appeared to undergo changes that were highlighted by condensation of the nucleus, cell shrink-age, and fragmentation.1 The term ‘apoptosis’ was coined from the Greek for ‘falling apart.’ The suicide pathway Distinct morphologic and biochemical events characterize apoptosis. These include nuclear condensation, membrane blebbing, and DNA fragmentation.1The first genetic system in which apoptosis was unraveled involved the developing nematode Caenorhabditis elegans, in which a group of ‘C. elegans death’ (ced) genes were discovered,2,3 some of which positively affect apoptosis, while others negatively regulate the pathway. In this worm, all cell deaths have been histologically mapped during development, and are mediated by the actions of three genes termed ced-9, ced-4, and ced-3. While ced-9 is anti-apoptotic, ced-3 and ced-4 promote cell death.2,3 The biochemical mechanisms that link these molecules to regulation of death are gradually coming to light through the identification of complexes in which they are found, as well as through understanding the relationship of these factors to the active enzymes that produce the end products of apoptosis. The nematode ced-3 gene is homologous to the caspase family of cysteine proteases.4 Caspases are cysteine aspartases, which employ cysteine at their active sites and cleave proteins at aspartic acid residues located within specific consensus sequences.5 The human counterpart of the CED-4 protein is called Apaf-1 and regulates caspase activation in concert with cytochrome c.6 Caspases exist as pro-enzymes (zymogens) which are cleaved by other caspases to remove the inactivating prodomain—as discussed in greater detail below (in the subsection on ‘Caspaso regulation in apoptosis’; see Figure 11.3). This mechanism results in an amplification of the death signal.

Comprehensive Geriatric Oncology

244

The two apoptosis pathways Two major apoptosis pathways appear to modulate caspase activation (Figure 11.1). One of these, known as the

Figure 11.1 The two major pathways to apoptosis and caspase activation. Two pathways, the death receptor pathway and the mitochondrial pathway, converge on activation of ‘initiator’ caspases, which in turn activate downstream ‘executioner’ caspases that mediate cleavage of death substrates. In the death receptor pathway, death ligands trigger oligomerization of their receptors, leading to recruitment of multiprotein

Apoptosis, chemotherapy, and aging

245

complexes that include procaspase-8. High local concentration of procaspase-8 leads to autocleavage/activation, resulting in active enzyme, which can alternatively cleave procaspase-3 directly or activate the mitochondrial pathway via cleavage of Bid. The mitochondrial pathway is stimulated by numerous cellular stresses, resulting in release of cytochrome c, which stimulates the formation of an apoptosome complex, resulting in caspase-9 activation. mitochondrial pathway, involves the release of cytochrome c from mitochondria, permitting cytochrome c to bind Apaf-1, whereupon Apaf-1 recruits procaspase-9 into a complex known as the apoptosome.7,8 Caspase-9 is then activated and in turn activates downstream caspases such as caspases-3 and -7, via cleavage of their prodomains. Another mitochondrial protein, called Smac/DIABLO, is also released together with cytochrome c, and appears to participate in caspase activation as well. Smac/DIABLO antagonizes proteins called inhibitors of apoptosis (IAPs), which block caspase activation by binding to inactive caspases. Smac/DIABLO prevents IAPs from binding the inactive caspases, thereby releasing the procaspases for proteolytic activation. Still another mitochondrial factor that modulates apoptotic death is AIF (apoptosis-inducing factor). Mice deficient in this gene exhibit a severe apoptosis defect very early in development. The second apoptosis pathway is called the death receptor pathway. Receptors in the TNF-Fas family are activated by ligands, oligomerize, and recruit adapters to the cytoplasmic face. The major adapter, called FADD (Fas-associated death domain)9 in turn recruits a specific procaspase that contains both a motif for recruitment to this complex as well as the machinery to become an active caspase enzyme.10 This dual molecule is called caspase-8, and it becomes activated by high local concentrations within the death receptor complex.11 In turn, caspase-8 can directly cleave procaspase-3, thereby activating the downstream ‘executioner’ caspase cascade. Alternatively, caspase8 may cleave a protein in the Bcl-2 family, called Bid, resulting in its translocation to mitochondria, where it facilitates release of cytochrome c and subsequent steps as with the mitochondrial death pathway.12,13 Caspase activation is discussed in greater detail below in the subsection on ‘Caspase activation in apoptosis’. Assays for apoptosis The ‘gold standard’ for the identification of apoptotic cells is cellular morphology. Using either electron or light microscopy, it is possible to distinguish the features of cells undergoing apoptosis from those dying by other means. Apoptotic death typically

Comprehensive Geriatric Oncology

246

involves individual cells, whereas necrosis may be the result of massive tissue injury (such as from burning or ischemia). While necrotic death is thought to result purely from environmental insults, apoptotic death is more often thought of as death ‘from the inside out’. Plasma membrane integrity is lost early in necrosis, but more often late in apoptosis. A membrane feature that characterizes apoptotic cells is the flipping of phosphatidylserine from the inner cytoplasmic membrane, such that it is detectable in the annexin stain at the outer cytoplasmic surface. Necrotic cells typically swell, whereas apoptotic cells typically shrink. Inflammation typified by the presence of neutrophils is usually significant among necrotic tissues, whereas inflammation is minimal in the context of apoptosis. Phagocytosis is mediated predominantly by macrophages in the case of necrosis, whereas an interesting feature of apoptotic cells is that they tend to be phagocytized by surrounding cells that are otherwise not phagocytic. Thus, it is not uncommon to see apoptotic tumor cells undergoing phagocytosis by surrounding viable non-macrophage tumor cells. The other morphologic feature that is easily recognizable in apoptosis is chromosomal condensation leading to intensely stained nuclei. Fluorescent DNA interchelating dyes are frequently used to stain cells undergoing apoptosis. The nucleus is typically small, brightly stained, and frequently fragmented into small bodies, which when broken away from the intact cell are called ‘apoptotic bodies’. A biochemical hallmark of apoptosis is endonucleolytic DNA cleavage into fragments of approximately 100 kbp down to approximately 150 bp in length. The cleavage represents the activity of specific endonucleases, and reflects internucleosomal cleavage. This leaves 150–200 bp units representing the length of individual histone-bound nucleosomes. Stains have also been developed to aid in the identification of cells undergoing DNA fragmentation, known as TUNEL staining. These stains utilize enzymes (such as terminal deoxynucleotidyl transferase or the Klenow fragment of Escherichia coli DNA polymerase) to enzymatically incorporate nucleotide analogs onto the ends of DNA molecules.14 In cells undergoing DNA fragmentation, the concentration of free DNA ends becomes extremely high, producing high levels of nucleotide analog incorporation. A variety of different analogs have been used, typically as part of a ‘sandwich’ staining protocol to produce fluorescent, colored, or radioactive signals within the cell. These methods have been applied to histologic analysis of tissues, as well as to the study of cells in culture. While DNA fragmentation accompanies apoptosis, it should be noted that it is not causative, but rather an indicator of apoptosis. A mutant (nuc-1) exists in C. elegans in which DNA fragmentation is impeded. This mutant is nonetheless efficient at apoptosis during development.15,16 Furthermore, Fas-mediated apoptosis has been shown to occur even in the absence of a cell nucleus or DNA fragmentation.17 DNA fragmentation could be advantageous during apoptosis to minimize the propagation of dangerous nucleic acids, such as viral genomes. Therefore, it is plausible that DNA fragmentation is not in itself the ‘final death blow’. Apoptosis in development and aging With the recognition that apoptosis is a discrete death process, it has been seen in the normal development of virtually every organ system in the body. One striking example is

Apoptosis, chemotherapy, and aging

247

the nervous system, in which approximately threefold more neurons exist at birth than in adulthood—approximately two-thirds dying, probably from apoptosis, in response to the presence or absence of specific trophic or toxic cell-cell connections. The immune system is replete with examples of apoptosis. Thymic selection and deletion of T and B cells all appear to involve the induction of apoptosis. While the specific triggers of apoptosis in each case remain uncertain, one pathway, the Fas pathway, has been determined to play a major role in the deletion of autoreactive peripheral T cells. The Fas trigger of apoptosis is a membrane receptor protein (CD95) with some sequence homology to the tumor necrosis factor (TNF)-α receptor (reviewed by Nagata and Golstein18). Both Fas and the TNF-α receptor are stimulated upon ligand binding to initiate a metabolic cascade that ends in apoptotic death. While the biochemical mechanisms underlying this pathway are incompletely understood, both of these receptors contain a homologous peptide motif within the cytoplasmic tails. This motif has been termed the ‘death’ domain, and biochemical studies are underway to examine the consequences of protein interactions in this region. Subsequent protein phosphorylation is likely to play a role in mediating the signaling pathway, which ultimately activates ICElike proteases and subsequent apoptotic death. Strong evidence that the Fas pathway is involved in deletion of autoreactive T cells was obtained with the recognition that two mouse strains with severe autoimmune pathologies contain mutations in either Fas or its ligand (FasL/CD95L), which is also a membrane-associated protein.18 These two mouse strains, lpr and gld, are animal models for autoimmune diseases such as lupus. Other examples of apoptosis in development include hormone-dependent tissues such as breast epithelial tissue, which undergoes involution following lactation. These and numerous other hormone-dependent cell proliferation events have been found to involve apoptosis under the condition of hormone deprivation. It is interesting that hormonal therapies of various malignancies may similarly kill tumor cells via hormone-dependent apoptosis. In fact, given the clinical efficacy of hormonal therapies in cancer (including anti-estrogens, anti-androgens and high-dose glucocorticoid therapies), the potency of apoptosis induction as an antineoplastic strategy is quite evident. A remarkable exception to the rule that cysteine proteases mediate apoptosis involves the enzyme granzyme B, a serine protease that mediates cell death triggered by cytotoxic T lymphocytes (CTL). Upon attacking target cells, CTL release perforin, a permeabolizing factor that, together with ATP, translocates granzyme B into the cytoplasm of the targeted cell. Despite its serinebased active site structure, granzyme B retains a very similar sequence specificity to caspases (aspartatetargeted), resulting in the direct cleavage and activation of procaspase-3.19 Granzyme B thus represents a short-cut to caspase activation in mediating the apoptotic response to CTL. Pro-survival signals Survival signals may be triggered by a variety of cytokines and thus mediate important life-or-death decisions during normal development. These pathways appear to be extensively involved in human cancers. One such survival pathway utilizes phosphatidylinositol 3'-kinase (PI3-K) to activate (via phosphorylation) the Akt kinase. This phosphorylation event is prone to regulation by a variety of factors, including cell surface receptors as well as the negative regulatory phosphatase PTEN. Loss of PTEN is

Comprehensive Geriatric Oncology

248

heavily implicated in prostate tumorigenesis. Activity of PTEN suppresses PI3-K, thereby impeding Akt activation. Loss of PTEN therefore enhances survival. Akt (also called protein kinase B, PKB) exerts antiapoptotic survival signals in response to a variety of PI3-K triggers. Activated Akt may phosphorylate members of the Bcl-2 family (see below), as well as caspases and a specific transcription factor family called forkhead. Phosphorylation of the Bcl-2 family member Bad causes translocation of Bad away from mitochondria, thus preventing its interaction with Bcl-xL and promoting survival.20–22 Akt may directly phosphorylate caspase-9, inhibiting its proteolytic (and apoptotic) activity.23 Disruption of the forkhead (FKHR) transcription factor occurs in alveolar rhabdomyosarcoma. Akt can phosphorylate FKHR at two sites,24 resulting in binding of FKHR to 14-3-3 proteins, which sequester it in the cytoplasm. When FKHR becomes dephosphorylated (after removal of survival signals), it translocates to the nucleus and becomes transcriptionally active. Its targets appear to mediate apoptosis, and are currently being characterized. Apoptosis and tumorigenesis The first clear connection between human malignancy and modulators of apoptosis came following the identification of the molecular participants in the translocation occurring in follicular lymphoma.25–27 In this tumor, a translocation, t(14; 8), occurs between chromosomes 18 and 14 in nearly 100% of cases, and places the bcl-2 gene under the transcriptional regulation of the immunoglobulin heavy-chain gene. This constitutive expression appears to contribute critically to establishment of the neoplastic phenotype. Gene transfer studies demonstrated the important behavior that constitutive Bcl-2 overexpression permits survival of growth-factor-deprived hematopoietic cells (Figure 11.2), which would otherwise die under such stressful culture conditions, suggesting that the t(14; 18) of follicular lymphoma may similarly enhance tumorigenesis

Figure 11.2 Depiction of the cell survival activity of Bcl-2.

Apoptosis, chemotherapy, and aging

249

Hematopoietic cells that require growth factor supplementation for survival in culture will die within hours if starved of essential growth factor. However, enforced overexpression of Bcl-2 produces survival under identical growth factor starvation, through interfering with execution of the apoptosis program. through permitting the pathologic survival of cells otherwise destined for apoptotic death.28–33 Numerous molecular studies have established that Bcl-2 is part of a large family of proteins that modulate apoptosis through a shared series of motifs known as Bcl-2 homology domains 1 through 4 (BH1–4). Of the greater than 15 proteins in this family, some like Bcl-2 are anti-apoptotic, while others are pro-apoptotic.28,34,35 Certain family members contain one or only restricted BH domains.36 BH3-only proteins, for example play a critical pro-apoptotic role.37–39 Bcl-2 contains a C-terminal membrane docking domain that localizes the protein to the outer mitochondrial membrane, where it is thought to exert much of its activity via modulating the release of cytochrome c. Bcl-2 family members commonly oligomerize, typically as dimers via BH interaction motifs, and are also thought to participate in formation of membrane-spanning channellike structures.40 It is likely that such dimerization interactions may titrate pro- or antiapoptotic family members away from one another in a manner that modulates the formation of factors that decisively regulate death signals,41 and considerable redundancy appears to exist among both pro- and anti-apoptotic factors.40 Channel formation has suggested that Bcl-2 family members may either mediate cytochrome c release directly or else regulate transit of other factors (possibly ions) that in turn influence cytochrome c release. Ion channel activity has been specifically suggested for several family members using lipid bilayer reconstitution assays.42–46 Caspase regulation in apoptosis As with many zymogens, caspases are synthesized initially as inactive pro-enzymes (procaspases). Processing is

Comprehensive Geriatric Oncology

250

Figure 11.3 Caspase activation is a multistep zymogen-like pathway. Caspases exist as pro-enzymes, requiring cleavage of an N-terminal prodomain for activation. This cleavage is usually mediated by high local concentrations of other procaspase molecules. Subsequently, additional cleavage of large and small subunits precedes the formation of tetramers consisting of two small and two large subunits that are catalytically active, often capable of cleaving additional procaspase molecules. mediated through proteolytic cleavages, producing large and small subunits, which dimerize to the same subunits from another procaspase precursor, to produce a tetrameric protease with two large and two small subunits (Figure 11.3). Cleavage/activation of procaspases entails removal of an N-terminal prodomain and a linker region separating large and small subunits.47,48 As a tetramer, each enzyme thus contains two catalytic active sites.49–51

Apoptosis, chemotherapy, and aging

251

Caspases have been classified as initiators or effector caspases. Initiators typically represent the point at which the apoptosis pathway first activates a caspase, usually in a tightly regulated process. Caspases-8 and -9 are the best characterized initiators. They are notable for their large prodomains and a ‘death effector domain’ (DED) or a ‘caspase recruitment domain’ (CARD). The DED domain on caspase-8 recruits the pro-enzyme to death domain-containing complexes. The CARD domain recruits caspase9 onto complexes containing Apaf-1/cytochrome c. Activation/cleavage of the procaspases is then thought to occur through the effects of high local concentrations of procaspases and auto-activation of like proteases within the complexes. Once activated, the initiators directly cleave downstream effector caspases in a cascade-like (amplifying) fashion. Effector caspases contain short prodomains, which are cleaved by several pathways, such as the initiator caspases as well as the serine protease granzyme B.47,52,53 Caspases cleave numerous cellular targets to produce the apoptotic phenotype. Target classes include factors influencing DNA integrity and membrane lipid stability, as well as numerous regulatory kinases and signaling factors, many of which are cleaved in a fashion that feeds back on the death pathway itself. The caspase proteolytic target sequence typically contains four-amino-acid consensus sequences located N-terminal to the aspartate, which is cleaved at its C terminus. Sequence variations within these four upstream amino acids generate target specificity for the different caspases.54,55 DNA fragmentation during apoptosis occurs through the action of DFF40/CAD, a factor that is repressed in viable cells by an inhibitor called ICAD. Effector caspases cleave and de-repress ICAD, thereby liberating the DFF40/CAD endonuclease.56,57 Bcl-2 family members may also be targeted by caspases,36,58,59 as are various cytoskeletal proteins, including nuclear lamins, actin, and other associated proteins.60–65 Caspase activation is also regulated by inhibitory peptides called inhibitors of apoptosis (IAPs). Multiple IAPs have been identified, and their activity involves direct binding to active caspases to prevent cleavage of caspase substrates. Smac/DIABLO, another modulator of apoptosis, which is released upon mitochondrial activation, sequesters IAPs and de-represses caspase activity. Activation of caspase-9 has been largely determined through intricate biochemical studies employing cell-free extracts derived from HeLa (cervical carcinoma) cells. In this important pathway, mitochondria were shown to release cytochrome c, which, together with Apaf-1, dATP, and procaspase-9, form a complex known as the apoptosome. The high local concentration of procaspase-9 is then thought to trigger auto-activation and production of active caspase-9. The latter is then released from the complex and activates/cleaves downstream caspases,66 although procaspase-3 may be recruited to the same complex via WD-40 repeats found in Apaf-1.67 A rapidly amplifying cascade occurs downstream of active caspase-9, through its initial cleavage of procaspase-3 molecules. Caspase-3 in turn may activate caspases-6 and -2. As mentioned above, the granzyme B pathway represents a novel serine proteasemediated caspase activation event that directly cleaves and activates procaspase-3 in cells targeted by CTLs.68 Chemotherapy and the induction of apoptosis

Comprehensive Geriatric Oncology

252

One of the most important medical implications of apoptotic death is its role in the therapy of human malignancy. With the morphologic characterization of apoptosis, it has been recognized for a number of years that tumor samples either following treatment or even without treatment may contain significant numbers of morphologically apoptotic cells. Moreover, it has increasingly become clear that the presence of certain molecular genetic aberrations may correlate with poor prognosis in a fashion that could reflect the ‘disabling’ of an apoptotic pathway. Perhaps the most striking such molecular association has been made with the p53 tumor suppressor gene (also known as TP53). p53 was originally identified as a protein that co-immunoprecipitated with the Tantigen oncoprotein in SV40-transformed cells.69,70 Its function as a tumor suppressor became clear with the observation that mutations or deletions in p53 are probably the most common genetic alteration in human cancer.71 In addition, germline mutations in p53 have been identified in the familial cancer predisposition Li-Fraumeni syndrome.72 While affected individuals carry constitutive mutations in one p53 allele, their tumors display aberrations in both alleles. A molecular connection between p53 and apoptosis was made in 199173 with the observation that overexpression of p53 induced massive apoptosis in a myeloid leukemia cell line. Subsequently, it was demonstrated that radiation-induced apoptosis of thymocytes was dependent upon the presence of p53 and did not occur in mice ‘knockedout’ for the p53 gene.74,75 The normal functions of p53 have suggested certain tumor-specific activities. A series of studies on cell cycle regulation76–78 suggested that p53 regulates entry of cells into S phase in response to DNA damage such as irradiation. Since p53 is a DNA-binding transcription factor,79,80 it was assumed that this cell cycle regulation may involve the transcription of specific target genes. One such gene, p21, was shown to be transcriptionally regulated by p53 and capable of impeding entry into S phase through the ability to bind and inactivate cyclin-dependent kinases.81–83 A knockout of p21 demonstrated partial loss of the p53-dependent G1/S checkpoint.84 However, a partial checkpoint still remains, suggesting that p21 may only be modulating a portion of the cell cycle activity of p53. Furthermore, thymic irradiation in these mice produces apoptosis, suggesting that this p53-dependent apoptosis does not require p21. The suggestion that p53 may not produce apoptosis via its transcriptional activity has been made previously, based on studies demonstrating that p53-dependent apoptosis could occur in the presence of high doses of actinomycin D (dactinomycin), where gene transcription was nonspecifically inhibited.85,86 Since radiation causes p53 to alter the cell cycle (in normal cells), it was of interest to examine whether the ability of p53 to induce apoptosis would also respond to this trigger, particularly within oncogenically transformed cells. Utilizing fibroblast cells derived from either wild-type or p53 knockout mice, Lowe et al87 generated oncogenetransformed cells that were genetically matched except for

Apoptosis, chemotherapy, and aging

253

Figure 11.4 The role of p53 in modulating transformation-selective apoptosis in cancer cells. Primary fibroblasts (shown at the top of the figure) undergo cell cycle arrest when irradiated. Primary fibroblasts that are deficient in p53 (such as p53 knockout cells, p53−/−) display defective cell cycle arrest in response to ionizing radiation, but still arrest (primarily in G2/M rather than in G1/S). In contrast, fibroblasts that have been oncogenically transformed by a variety of oncogenes (such as E1A and ras) undergo massive apoptotic death in response to ionizing radiation—but

Comprehensive Geriatric Oncology

254

only if they retain wild-type p53. In the absence of p53, such transformed fibroblasts largely escape apoptotic death, rendering them more capable of surviving stresses during tumor progression as well as following antineoplastic therapies. the presence or absence of wild-type p53. Using these cells, they demonstrated that whereas untransformed fibroblasts would arrest growth in response to DNA-damaging radiation or drugs, transformed p53 wild-type cells would enter apoptosis (Figure 11.4). This observation suggested a mechanism by which a therapeutic window could be achieved during anticancer therapy.88 If a drug produced apoptosis in transformed cells but cell cycle arrest in normal cells, it would display tumor-specific toxicity via apoptosis. Note that the normal response to DNA damage is cell cycle arrest at both a G1/S checkpoint and a G2/M checkpoint. The selective loss of a G1/S check-point that accompanies p53 deficiency renders the cell sensitive to the accelerated accumulation of DNA errors just prior to genome replication. The additional key observation by Lowe et al75 was that lack of p53 in matched transformed cells was associated with resistance to the induction of apoptosis by identical anticancer treatments. This cell system was then studied in a solid tumor nude mouse model,87 and demonstrated that solid tumors containing p53 were highly radiation- and drug-sensitive, while those lacking p53 were resistant. Moreover, in p53 wild-type tumors treated repetitively with radiation, but ultimately achieving radioresistance, acquired p53 mutations could be identified.87 Thus, apoptosis was suggested to play a major role in determining the efficacy of anticancer therapies, and p53 emerged as a major regulator of this therapy-induced apoptotic response. In the field of radiation oncology, it has long been recognized that one means by which a tumor cell could become radioresistant is through an enhanced ability to repair DNA damage. Results with p53 and its modulation of apoptosis have suggested an alternative model88 in which an important determinant of radiation resistance is the ability to trigger apoptotic rather than non-apoptotic cell death. This suggestion has sparked significant interest in understanding the biochemical mechanisms by which p53 triggers apoptosis, with the hope of exploiting this pathway in the induction of apoptotic death by better anticancer agents. The specific chemotherapy families that have been suggested to induce apoptotic death in a p53-dependent fashion include antimetabolites, alkylating agents, anthracyclines, topoisomerase inhibitors, and a continuously growing list of other factors. Other apoptosis-modulating factors also represent potential drug targets for anticancer therapy. For example, inhibition of Bcl-2 activity could substantially lower the threshold for the induction of apoptosis. A variety of studies have demonstrated that overexpression of Bcl-2 may render a cell relatively drug-resistant.89 Thus, inhibition of endogenous Bcl2 may be therapeutically advantageous. It must be noted, however, that such Bcl-2 inhibition may have more systemic effects as well, since the bcl-2 knockout mouse demonstrates increased apoptotic death in a wide variety of organ systems.90 Perhaps

Apoptosis, chemotherapy, and aging

255

other Bcl-2 family members will be found to display tissue-type specificity, and perhaps tumor cell specificity. Finally, the tumor-selective induction of apoptosis that occurs in cells transformed by dominant oncogenes such as myc91 suggests that dominant oncogene activity sensitizes a cell to the induction of apoptosis. While the loss of other apoptosis modulators may neutralize this sensitization, a better biochemical understanding of these events may allow for enhanced targeting of this tumor-specific pathway. For example, Myc overexpression (which occurs in a significant fraction of human tumors) triggers apoptosis in cells that are deprived of certain critical growth factors. These growth factors have been identified using defined growth conditions,92 and thereby demonstrate a connection between extracellular growth factor availability and nuclear oncogene activity. The accessibility of growth factor receptors on the plasma membrane coupled to a better understanding of how its signaling may clash with Myc overexpression (to produce apoptosis) provides a new opportunity to potentially trigger oncogene-selective apoptosis from the cell surface. Similarly, adhesion-dependent apoptosis,93 as well as Fas and TNF receptors, may offer extracellular targets for apoptosis isolation in tumor cells. Tumor cell-selective toxicity will, however, have to be established to be therapeutically useful. Future prospects A considerable body of knowledge has accumulated regarding some of the key mechanistic steps in the induction of apoptosis. Much of this information has been derived from studies of primitive organisms, but is exciting because of the apparent biochemical parallels in mammalian and human systems. Enhanced capabilities at blocking apoptosis, for example with inhibitors of cysteine proteases, may hold promise for diseases of excessive cell death, such as neurodegenerative, rheumatologic, or other inflammatory conditions. The recognition that apoptotic death occurs in human cancer therapy has suggested important mechanisms for anticancer therapy success as well as failure. Critical regulators of apoptosis induction by chemotherapeutics have been successfully correlated with prognosis in a large number of human malignancies. An important implication of these observations is that chemotherapeutic agents may produce tumor cell death not by ‘strangulating’ the cell through extreme disruption of metabolism but by neatly causing a cell to commit suicide through the induction of apoptosis. With this understanding, coupled to an increased understanding of the biochemistry of apoptosis, it appears likely that future generations of cancer therapeutics will focus on manipulating the apoptotic pathway. For example, strategies have been developed that attempt to exploit the selective loss of p53 in tumors (versus retention of p53 among normal cells) and to devise p53 inhibitors that might protect normal cells against certain side-effects of chemotherapy or radiation therapy. Similarly, modulation of cell cycle kinetics may alter the susceptibility of cells in the hair follicle from dying in response to chemotherapeutic agents. Probably the most remarkable contribution of apoptosis to the field of cancer biology has been the introduction of the concept that cancer represents a disease of dysregulated death, and that this lack of cell death is as important (if not more so) than the

Comprehensive Geriatric Oncology

256

dysregulation of proliferation that accompanies the actions of many oncogenes. This observation has impacted numerous fields beyond cancer biology as well, since virtually no aspect of human development appears to be independent of normal ‘death events’. Even the aging process itself is likely to represent cumulative individual death events, as well as senescence. Most importantly, through the analysis of apoptosis, the field of molecular oncology now finds itself focusing not only on pathways involved in tumorigenesis, but also on how these pathways carry likely clues for therapy. In the current post-genomic era, it is more likely than ever that systematic understanding of the pathways and networks regulating proliferation as well as survival will be unraveled. As this understanding is coupled to pharmacogenomics as well as to the enormous advances in structural biology and rational drug design, the coming years will hopefully herald a new era in cancer therapy as targeted therapeutics enter the clinical arena. References 1. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26:239–57. 2. Ellis HM, Horovitz H. Genetic control of programmed cell death in the nematode C. elegans. Cell 1986; 44:817–29. 3. Hengartner MO, Horovitz HR. C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell 1994; 76:665–76. 4. Yuan J, Shaham S, Ledoux S et al. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1β-converting enzyme. Cell 1993; 75:641–52. 5. Thornberry NA, Bull HG, Calaycay JR et al. A novel heterodimeric cysteine protease is required for interleukin-1β processing in monocytes. Nature 1992; 356:768–74. 6. Zou H, Henzel WJ, Liu X et al. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell 1997; 90:405–13. 7. Li P, Nijhawan D, Budihardjo I et al. Cytochrome c and dATP-dependent formation of Apaf1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997; 91:479–89. 8. Srinivasula SM, Ahmad M, Fernandes-Alnemri T, Alnemri ES. Autoactivation of procaspase-9 by Apaf-1-mediated oligomerization. Mol Cell 1998; 1:949–57. 9. Chinnaiyan AM, O’Rourke K, Tewari M, Dixit VM. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 1995; 81:505–12. 10. Boldin MP, Goncharov T, Goltsev YV, Wallach D. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1-and TNF receptor-induced cell death. Cell 1996; 85:803–15. 11. Muzio M, Stockwell BR, Stennicke HR et al. An induced proximity model for caspase-8 activation. J Biol Chem 1998; 273:2926–30. 12. Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 1998; 94:491–501. 13. Luo X, Budihardjo I, Zou H et al. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 1998; 94:481–90. 14. Gavrieli Y, Sherman Y, Ben-Sassoon A. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 1992; 119:493–501. 15. Ellis RE, Jacobson DM, Horvitz HR. Genes required for the engulfment of cell corpses during programmed cell death in Caenorhabdtitis elegans. Genetics 1991; 129:79–94. 16. Hevelone J, Hartman PS. An endonuclease from Caenorhabditis elegans: partial purification and characterization. Biochem Genet 1988; 26:447–61.

Apoptosis, chemotherapy, and aging

257

17. Schulze-Osthoff K, Walczak H, Droge W, Krammer PH. Cell nucleus and DNA fragmentation are not required for apoptosis. J Cell Biol 1994; 127:15–20. 18. Nagata S, Golstein P. The Fas death factor. Science 1995; 267: 1499–556. 19. Darmon AJ, Nicholson DW, Bleackley RC. Activation of the apoptotic protease CPP32 by cytotoxic T-cell-derived granzyme B. Nature 1995; 377:446–8. 20. Datta SR, Dudek H, Tao X et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997; 91:231–41. 21. del Peso L, Gonzalez-Garcia M, Page C et al. Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 1997; 278:687–9. 22. Pastorino JG, Tafani M, Farber JL. Tumor necrosis factor induces phosphorylation and translocation of BAD through a phosphatidylinositide-3-OH kinase-dependent pathway. J Biol Chem 1999; 274: 19411–16. 23. Cardone MH, Roy N, Stennicke HR et al. Regulation of cell death protease caspase-9 by phosphorylation. Science 1998; 282: 1318–21. 24. Biggs WH 3rd, Meisenhelder J, Hunter T et al. Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHRl. Proc Natl Acad Sci USA 1999; 96: 7421–6. 25. Bakhshi A, Jensen JP, Goldman P et al. Cloning the chromosomal breakpoint of t(14; 18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 1985; 41: 899–906. 26. Cleary ML, Smith SD, Sklar J. Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14; 18) translocation. Cell 1996; 47:19–28. 27. Tsujimoto Y, Finger LR, Yunis J et al. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14; 18) chromosome translocation. Science 1984; 226:1097–9. 28. Chao DT, Korsmeyer SJ. BCL-2 family: regulators of cell death. Annu Rev Immunol 1998 16:395–419. 29. Cory, S. Regulation of lymphocyte survival by the bcl-2 gene family. Annu Rev Immunol 1995; 13:513–43. 30. Cory S, Strasser A, Jacks T et al. Enhanced cell survival and tumorigenesis. Cold Spring Harb Symp Quant Biol 1994; 59:365–75. 31. Strasser A, Huang DC, Vaux DL. The role of the bcl-2/ced-9 gene family in cancer and general implications of defects in cell death control for tumourigenesis and resistance to chemotherapy. Biochim Biophys Acta 1997; 1333: F151–78. 32. Vaux DL, Cory S, Adams JM. bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 1998; 335:440–2. 33. Yang E, Korsmeyer SJ. Molecular thanatopsis: a discourse on the BCL2 family and cell death. Blood 1996; 88:386–401. 34. Reed, J. Bcl-2 and the regulation of programmed cell death. J Cell Biol 1994; 124:1–6. 35. Zamzami N, Brenner C, Marzo I et al. Subcellular and submitochondrial mode of action of Bcl2-like oncoproteins. Oncogene 1998; 16:2265–82. 36. Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science 1998; 281:1322–6. 37. Chittenden T, Flemington C, Houghton AB et al. A conserved domain in Bak, distinct from BH1 and BH2, mediates cell death and protein binding functions. EMBO J 1995; 14:5589–96. 38. Conradt B, Horvitz HR. The C. elegans protein EGL-1 is required for programmed cell death and interacts with the Bcl-2-like protein CED-9. Cell 1998; 93:519–29. 39. Kelekar A, Thompson CB. Bcl-2-family proteins: the role of the BH3 domain in apoptosis. Trends Cell Biol 1998; 8:324–330. 40. Reed, J. Bcl-2 family proteins. Oncogene 1998; 17:3225–36. 41. Oltvai ZN, Korsmeyer SJ. Checkpoints of dueling dimers foil death wishes. Cell 1994; 79:189– 92.

Comprehensive Geriatric Oncology

258

42. Antonsson B, Conti F, Ciavatta A et al. Inhibition of Bax channel-forming activity by Bcl-2. Science 1997; 277:370–2. 43. Lam M, Bhat MB, Nunez G et al. Regulation of Bcl-xl channel activity by calcium. J Biol Chem 1998; 273:17307–10. 44. Minn AJ, Velez P, Schendel SL et al. Bcl-xL forms an ion channel in synthetic lipid membranes. Nature 1997; 385:353–7. 45. Schendel SL, Xie Z, Montal MO et al. Channel formation by antiapoptotic protein Bcl-2. Proc Natl Acad Sci USA 1997; 94: 5113–18. 46. Schlesinger PH, Gross A, Yin XM et al. Comparison of the ion channel characteristics of proapoptotic BAX and antiapoptotic BCL-2. Proc Natl Acad Sd USA 1997; 94:11357–62. 47. Nicholson DW, Thornberry NA. Caspases: killer proteases. Trends Biochem Sci 1997; 22:299– 306. 48. Salvesen GS, Dixit VM. Caspases: intracellular signaling by proteolysis. Cell 1997; 91:443–6. 49. Rotonda J, Nicholson DW, Fazil KM et al. The three-dimensional structure of apopain/CPP32, a key mediator of apoptosis. Nat Struct Biol 1996; 3:619–25. 50. Walker NP, Talanian RW, Brady KD et al. Crystal structure of the cysteine protease interleukin-1β-converting enzyme: a (p20/p10)2 homodimer. Cell 1994; 78:343–52. 51. Wilson KP, Black JA, Thomson JA et al. Structure and mechanism of interleukin-1β converting enzyme. Nature 1994; 370:270–5. 52. Nunez G, Benedict MA, Hu Y, Inohara N. Caspases: the proteases of the apoptotic pathway. Oncogene 1998; 17:3237–45. 53. Thornberry NA, Lazebnik Y. Caspases: enemies within. Science 1998; 281:1312–16. 54. Talanian RV, Quinlan C, Trautz S et al. Substrate specificities of caspase family proteases. J Biol Chem 1997; 272:9677–82. 55. Thornberry NA, Rano TA, Peterson EP et al. A combinatorial approach defines specificities of members of the caspase family and granzyme B. Functional relationships established for key mediators of apoptosis. J Biol Chem 1997; 272:17907–11. 56. Enari M, Sakahiri H, Yokoyama H et al. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 1998; 391:43–50. 57. Liu X, Zou H, Slaughter C, Wang X. DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell 1997; 89:175–84. 58. Cheng EH, Kirsch DG, Clem RJ et al. Conversion of Bcl-2 to a Bax-like death effector by caspases. Science 1997; 278:1966–8. 59. Xue D, Horvitz HR. Caenorhabditis elegans CED-9 protein is a bifunctional cell-death inhibitor. Nature 1997; 390:305–8. 60. Brockstedt E, Rickers A, Kostka S et al. Identification of apoptosisassociated proteins in a human Burkitt lymphoma cell line. Cleavage of heterogeneous nuclear ribonucleoprotein Al by caspase 3. J Biol Chem 1998; 273:28057–64. 61. Cryns VL, Bergeron L, Zhu H et al. Specific cleavage of α-fodrin during Fas- and tumor necrosis factor-induced apoptosis is mediated by an interleukin-1β-converting enzyme/Ced-3 protease distinct from the poly(ADP-ribose) polymerase protease. J Biol Chem 1996; 271:31277–82. 62. Janicke RU, Ng P, Sprengart ML, Porter AG. Caspase-3 is required for oc-fodrin cleavage but dispensable for cleavage of other death substrates in apoptosis. J Biol Chem 1998; 273:15540–5. 63. Mashima T, Naito M, Noguchi K et al. Actin cleavage by CPP-32/apopain during the development of apoptosis. Oncogene 1997; 14: 1007–12. 64. Nath R, Raser KJ, Stafford D et al. Non-erythroid oc-spectrin break-down by calpain and interleukin 1β-converting-enzyme-like protease(s) in apoptotic cells: contributory roles of both protease families in neuronal apoptosis. Biochem J 1996; 319:683–90. 65. Takahashi A, Alnemri ES, Lazebnik YA et al. Cleavage of lamin A by Mch2α but not CPP32: multiple interleukin 1β-converting enzyme-related proteases with distinct substrate recognition properties are active in apoptosis. Proc Natl Acad Sci USA 1996; 93:8395–400.

Apoptosis, chemotherapy, and aging

259

66. Saleh A, Srinivasula SM, Acharya S et al. Cytochrome c and dATP-mediated oligomerization of Apaf-1 is a prerequisite for procaspase9 activation. J Biol Chem 1999; 274:17941–5. 67. Hu Y, Benedict MA, Ding L, Nunez G. Role of cytochrome c and dATP/ATP hydrolysis in Apaf-1-mediated caspase-9 activation and apoptosis. EMBO J 1999; 18:3586–95. 68. Beresford PJ, Xia Z, Greenberg AH, Lieberman J. Granzyme A loading induces rapid cytolysis and a novel form of DNA damage independently of caspase activation. Immunity 1999; 10:585– 94. 69. Lane DP, Crawford LV. T antigen is bound to a host protein in SV40-transformed cells. Nature 1979; 278:261–3. 70. Linzer DI, Levine AJ. Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell 1979; 17:43–52. 71. Harris CC, Hollstein M. Clinical implications of the p53 tumor-suppressor gene. N Engl J Med 1993; 329:1318–27. 72. Malkin D, Li FP, Strong LC et al. Germline p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 1990; 250:1233–8. 73. Yonish-Rouach E, Resnitzky D, Lotem J et al. Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin6. Nature 1991; 352:345–7. 74. Clarke AR, Purdie CA, Harrison DJ et al. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature 1993; 362:849–52. 75. Lowe SW, Ruley HE, Jacks T, Houseman DE. p53-dependent apoptosis modulates the cytotoxicity of anti-cancer agents. Cell 1993; 74:957–67. 76. Kastan MB, Onyekwere O, Sidransky D et al. Participation of p53 protein in the cellular response to DNA damage. Cancer Res 1991; 51:6304–11. 77. Kastan MB, Zhan Q, El-Deiry WS et al. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxiatelangiectasia. Cell 1992; 71:587–97. 78. Kuerbitz S, Plunkett B, Walsh W, Kastan M. Wildtype p53 is a cell cycle checkpoint determinant following irradiation. Proc Natl Acad Sci USA 1992; 89:7491–5. 79. Kern SE, Pietenpol JA, Thiagalingam S et al. Oncogenic forms of p53 inhibit p53-regulated gene expression. Science 1992; 256:827–30. 80. Vogelstein B, Kinzler KW. p53 function and dysfunction. Cell 1992; 70:523–6. 81. El-Deiry WS, Tokino T, Velculescu VE et al. WAF1, a potential mediator of p53 tumor suppression. Cell 1993; 75:817–25. 82. Harper JW, Adami GR, Wei N et al. The p21 Cdk-interacting protein Cipl is a potent inhibitor of Gl cyclin-dependent kinases. Cell 1993; 75:805–16. 83. Xiong Y, Hannon GJ, Zhang H et al. p21 is a universal inhibitor of cyclin kinases. Nature 1993; 366:701–4. 84. Deng C, Zhang P, Harper WJ et al. Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in Gl checkpoint control. Cell 1995; 82:675–84. 85. Caelles C, Helmberg A, Karin M. p53-dependent apoptosis in the absence of transcriptional activation of p53-target genes. Nature 1994; 370:220–3. 86. Wagner AJ, Kokontis JM, Hay N. Myc-mediated apoptosis required wild-type p53 in a manner independent of cell cycle arrest and the ability of p53 to induce p21waf1/cip1. Genes Dev 1994; 8:2817–30. 87. Lowe LW, Bodis B, McCarthy A et al. p53 can determine the efficacy of cancer therapy in vitro. Science 1994; 266:807–10. 88. Fisher D. Apoptosis in cancer therapy: crossing the threshold. Cell 1994; 78:539–42. 89. Reed, JC. Bcl-2 family proteins: regulators of chemoresistance in cancer. Toxicol Lett 1995; 82–83:155–8. 90. Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ. Bcl-2 deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 1993; 75:229–40. 91. Evan, GI, Wyllie AH, Gilbert CS et al. Induction of apoptosis in fibroblasts by c-myc protein. Cell 1992; 69:119–28.

Comprehensive Geriatric Oncology

260

92. Harrington EA, Bennett MR, Fanidi A, Evan GI. c-Myc-induced apoptosis in fibroblasts is inhibited by specific cytokines. EMBO J 1994; 13:3286–95. 93. Ruoslahti E, Reed JC. Anchorage dependence, integrins, and apoptosis. Cell 1994; 77:477–8.

12 Tumor-host interactions, aging, and tumor growth William B Ershler Introduction Cancer is a geriatric disease. As described elsewhere in this text, over 50% of all cancers occur in the 13% of the population over 65 years old and this population sustains over 60% of all cancer deaths. Neoplastic transformation at the cellular level involves many of the same genetic and molecular pathways as normal cellular senescence. Cell immortalization and senescence reflect contrasting outcomes that involve similar metabolic and molecular pathways. In this chapter, there is a discussion of certain of these common, clinically relevant principles relating cancer and aging. Additionally, host factors that influence the development and growth of cancer are discussed. Biological principles of aging that may relate to carcinogenesis and tumor growth All normal mammalian cells have a finite lifespan determined by a complex interplay of replicative capacity, ability to maintain proliferative quiescence (e.g. in G0 phase of the cell cycle) and the propensity to self-destruct independently of cell age but in response to a variety of noxious stimuli. This latter process is by a series of genetically programmed events collectively termed apoptosis. Cancers arise when genetic or epigenetic events interfere with normal cellular senescence; cellular lifespan is extended and an anomalous collection of cells occurs. In recent years, one ‘epigenetic’ mechanism has been postulated to be causally related to both cellular aging and cancer. DNA strands segregated into chromosomes are terminated at either end by common, repetitive DNA sequences termed telomeres. Telomere length shortens with each cellular division in vitro, and, interestingly, in vivo as well. Blood cells and fibroblasts obtained from individuals of varying age also show shorter telomere length.1 Certain tumor cell lines have also been demonstrated to have shorter telomere length, and in these cases this has been related to end-to-end chromosomal hybridization and other signs of chromosomal instability.2 In contrast, the mechanism now proposed for the maintenance of telomere length (activation of an enzyme termed telomerase) may explain some of these phenomenon. Telomerase levels are elevated in germline cells but are decreased in somatic cells.3 Another mechanism whereby cells might proliferate inappropriately is if the gene encoding telomerase is

Comprehensive Geriatric Oncology

262

expressed, resulting in enhanced replicative capacity. For reviews on this subject, the reader is directed to Urquidi et al4 and Shay and Wright.5 Linking features of cellular senescence and carcinogenesis, Krtolica and colleagues6 demonstrated that senescent human fibroblasts stimulate premalignant and malignant, but not normal, epithelial cells to proliferate in culture and in xenogenic tumor models. Further, they showed in mice that senescent fibroblasts caused premalignant and malignant epithelial cells to form tumors, suggesting that the process of cellular senescence within the tissue microenvironment promotes tumorigenesis. Dietary restriction/cancer/aging One common gerontologic experimental intervention that has repeatedly and robustly resulted in a reversal of selected biologic markers of aging is a careful reduction in caloric intake (for a comprehensive review, see Weindruch and Walford7). Under experimental circumstances, this has been associated with a decrease in age-associated disease processes and a retardation of the rate of normal physiologic aging. To date, this intervention has only been satisfactorily applied in rodent species or lower, although early data from experiments in non-human primates are encouraging8 and the US National Institute on Aging has recently funded a few carefully designed human trials. In rodents, however, the argument that caloric restriction influences primary aging is strengthened by experiments in which microarray technology was used to examine gene expression in skeletal muscle from restricted or ad libitum fed mice. It was found that aging resulted in a differential expression of certain genes (particularly an increase in those related to the stress response and a decrease in those associated with metabolism and biosynthesis) and that the transcriptional patterns of those animals subjected to caloric restriction were less affected by these age-associated patterns. Evidence that certain tumors (or perhaps cancer in general) are related to primary aging processes can be put forward based upon the observation from several laboratories in which the dietary restriction paradigm has demonstrated reduced appearance of primary and induced cancers and reduced tumor growth rates.9,10 Explanations for the increase in tumor incidence with age Carcinogenesis is a multistage process involving serial alterations of cellular genes. These include oncogenes and antiproliferative genes (anti-oncogenes), which modulate cell proliferation, and genes that prevent apoptosis (as above). It is now understood that oncogenes encode proteins with a myriad of functions, including growth factors, growth factor receptors, enzymes involved in the transduction of proliferative signals, DNA synthesis and replication (for a review, see Weinberg11). Similarly, anti-oncogenes encode proteins that inhibit cell proliferation or DNA replication, and apoptosispreventing genes encode proteins that inhibit the activation of endonucleases that would otherwise disrupt the template function of DNA and result in cell death.12 Another aspect of carcinogenesis that is relevant to aging is the abnormal differentiation of neoplastic cells. For example, in geriatric populations, acute leukemia is often preceded by a myelodysplastic syndrome. In many of these cases, abnormalities of

Tumor-host interactions, aging, and tumor growth

263

transcription factors (TF), and formation of fusion molecules from TF or TF RNA are associated with differentiation inhibition.13 The genetic abnormalities responsible are largely unknown. Different carcinogens may influence the process of transformation and progression at different steps. Consequently, carcinogens have been classified as early- and late-stage carcinogens, or (more commonly) mutagens and promoters.14 These distinctions have practical implications, because the effects of late-stage carcinogens (promoters), unlike those of early-stage carcinogens (mutagens), may be reversible by environmental management and by chemoprevention.15 The multistage nature of carcinogenesis has been demonstrated in experimental models, with strong circumstantial support in human cancers. For example, for the case of colorectal cancer, Vogelstein and colleagues16 described a sequence of genetic alterations leading from normal mucosal epithelium to invasive carcinoma. One step, the loss of the familial adenomatous polyposis (FAP) gene (APC) on chromosome 5, is associated with hyperproliferation of mucosal cells and the formation of adenomatous polyps. Additional changes in the expression of the p53 gene on chromosome 18 and the DCC (‘deleted in colorectal cancer’) gene on chromosome 17 may lead to a more malignant phenotype. Likewise, in the case of brain tumors, loss of all or part of the short arm of chromosome 17 (17p) is seen in malignancy of all grades, whereas loss of chromosome 10 and of the genes encoding interferon receptors has been found only in glioblastoma multiforme.17 These changes may provide the genetic basis for the transformation from indolent to more aggressive disease. Sequential genetic changes leading to more aggressive neoplasms have been reported in many other diseases, including breast, cervical, renal, and lung cancer.18–25 The interpretation of carcinogenesis as a multistage process presents at least two nonmutually exclusive explanations for the increasing incidence of cancer with age. The first and simplest is that the tissues of an older person will have, over time, sustained the serial stochastic events involved in carcinogenesis. Accordingly, the cancers more prevalent among the aged, such as prostate, colon, and breast cancer, are those involving a greater number of steps. In contrast, this hypothesis would predict that tumors more common in young people (lymphoma, leukemia, neuroblastoma, etc.) would require fewer steps in the progression from the normal to the malignant state. The second hypothesis holds that age itself is a risk factor for cancer because the process of aging involves genetic events that are similar to those occurring during early carcinogenesis. Thus, the number of cells that would be susceptible to the effects of latestage carcinogens increases with age. Both experimental and clinical evidence support this theory. Cytogenetic and molecular changes observed in early carcinogenesis are also seen in cells maintained in long-term culture. These changes include formation of DNA adducts, DNA hypomethylation, and chromosomal breakage and translocation (see Chapters 8 and 9 of this volume26,27). Also, the accumulation of iron commonly observed in some aging cells may cause oncogene activation and anti-oncogene suppression28 (and see Chapter 927). The likelihood of neoplastic transformation after exposure to late-stage carcinogens is higher in tissues for older animals than in those of younger animals, both in tissue culture and in cross-transplant experiments.29–32 Thus, the now commonly held notion of multistep mutation leading to transformation and tumor development has recently been challenged, calling upon several of the above-

Comprehensive Geriatric Oncology

264

mentioned features of cellular senescence.33 From a subcellular perspective, the experimental data now indicate that the striking propensity for cancer development in the elderly relates to the pathogenic effect of mutational load, telomere dysfunction, epigenetic regulation, and altered stromal milieu.34 Furthermore, epidemiologic data for some cancers suggest that the susceptibility to late-stage carcinogens increases with age.35 The comparison between the incidence of melanoma and that of squamous cell carcinoma (SCC) of the skin is particularly illustrative.36,37 Whereas, in the USA, the incidence of melanoma plateaus at age 45 for women and 61 for men, the incidence of SCC continues to rise even beyond age 85. This is what might be predicted if there were more steps in the generation of SCC than in that of melanoma. However, the increased number of steps is not the total explanation, because the incidence of SCC increases logarithmically with age.37 This suggests either the association of longevity with a genetic predisposition to SCC (unlikely) or the increased susceptibility with age to late-stage carcinogens. It should be underscored that both basic and clinical data suggest that there is an increased susceptibility and that it may be tissue- and organ-specific. For example, skin epithelium, liver, and lymphoid tissues, but not nervous or muscular tissues, show increased susceptibility to late-stage carcinogens in older rodents.38 Similarly, the incidences of melanoma and mesothelioma in humans demonstrate age-related plateaus and, accordingly, do not support ageenhanced susceptibility to late-stage carcinogens for these tissues.35–37 Other age-related factors that may increase the risk of cancer include reduced DNArepair capability and decreased carcinogen catabolism.39,40 It has been proposed that these lead to an accelerated carcinogenic process with more rapid generation of cells susceptible to late-stage carcinogens (promoters).41 That a link between DNA repair, cancer, and aging exists is supported by the observations that mutations in various DNA repair enzymes, such as the RecQ family of helicases, result in both premature aging (e.g. Werner syndrome and Bloom syndrome) and predisposition to cancer.42 Finally, a discussion of cancer development and aging would not be complete without considering the importance of the decline in immunity and associated failure of ‘immune surveillance’. It has long been proposed that the decline in immune function contributes to the increased incidence of malignancy. However, despite the appeal of such a hypothesis, scientific support has been limited, and the topic remains controversial.43,44 Proponents of an immunologic explanation point to experiments in which outbred strains of mice with heterogeneous immune functions were followed for their lifespan.45 Those that early in life demonstrated better functions (as determined by a limited panel of assays available at the time on a small sample of blood) were found to have fewer spontaneous malignancies and a longer life than those estimated to be less immunologically competent. Similarly, in a longitudinal analysis of a relatively large cohort of individuals for whom a baseline level of lymphocyte (natural killer cell)-mediated natural cytotoxicity was available, it was found after 11 years that a lower baseline level of activity was associated with a greater risk for cancer.46 This study may provide the strongest clinical data available supporting the concept of immune surveillance. It is difficult to deny that profoundly immune-deficient animals or humans are subject to a more frequent occurrence of malignant disease, and it would stand to reason that others with less severe immune deficiency would also be subject to more malignancy (perhaps less dramatically so). However, the malignancies associated with profound immune

Tumor-host interactions, aging, and tumor growth

265

deficiency (such as with the acquired immune deficiency syndrome (AIDS) or after organ transplantation) are usually lymphomas, Kaposi sarcoma, or leukemia, rather than the more common malignancies of geriatric populations (lung, breast, colon, and prostate cancers). Accordingly, it is fair to say that the question of the importance of age-acquired immune deficiency on the incidence of cancer in the elderly is unresolved. However, there is much greater consensus regarding the importance of the immune deficiency of aging for the clinical management of cancer in the control of problems associated with infection and disease progression. Immune senescence and lymphomagenesis Both old humans and old mice have commonly exhibited a monoclonal gammopathy (paraprotein) in the last quartile of the lifespan.47–50 Indeed, 50% of B6 mice aged 24 months show monoclonal immunoglobulin.49 Radl47 defined four categories of ageassociated monoclonal gammopathy: (i) myeloma or related disorders; (ii) benign B-cell neoplasia; (iii) immune deficiency, with T-cell loss greater than B-cell loss; and (iv) chronic antigen stimulation. He speculated that the third category is by far the most common, and this imbalanced immune function is what is considered typical of immune senescence. In addition to the appearance of paraprotein, this same mechanism probably accounts for the age-associated occurrence of autoantibody.51 For example, antinuclear antibodies, rheumatoid factor, antimitochondrial antibodies, etc. are found with increasing frequency in late life, but these are considered to be of little clinical consequence.52 It is quite possible that immune senescence is initially associated with markers of aberrant immune regulation, such as paraproteinemia and/or autoantibody, and later contributes to the pathogenesis of lymphoma. An abundant literature shows that lymphomas commonly and spontaneously occur in old mice.53–58 The vast majority of these are B-cell lymphomas.57,59,60 Pattengale and Frith61 described the immunomorphologic characteristics of 601 spontaneously occurring lymphoid neoplasms found in aged mice from many inbred strains. About 85% of these appeared histologically to be follicular center cell lymphomas with a small lymphocyte morphology (characteristic of a murine B-cell lymphoma). The B-cell phenotype was confirmed immunohistochemically in nearly all of these tumors. In the commonly studied C57BL/6 (B6) strain of mice, spontaneous lymphoma commonly occurs with advanced age. In Weindruch’s experience in the dietary restriction/aging model (reviewed by Weindruch and Walford7), there was an incidence of lymphoma of 50–70% in four groups of ad libitum fed mice that lived out their natural lifespans.56 Lymphoma incidence was not overtly affected by the animal’s sex. In a lifespan study of B6 males, lymphomas occurred in 47% of mice fed ad libitum.58 Not surprisingly, lymphoma incidence is much lower in studies where B6 mice are sacrificed prior to reaching truly old ages. For example, Frith et al59 found that several groups of male and female B6 mice killed for pathologic study between 17 and 23 months of age showed lymphoma incidences of 27% or less. Histologically similar lymphomas also occur in states of more dramatic immune deficiency, such as organ or bone marrow transplant recipients who are pharmacologically immunosuppressed,62–64 children with severe combined immune deficiency (SCID),65 and AIDS patients.66 In these clinical situations of profound immune

Comprehensive Geriatric Oncology

266

deficiency, a curious lymphoproliferative disorder is frequently observed as an antecedent of the lymphoma, characterized by polyclonal B-cell proliferation followed by the development of a monoclonal immunoblastic lymphoma of B-cell type. It has been suggested that a defect in T-cell immunity results in an imbalanced (dysregulated) immunity, with the balance favoring B-cell proliferation. Nowhere is this clearer than in situations in which children with SCID developed lymphoma after partial immunologic reconstitution by either bone marrow or thymus transplantation.67,68 Ultimately, from this polyclonal lymphoproliferative state, a single clone takes over, and this may reflect another genetic change, as Weinberg69 suggests, resulting in growth advantage. The polyclonal lymphoproliferation may be considered a premalignant lesion or an early step in a multistep progression to overt lymphoma. The absence of immunoregulatory function, which is normally provided by competent T cells, may be reflected by an overexpression of the c-myc oncogene. This is suggested because c-myc encodes a protein with DNA-binding activity that presumably regulates cell growth and proliferation.70 Similarly, it is possible that overexpression or alteration of Ha-ras, often considered a complementary oncongene to c-myc,69 may be sufficient to render a particular clone growth advantage and herald the appearance of monoclonal lymphoma. Tumor ‘aggressiveness’ and aging There has been a long-held but incompletely documented clinical dogma that cancers in older people are ‘less aggressive’. Older patients with tumors originating in breast, colon, lung, prostate, or kidney have been reported to have reduced tumor growth rates or longer survival than younger patients; for a review of these reports, see Mor et al.71 However, epidemiologic data from tumor registries and large clinical trials have not been supportive. This may be because this type of data is confounded by special problems common to geriatric populations (e.g. comorbidity, ‘polypharmacy’, physician or family bias regarding diagnosis and treatment in the elderly, and age-associated life stresses, which may be as apparently trivial as the inability to get to a medical center for treatment72). These factors may counter any primary influence that aging might have on tumor aggressiveness. The imprecise term ‘tumor aggressiveness’ encompasses several heterogeneous variables such as histologic grade, mitotic index, receptor status, tumor antigen profile, chromosomal abnormalities, the presence and site of metastatic disease, and the presence or absence of tumor-controlling and/or tumor-promoting host factors (such as the interferons or tumor necrosis factor). We intuitively associate more aggressive tumor behavior with a poorer outcome, and in most cases this association is valid. Nevertheless, for some aggressive tumors (such as large cell lymphoma), the high mitotic index may actually render the tumor more responsive to cell cycle-specific chemotherapy. In contrast, less aggressive tumors with a low mitotic index may initially have a better prognosis, but are most resistant to chemotherapy and usually incurable once disseminated. As alluded to above, the clinical data used to evaluate the relationship between tumor aggressiveness and age are confounded by other variables. For example, older patients are much more likely to suffer from comorbid conditions and have more limited access to

Tumor-host interactions, aging, and tumor growth

267

healthcare.73 Furthermore, there is the issue of physician bias, which may result in a failure to administer potentially effective therapy to older patients.72,74,75 Finally, data retrieved from death certificates are often fraught with inaccuracies, errors of omission, and inadequate documentation of competing morbidities.76 Even data that compare the survival of patients of varying age who present with the same type and stage of tumor are subject to bias. For example, although 45% of new breast cancers are detected after the age of 65,77 only 16% of mammograms are done in women over the age of 60.78 This alone may explain why older patients with this disease present to their physician with more advanced disease.74,79,80 A similar age bias for cancer screening has been described for cervical cancer.78 With the above caveats in mind, it is not difficult to understand why the clinical impression of less aggressive tumors in older patients has not been verified by epidemiologic investigation. In fact, epidemiologic investigation might suggest the opposite to be true. For example, one could interpret recent data from the US National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) program to suggest that older patients present with more advanced disease and survive a shorter period after diagnosis. But, for the reasons mentioned and until there is a prospective evaluation in which age bias is minimized, the data remain inconclusive. There are, however, two tumors that bear special mention. The first is breast cancer, for which there is clearly the most controversy. There is evidence that breast cancer is more aggressive in young women,81 yet several reports indicate that the disease is diagnosed at a more advanced stage in older women74,79,80 while other reports are inconclusive in this regard.71,82 The survival data are even more contentious: some studies indicate that older women with breast cancer have a higher overall survival rate than younger women,83,84 while other studies report the opposite.85,86 However, pathologic data suggest that breast carcinomas in elderly women have more ‘favorable’ characteristics, such as a greater frequency of estrogen receptor positivity,87 a predominantly diploid rather than aneuploid chromosomal pattern,87,88 and a lower incidence of medullary and inflammatory characteristics.75 In fact, based upon epidemiologic data, some have speculated that these markers would suggest that breast cancer appearing in young versus old women is actually two distinct diseases.89 Why these more favorable characteristics fail to translate into a more clearly demonstrable survival advantage is unclear. Perhaps it is related to the comorbidity issues mentioned above, or to the unproven speculation that older women are treated less aggressively.72,74,75 The second specific tumor that bears mention is lung cancer. Unlike the situation for breast cancer, for lung cancer there is a clearly documented inverse relationship between patient age and tumor stage at the time of diagnosis.74,79,80,90–92 Older patients appear to have more squamous cell cancers (as opposed to adenocarcinoma or large cell or small cell variants93). Compared with the other histologic types, squamous cell carcinomas of the lung more typically present in a proximal location and are more likely to cause symptoms early. This may, in part, explain the curious inverse stage/age relationship observed for lung cancer.93 Other factors, such as age-associated obstructions in lymphatic drainage, may reduce the likelihood of tumor spread in elderly patients.90 Some workers have suggested that patients who are susceptible to aggressive tumors die after a shorter illness, and that the elderly represent a biologically select group.91

Comprehensive Geriatric Oncology

268

We favor the concept that slower tumor proliferation is the result of physiologic restraints conferred by senes cent tissues and that the phenomenon observed in lung cancer patients may be a general one. This concept is difficult to study in the highly heterogeneous population of elderly patients, but can be rigorously tested in animal models. Providing explanations for reduced tumor growth with age: animal models There is experimental support for the hypothesis that there is a reduction in tumor aggressiveness with age. Data obtained from laboratory animals with a wide range of tumors under highly controlled circumstances demonstrate slower tumor growth, fewer experimental metastases, and longer survival in the older cohorts (Table 12.1).94–97 What accounts for the age-associated changes observed in these experimental systems? One explanation derives from the understanding that the tumors, although histologically quite similar, may be biologically very different (‘seed versus soil’) in old patients. For example, breast cancer cells are more likely to contain estrogen receptors, and leukemic cells more likely to harbor cytogenetic abnormalities, in elderly patients with those disorders. Each of these associations has prognostic significance. Furthermore, there is the issue of the ‘time line’ artifact (Figure 12.1), which implies that old patients (more so than young) may develop slowly growing tumors on the basis of time required to develop such slow tumors. This is, of course, consistent with the multistep hypothesis as discussed above. It is probable that certain factors that influence tumor growth change with age. With this in mind, various endocrine, nutritional, wound-healing, and angiogenic factors have been explored. For some tumors, age-associated changes in these factors have been correlated with reduced

Table 12.1 The effect of aging on the growth rate of experimental murine tumors Decreased growth rate in older mice •

B16 melanoma94,95

•

Teratocarcinoma OTT60–50116

•

Lewis lung carcinoma95

•

Line 1 alveolar carcinoma117

•

Mammary carcinoma

Increased growth rate in older mice •

EMT6118

•

3-Methylcholanthrene-induced sarcomas119

•

UV light-induced sarcomas120

Tumor-host interactions, aging, and tumor growth

269

Figure 12.1 One explanation for the variation in tumor aggressiveness with age. Rates of tumor proliferation may play a role in the apparently slower growth of tumors. For example, if two tumors—one fast growing and one slow—both arise at the same stage of life, the faster growing tumor would present clinically at a younger age. This model might explain why tumors arising in younger patients tend to be more aggressive, and why there is such great heterogeneity in tumor characteristics (such as aggressiveness) in older individuals. tumor growth.94,95,97,98–100 However, several early observations led to the seemingly paradoxical conclusion that immune senescence accounted for a large component of the observed reduced tumor growth with age. For example, B16 melanoma grows less well in congenitally immune-deficient mice101 and in young mice rendered T-cell-deficient.96 Furthermore, when young, thymectomized, lethally irradiated mice received bone marrow or splenocytes from old donor mice, tumor growth was less that when the spleen or bone marrow was from young donor mice.96,102 It is believed that competent immune cells provide factors that augment tumor growth under certain circumstances. If a tumor is only weakly antigenic, non-specific growthstimulatory factors provided by lymphocytes or monocytes may actually counteract the inhibitory forces provided by those same cells (because of the lack of tumor antigen). In this situation, immune deficiency does not render a host more susceptible to aggressive

Comprehensive Geriatric Oncology

270

tumor growth and spread; in fact, immune deficiency renders a host more resistant, because those cells are less likely to provide the non-specific stimulatory factors. This hypothesis is akin to the immune enhancement theory promoted several decades ago by Prehn and colleagues.103,104 Briefly stated, in the context of cancer and aging, the nonspecific production of positive growth, angiogenic, and other tumor-stimulatory signals by cells considered part of the immune system is less in the case of cells from old animals. In other words, the ‘soil’ is less fertile for aggressive tumor growth (Figure 12.2). How can the data from experiments examining the influence of age on tumor growth be summarized? Some

Figure 12.2 Immune forces, tumor antigenicity, and age: illustration of the proposed counter-immune forces that might influence tumor growth. Shaded figures of different sizes reflect tumors growing at different rates. Tumors 2 and 4 represent poorly antigenic tumors, whereas 1 and 3 represent strongly antigenic tumors. The upper figures are tumors in an immunecompetent (or young) host, while those below are tumors in an immunedeficient (or old) host. Strengths of

Tumor-host interactions, aging, and tumor growth

271

immune-facilitating forces (for each tumor, the set of arrows within the tumor) and of immunosuppressive forces (for each tumor, the left-sided external arrow) are represented by the size of the arrows. Strongly antigenic tumors induce strong immunosuppressive responses only in immune-competent hosts, and tumor growth is thereby inhibited. Immunedeficient hosts produce a weak immunosuppressive response to a strongly antigenic tumor, and tumor growth is correspondingly greater. Poorly antigenic tumors induce little immunosuppressive response in either immune-competent or immunosuppressed hosts. The immune-competent host will produce a greater immune-facilitating response, and tumor growth will be greater than in the immunosuppressed host. This hypothesis would predict that in immune-deficient (aged) hosts, with weakly antigenic tumors, the tumor growth would be slow compared with the growth of the same tumor in immune-competent young hosts. (perhaps most) models show a slower growth of tumors in older animals, whereas some others show a faster, more malignant growth. While data remain somewhat conflicting, it appears that the strongly immunogenic tumors have a growth advantage in older animals, while more poorly antigenic tumors may have a growth advantage in younger animals (Figures 12.2–12.5; Table 12.1). The underlying mechanism for this is most probably related to senescence of the immune system. Before exploring immune senescence, some alternatives will be considered. In the B16 murine melanoma model, hormonal factors clearly influence growth.98,105,106 The proposal that age-associated decreased secondary sex steroid levels may be the cause of decreased B16 growth was excluded by showing that B16 actually had increased growth in

Comprehensive Geriatric Oncology

272

Figure 12.3 Proposed model of B-cell lymphoma development in old C57BL/6 mice. In this mouse strain, a B-cell lymphoma develops in approximately 50% of mice by 24 months of age. The model suggests that the dysregulation of various cytokines (e.g. interleukin-6, IL-6) contributes to the lymphoproliferation that is an antecedent to the monoclonal lymphoma.

Figure 12.4 (a) Growth of B16 melanoma in young (2–4 months) and old (24 months) C57BL/6 mice. B16F10 cells (105) were injected

Tumor-host interactions, aging, and tumor growth

273

subcutaneously in the mice and the tumor size was measured in two dimensions every 3 days. (b) Growth of Lewis lung carcinoma growth after subcutaneous injection of 105 tumor cells into young (2–3 months) and old (24 months) C57BL/6 mice. Tumor size was measured in two dimensions approximately every 2 days. (c) Growth of the fibrosarcoma S180 in young (2–4 months) and old (24 months) Balb/c mice. Cells (105) were injected subcutaneously, and tumor size was measured in two dimensions approximately every 3 days. This tumor, in contrast to the B16 melanoma and Lewis lung carcinoma, is highly antigenic and shows no significant growth advantage in young mice (WB Ershler, unpublished data). In each plot, tumor volume is presented as mean±SEM for groups of 10 mice. (a) is modified from reference 99 and (b) from reference 102. castrated young mice.98 This does, however, reveal the importance of considering hormonal influences in tumor models other than those traditionally thought to be hormonally responsive tumors. Nutritional factors may also be important, since aging in mice brings about dietary changes such as decreased total food consumption.107 Dietary changes, especially calorie restriction, may have profound effects on the aging immune system. In mice, a 30% reduction in calories leads to a delay in immune senescence108 and prolonged survival.56 The effects of this on tumor growth and spread are as yet incompletely determined. We9 and several others (reviewed by Weindruch and Walford7) have previously reported that B16 melanoma grows more slowly in calorie-restricted mice, and it is possible that the beneficial effects of undernutrition, which might occur spontaneously in old mice, might actually account for some of the observed ‘age-advantage’ in certain of these models. The ability of the body to heal wounds is decreased with age.109 Wound healing shares many characteristics of tumor growth and spread: cell localization with specific receptors, mitogenesis, tissue invasion, angiogenesis, and extracellular matrix deposition. Changes in these factors with age may result in changes in tumor growth. Collagens are known to

Comprehensive Geriatric Oncology

274

change with age, mainly demonstrating increased crosslinking110 without primary sequence

Figure 12.5 Formation of pulmonary tumor colonies in young (2–4 months) and old (24 months) C57BL/6 mice after intravenous injection of 105 B16 F1 cells into the lateral tail vein. Fourteen days later, mice (10 per group) were sacrificed and the number of colonies (±SEM) counted. Modified from reference 95. alteration.111 Inhibition of collagen deposition around tumors by administration of dehydroproline caused enhanced growth and invasiveness of B16 melanoma.94 Fibrosis surrounding B16 melanoma implants is enhanced in old mice.9 All of these ‘alternative’ mechanisms deserve further study. What we shall consider below, however, is how the immune system may act to enhance as well as inhibit the growth of tumors.

Tumor-host interactions, aging, and tumor growth

275

Immune senescence and tumor growth It has been proposed that competent immune cells provide factors that can augment turnor growth under certain circumstances.104 If a tumor is only weakly antigenic, then non-specific growth-stimulatory factors provided by lymphocytes or monocytes may actually outweigh the inhibitory forces provided by those same cells (because of the lack of tumor antigen). In this situation, therefore, immune deficiency does not render a host more susceptible to aggressive tumor growth and spread, but in fact renders the host more resistant because those cells are less likely to provide the non-specific stimulatory factors (i.e. less fertile ‘soil’) (Figures 12.6 and 12.7). A large series of early-stage breast cancer patients has been reported in which predictive factors were determined that were associated with local relapse after breastconserving therapy.12 The local relapse rate was 21% in those under 40 years compared with 11% in those older. Multivariate analysis of 18 potential factors revealed four

Figure 12.6 Effect of thymectomy and anti-T-cell antiserum on the growth of B16-F1 melanoma in young mice (2–4 months). Mice were thymectomized 8 weeks before inoculation of tumor cells (on day 0). Rabbit anti-q (anti-Tcell) antiserum was injected twice (on days –7 and –4). (a) Sham thymectomized. (b) Thymectomized.

Comprehensive Geriatric Oncology

276

(c) Thymectomized and injected with anti-q antiserum. Tumor volume is presented as mean ±SEM for groups of 8 mice. Modified from reference 96.

Figure 12.7 Growth of B16 melanoma in mice inoculated with splenocytes from old (24 months) or young (2–4 months) donor mice. Young mice (2–4 months) were thymectomized, and 8 weeks later were lethally irradiated and given intravenous injections of 80×106 spleen melanoma cells from syngeneic young or old mice. Seventeen days later, mice were inoculated with B16 cells subcutaneously (day 0). Tumor volume is presented as mean±SEM for groups of 6 mice. (a) Young controls. (b) Young, thymectomized, irradiated recipients of spleen cells from young donors. (c) Old (uninoculated) control

Tumor-host interactions, aging, and tumor growth

277

mice. (d) Young, thymectomized, irradiated recipients of spleen cells from old donors. Modified from reference 96. that significantly determined risk: (i) unsatisfactory margin resections; (ii) increasing histologic grade; (iii) extensive intraductal cancer within the primary tumor; and (iv) major lymphocyte stromal reaction (MCR). The latter factor may well pertain to the observed changes in tumor growth with advanced age. Compared with older patients, those younger that 40 years had tumors that more often exhibited MCR (36% versus 20%; p<0.01). Although there are several other explanations for this finding, one plausible choice is that these infiltrating host cells are a component of an inflammatory response that indirectly promotes tumor growth. It is likely that, with age, a less rigorous cellular inflammatory response occurs. One candidate tumor-enhancing cytokine is lymphocyte-induced angiogenesis factor, believed to be important in the inflammatory response.113–115 This factor may contribute to tumor vascularization,99 and its production has been shown to decline with age.100 Additionally, we have identified a factor produced by cultured splenic macrophages from young mice that stimulates the proliferation of various murine tumor cells. Preliminary data indicate that this factor is produced to a lesser extent by cells from old mice and that the tumor-promoting activity results from a single protein (~50 kDa) that is heat-stable, pH-labile, and sensitive to trypsin and to reduction by 2-mercaptoethanol. Using purified factors or antibody to factors, we have demonstrated that the enhancing activity is not interleukins-1 through -7, epidermal growth factor (EGF), fibroblast growth facor (FGF), platelet-derived growth factor (PDGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), or transforming growth factor β (TGF-β). Conclusions There is no doubt that cancer occurs more frequently in older people and that this is a reflection both of the time it takes for a cell destined to become malignant to undergo the requisite events that render it both transformed and invasive and of the physiologic changes that accompany aging. These include increased susceptibility to carcinogens, less successful DNA-repair mechanisms, and immune senescence. These same factors may be held accountable for the decreased tumor ‘aggressiveness’ observed experimentally in rodent systems and possibly clinically for several of the common tumors (e.g. breast, prostate, and lung carcinomas). There are several features of cancer and aging that are common, and future research in either area is bound to shed light on the other. References 1. Harley CB, Futcher AB, Greider CW. Telomeres shorten during aging of human fibroblasts. Nature 1990; 345:458–60.

Comprehensive Geriatric Oncology

278

2. Hastie ND, Allshire RC. Human telomeres: fusion and interstitial sites. Trends Genet Sci 1989; 5:326–31. 3. De Lange T, Shiue L, Myers R et al. Structure and variability of human chromosome ends. Mol Cell Biol 1990; 10:518–27. 4. Urquidi V, Tarin D, Goodison S. Role of telomerase in cell senescence and oncogenesis. Annu Rev Med 2000; 51:65–79. 5. Shay JW, Wright WJ. Telomeres and telomerase: implications for cancer and aging. Radiat Res 2001; 155:188–93. 6. Krtolica A, Parrinello S, Lockett S et al. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci 2001; 98:12072–7. 7. Weindruch R, Walford R. The Retardation of Aging and Disease by Dietary Restriction. Springfield IL: Charles C Thomas, 1988. 8. Ramsey JJ, Colman RJ, Binkley NC et al. Dietary restriction and aging in rhesus monkeys: the University of Wisconsin study. Exp Gerontol 2000; 35:1131–49. 9. Ershler WB, Berman E, Moore AL. B16 melanoma growth is slower, but pulmonary colonization is greater in calorie restricted mice. J Natl Cancer Inst 1986; 76:81–5. 10. Volk MJ, Pugh TD, Kim MJ et al. Dietary restriction from middle age attenuates age-associated lymphoma development and IL-6 dysregulation in C57BL/6 mice. Cancer Res 1994; 54:3054– 63. 11. Weinberg RA. Oncogenes, antioncogenes and the molecular bases of multistep carcinogenesis. Cancer Res 1989; 49:3713–21. 12. Korsemeyer SJ. Programmed cell death: Bcl-2. In: Important Advances in Oncology, 1993 (De Vita VT, Hellman S, Rosenberg SA, eds). Philadelphia: Lippincott, 1993:19–28. 13. Nichols J, Nimer SD. Trancription factors, translocation and leukemia. Blood 1992; 80:2953– 63. 14. Shields PG, Harris CC. Principles of carcinogenesis: chemical. In: Cancer: Principles and Practice of Oncology, 4th edn (DeVita VT Jr, Hellman S, Rosenberg SA, eds). Philadephia: Lippincott, 1993: 200–12. 15. Meyskens FL. Strategies for prevention of cancer in humans. Oncology 1992; 6(2 Suppl): 15– 24. 16. Vogelstein B, Fearon ER, Hamilton SR et al. Genetic alterations during colorectal tumor development. N Engl J Med 1988; 319: 525–32. 17. James CD, Carlbom E, Dumanskji JP et al. Clonal genomic alterations in glioma malignancy stages. Cancer Res 1988; 48:5546–51. 18. Boyle P, Leake R. Progress in understanding breast cancer: epidemiological and biological interactions. Breast Cancer Res Treat 1988; 11:91–112. 19. Harris JR, Lippman ME, Veronesi U, Willett W. Breast cancer. N Engl J Med 1992; 327:319– 28, 390–8, 473–80. 20. Carney DN. Biology of small cell lung cancer. Lancet 1992; 339: 843–6. 21. Correa P. Biochemical and molecular methods in cancer epidemiology and prevention: the path between the laboratory and the population. Cancer Epidemiol Biomark Prev 1993; 2:85–8. 22. Vineis P. Epidemiological models of carcinogenesis: the example of bladder cancer. Cancer Epidem Biomark Prev 1992; 1:149–54. 23. el Azouzi M, Chung RY, Farmer GE et al. Lost of distinct regions on the short arm of chromosome 17 associated with tumorigenesis of human astrocytomas. Proc Natl Acad Sci USA 1989; 86: 7186–90. 24. Lenehan WM, Gnarra JR, Lerman MI et al. Genetic bases of renal cell cancer. In: Important Advances in Oncology, 1993 (De Vita VT; Hellman S, Rosenberg SA, eds). Philadelphia: Lippincott, 1993:47–70. 25. Franco EL. Prognostic value of human papillomavirus in the survival of cervical cancer patients: an overview of the evidence. Cancer Epidemiol Biomark Prev 1992; 1:499–504.

Tumor-host interactions, aging, and tumor growth

279

26. Anisimov VN. Age as a risk factor in multistage carcinogenesis. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:75–101. 27. Fernandez-Pol JA. Growth factors, oncogenes, and aging. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:102–26. 28. Stevens RG, Jones DY, Micozzi MS, Taylor PR. Body iron stores and the risk of cancer. N Engl J Med 1988; 319:1047–52. 29. Anisimov VN. Effect of age on dose-response relationship in carcinogenesis induced by single administration of N-methylnitrosourea in female rats. J Cancer Res Clin Oncol 1988; 114:628– 35. 30. Ward JM, Lynch P, Riggs C. Rapid development of hepatocellular neoplasms in aging male C3H/HeNcr mice given phenobarbital. Cancer Lett 1988; 39:9–18. 31. Ebbesen P. Reticulosarcoma and amyloid development in BALB/c mice inoculated with syngeneic cells from young and old donors. J Natl Cancer Inst 1971; 47:1241–5. 32. Anisimov VN, Loktionov AS, Khavinson VK, Morozov VG. Effect of low molecular weight factors of thymus and pineal gland on life span and spontaneous tumor development in female mice of different age. Mech Ageing Dev 1989; 49:245–57. 33. Simon JW. Coming of age: ‘dysgenetics’—a theory connecting induction of persistent delayed genomic instability with disturbed cellular aging. Int J Radiat Biol 2000; 76:1533–43. 34. DePinho RA. The age of cancer. Nature 2000; 408:248–54. 35. Kaldor JM, Day NE. Interpretation of epidemiological studies in the context of the multistage model of carcinogenesis. In: Mechanisms of Environmental Carcinogenesis, Vol 2 (Barrett JC, ed). Boca Raton, FL: CRC Press, 1987; 21–57. 36. Tantranond P, Karam F, Wang TY et al. Management of cutaneous squamous cell carcinoma in an elderly man. J Am Geriatr Soc 1992; 40:510–12. 37. Glass AG, Hoover RN. The emerging epidemic of melanoma and squamous cell carcinoma of the skin. JAMA 1989; 262:2097–100. 38. Matoha MF, Cosgrove JW, Atak JR, Rappoport SI. Selective elevation of the c-myc transcript levels in the liver of the aging Fischer 344 rat. Biochem Biophys Res Commun 1987; 147:1–7. 39. Bohr VA, Evans MK, Fornace AJ. Biology of disease: DNA repair and its pathogenetic implications. Lab Invest 1989; 61:143–61. 40. Balducci L, Wallace C, Khansur T et al. Aging, nutrition and cancer, an annotated review. I— Diet, carcinogenesis and aging. J Am Geriatr Soc 1986; 34:127–36. 41. Randerath K, Reddy MV, Disher RM. Age- and tissue-related DNA modifications in untreated rats: detection by 32P-post-labeling assay and possible significance for spontaneous tumor induction and aging. Carcinogenesis 1986; 7:1615–17. 42. Furuichi Y. Premature aging and predisposition to cancers caused by mutations in RecQ family helicases. Ann NY Acad Sci 2001; 928: 121–31. 43. Ershler WB. The influence of an aging immune system on cancer incidence and progression. J Gerontol 1993; 48: B3–7. 44. Miller RA. Aging and cancer: another perspective. J Gerontol 1993; 48: B8–10. 45. Covelli V, Mouton D, Majo V et al. Inheritance of immune responsiveness, life span and disease incidence in interline crosses of mice selected for high or low multispecific antibody production. J Immunol 1989; 142:1224–34. 46. Imai K, Matsuyama S, Miyake S et al. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Lancet 2000; 356:1795–9. 47. Radl J. Age-related monoclonal gammopathies: clinical lessons from the aging C57BL mouse. Immunol Today 1990; 11:234–6. 48. Radl J, Sepers JM, Skvaril F et al. Immunoglobulin patterns in humans over 95 years of age. Clin Exp Immunol 1975; 22:84–90.

Comprehensive Geriatric Oncology

280

49. Radl J, Hollander CF, Van Den Berg, P, De Glopper E. Idiopathic paraproteinemia studies in an animal model—the ageing C57BL/KaLwRij mouse. Clin Exp Immunol 1978; 33:395–401. 50. Radl J, De Glopper E, Schuit HRE, Zurcher C. Idiopathic paraproteinemia. II. Transplantation of the paraprotein producing clone from old to young C57BL/KaLwRij mice. J Immunol 1979; 122:609–13. 51. Goodwin JS, Searles RP, Tring ASK. Immunological responses of a healthy elderly population. Clin Exp Immunol 1982; 48:403–10. 52. Kay MMB, Makinodan T. In: Clinical Immunochemistry, Chemical and Cellular Bases and Applications in Disease (Natelson S, Pesce AJ, Dietz AA, eds). Washington, DC: American Association for Clinical Chemistry, 1978:192. 53. Smith GS, Walford RL, Mickey MR. Lifespan and incidence of cancer and other diseases in selected long-lived inbred mice and their Fl hybrids. J Natl Cancer Inst 1993; 50:1195–213. 54. Cheney KE, Liu RK, Smith GS et al. Survival and disease patterns in C57BL/6J mice subjected to undernutrition. Exp Gerontol 1980; 15:237–58. 55. Frith CH, Wiley LD. Classification and incidence of hyperplastic and neoplastic hemopoietic lesions in mice. J Gerontol 1981; 36: 534–45. 56. Weindruch R, Walford RL. Dietary restriction in mice beginning at one year of age: effect on life span and spontaneous cancer incidence. Science 1982; 215:1415–18. 57. Pattengale PK, Taylor CR. Experimental models of lymphoproliferative disease: the mouse as a model for human non-Hodgkin’s lymphomas and related leukemias. Am J Pathol 1983; 113:237–65. 58. Bronson RT. Rate of occurrence of lesions in 20 inbred and hybrid genotypes of rats and mice sacrificed at 6 month intervals during the first years of life. In: Genetic Effects on Aging (Harrison DE, ed). Caldwell, NJ: Telford Press, 1990; 279–357. 59. Frith CH, Highman B, Burger G, Sheldon WD. Spontaneous lesions in virgin and retired breeder BALB/c and C57BL/6 mice. Lab Anim Sci 1983; 33:273–86. 60. Pattengale PK, Frith CH. Immunomorphologic classification of spontaneous lymphoid cell neoplasms in female BALB/C mice. J Natl Cancer Inst 1983; 70:169–79. 61. Pattengale PK, Frith CH. Contributions of recent research to the classification of spontaneous lymphoid cell neoplasms in mice. CRC Crit Rev Toxicol 1986; 16:185–212. 62. Starzl TE, Penn I. Malignancies in renal transplant patients. Transplant Rev 1971; 7:112–22. 63. Penn I. Cancer as a complication of clinical transplantation. Transplant Proc 1977; 9:1121–7. 64. Penn, I. Allograft transplant cancer registry. In: Immune Deficiency and Cancer; Epstein Barr Virus and Lymphoproliferative Malignancies (Purtilo DT, ed). New York: Plenum, 1984:280–7. 65. Spector BD, Perry GS, Kersey JH. Genetically determined immunodeficiency diseases and malignancy: report from the Immunodeficiency-Cancer Registry. Clin Immunol Immunopathol 1978; 11:12–29. 66. Lipscomb H, Tatsumi E, Harada S et al. Epstein-Barr virus, chronic lymphadenomegaly and lymphoma in male homosexuals with acquired immunodeficiency syndrome (AIDS). AIDS Res 1983; 1:59–66. 67. Borzy MS, Hong R, Horowitz SD et al. Fatal lymphoma after transplantation of cultured thymus in children with combined immunodeficiency disease. N Engl J Med 1979; 301:565–73. 68. Reece ER, Gartner JG, Seemayer TA et al. Epstein-Barr virus in a malignant lymphoproliferative disorder of B cells occurring after thymic epithelial transplantation for combined immunodeficiency. Cancer Res 1981; 41:4243–8. 69. Weinberg RA. Oncogenes and the Molecular Origins of Cancer. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 1989. 70. Leder P, Battey J, Lenoir G et al. Translocations among antibody genes in human cancers. Science 1983; 222:765–71. 71. Mor V, Guadagnoli E, Masterson-Allen S et al. Lung, breast and colorectal cancer: the relationship between extent of disease and age at diagnosis. J Am Geriatr Soc 1988; 36:873–6.

Tumor-host interactions, aging, and tumor growth

281

72. Samet J, Hunt WC, Key C et al. Choice of cancer therapy varies with age of patient. JAMA 1986; 255:3385–90. 73. Linden G. The influence of social class in the survival of cancer. Am J Public Health 1969; 59:267–74. 74. Mor V, Masterson-Allen S, Goldberg RJ et al. Relationship between age at diagnosis and treatments received by cancer patients. J Am Geriatr Soc 1985; 33:585–9. 75. Allen C, Cox EB, Manton KG, Cohen HJ. Breast cancer in the elderly: current patterns of care. J Am Geriatr Soc 1986; 34 637–42. 76. Holmes FF. Clinical evidence for a change in tumor aggressiveness with age. Semin Oncol 1989; 16:34–40. 77. Robie PW. Cancer screening in the elderly. J Am Geriatr Soc 1989; 37:888–93. 78. Leventhal EA. The dilemma of cancer in the elderly. Front Radiat Ther Oncol 1986; 20:1–13. 79. Holmes FF, Hearne E. Cancer stage to age relationship: implications for cancer screening in the elderly. J Am Geriatr Soc 1981; 29: 55–7. 80. Goodwin JS, Samet JM, Key CR et al. Stage at diagnosis of cancer varies with age of the patient. J Am Geriatr Soc 1986; 34:20–6. 81. Noyes RD, Spanos WJ, Montague ED. Breast cancer in women aged 30 and under. Cancer 1982; 49:1302–7. 82. Rosen PP, Lesser ML, Kinne DW. Breast carcinoma at the extremes of age: a comparison of patients younger than 35 years and older than 75 years. J Surg Oncol 1985; 28:90–6. 83. Herbsman H, Feldman J, Seldera J et al. Survival following breast cancer surgery in the elderly. Cancer 1981; 47:2358–63. 84. Sondik EJ, Young JL, Horm JW. 1986 Annual Cancer Statistics Review. NIH Publication 87– 2789. Bethesda, MD: US Department of Health and Human Services, 1987. 85. Mueller CB, Ames F, Anderson GD. Breast cancer in 3,558 women: age as a significant determinant in the rate of dying and causes of death. Surgery 1978; 83:123–32. 86. Adami H-O, Malker B, Holmberg L et al. The relation between survival and age at diagnosis in breast cancer. N Engl J Med 1986; 315:559–63. 87. von Rosen A, Gardelin A, Auer G. Assessment of malignancy potential in mammary carcinoma in elderly patients. Am J Clin Oncol 1987; 10:61–4. 88. von Rosen A, Fallenius A, Sundelin B, Auer G. Nuclear DNA content in mammary carcinomas in women aged 35 or younger. Am J Clin Oncol 1986; 9:382–6. 89. Anderson WF, Chu KC, Chatterjee N et al. Tumor variants by hormone receptor expression in White patients with node negative breast cancer from the Surveillance, Epidemiology and End Results database. J Clin Oncol 2001; 19:18–27. 90. Onuigbo WIB. Lung cancer, metastasis and growing old. J Gerontol 1962; 17:163–6. 91. Suen KC, Lau LL, Yermakow V. Cancer and old age. An autopsy study of 3,535 patients over 65 years old. Cancer 1974; 33:1164–8. 92. Ershler WB, Socinski MA, Greene CJ. Bronchogenic cancer, metastases, and aging. J Am Geriatr Soc 1983; 31:673–6. 93. Teeter SM, Holmes FF, McFarlane MJ. Lung carcinoma in the elderly population: influence of histology on the inverse relationship of stage to age. Cancer 1987; 60:1331–6. 94. Ershler WB, Gamelli RL, Moore AL et al. Experimental tumors and aging: local factors that may account for the observed age advantage in the B16 murine melanoma model. Exp Gerontol 1984; 19: 367–76. 95. Ershler WB, Stewart JA, Hacker MP et al. B16 murine melanoma and aging: slower growth and longer survival in old mice. J Natl Cancer Inst 1984; 72:161–5. 96. Tsuda T, Kim YT, Siskind GW et al. Role of the thymus and T-cells in slow growth of B16 melanoma in old mice. Cancer Res 1987; 47:3097–100. 97. Ershler WB. Guest Editorial: Why tumors grow more slowly in old people. J Natl Cancer Inst 1986; 77:837–9.

Comprehensive Geriatric Oncology

282

98. Simon SR, Ershler WB. Hormonal influences on growth of B16 murine melanoma. J Natl Cancer Inst 1985; 74:1085–8. 99. Hadar E, Ershler WB, Kreisle RA et al. Lymphocyte-induced angiogenesis factor is produced by L3T4+ murine T lymphocytes, and its production declines with age. Cancer Immunol Immunother 1988; 26:31–7. 100. Kreisle RA, Stebler B, Ershler WB. Effect of host age on tumor associated angiogenesis in mice. J Natl Cancer last 1990; 82:44–7. 101. Fidler IJ, Gersten DM, Riggs CW. Relationship of host immune status to tumor cell arrest, distribution and survival in experimental metastases. Cancer 1977; 40:46–55. 102. Ershler WB, Moore AL, Shore H, Gamelli RL. Transfer of age-associated restrained tumor growth in mice by old to young bone marrow transplantation. Cancer Res 1984; 44:5677–81. 103. Prehn RT, Lappe, MA. An immunostimulation theory of tumor development. Transplant Rev 1971; 7:26–30. 104. Prehn RT. The immune reaction as a stimulator of tumor growth, Science 1972; 176:170–5. 105. Proctor JW, Auclair BG, Stokowski L. Endocrine factors and the growth and spread of B16 melanoma. J Natl Cancer Inst 1976; 57: 1197. 106. Proctor JW, Yammamura Y, Gaydos D, Matromatteo W. Further studies on endocrine factors and growth and spread of B16 melanoma. Oncology 1981; 38:102. 107. Greene EL. Handbook on Genetically Standardized Mice, 2nd edn. Bar Harbor, ME: Bar Harbor Time Publishing, 1977. 108. Weindruch RH, Kristie JA, Cheney KE, Walford RL. Influence of controlled dietary restriction on immunologic functioning and aging. Fed Proc 1979; 38:2007–16. 109. Cohen BJ, Danon D, Roth GS. Wound repair in mice is influenced by age and antimacrophage serum. J Gerontol 1987; 42:295. 110. Miyahara T, Murai A, Tanaka T et al. Age-related differences in human skin collagen: solubility in solvent, susceptibility to pepsin digestion, and the spectrum of solubilized polymeric collagen molecules. J Gerontol 1982; 37:651. 111. Miyahara T, Shiozawa S, Murai A. The effect of age on amino acid composition of human skin collagen. J Gerontol 1978; 33:498. 112. Kurtz JM, Jacquemier J, Amalric R et al. Why are local recurrences after breast conserving therapy more frequent in younger patients? J Clin Oncol 1990; 8:591–8. 113. Sidky Y, Auerbach R. Lymphocyte-induced angiogenesis: a quantitative and sensitive assay of the graft vs. host reaction. J Exp Med 1975; 141:1084. 114. Sidky Y, Auerbach R. Response of the host vasculature system to immunocompetent lymphocytes. Effect of pre-immunization of donor or host animals. Proc Soc Exp Biol Med 1979; 161:174. 115. Auerbach R, Kubai L, Sidty YA. Angiogenesis induction by tumors, embryomic tissue and lymphocytes. Cancer Res 1976; 36:3435. 116. Kubota K, Kubota R, Talkeda S, Matsuzawa T. Effects of age and sex of host mice on growth and differentiation of teratocarcinoma OTT60–50. Exp Gerontol 1984; 16:371–84. 117. Yuhas JM, Pazimo NH, Proctor JO, Toya RE. A direct relationship between immune competence and the subcutaneous growth rate of a malignant murine long tumor. Cancer Res 1974; 34:722–8. 118. Rockwell S. Effect of host age on the transplantation, growth and radiation response of EMT6 tumor. Cancer Res 1981; 41:527–31. 119. Stjernsward J. Age-dependent tumor-host barrier and effect of carcinogen-induced immunodepression on rejection of isografted methylcholanthrene-induced sarcoma cells. J Natl Cancer Inst 1966; 37:505–12. 120. Flood PM, Urban JL, Kripke ML et al. Loss of tumor specific and idiotype specific immunity with age. J Exp Med 1980; 154:275–90.

13 Immunological changes of aging Edith A Burns, James S Goodwin Introduction Immunological function declines with age, as do most physiological functions. As the reader will find by perusing other chapters in this volume, the incidence of many malignancies increases with increasing age, with greater associated mortality in adults over 65. At the same time, the invasive characteristics of many cancers are often different in old adults compared with young adults. Are the age-related changes in immunity responsible, at least in part, for the changing epidemiology of malignancy with increasing age? This chapter will give a basic outline of the immune system, and then describe changes in the system attributed to aging. Organization of the immune system The immune system provides a major protective defense against a variety of insults. The cellular immune response (Figure 13.1) is described as rejecting grafts of foreign tissues, killing virus-infected cells, some intracellular parasites, and fungi. It also prevents autoimmunity, and may play a defensive role against the growth of tumors. Many of these responses are mediated primarily by T lymphocytes (‘T’ for ‘thymus-derived’). The humoral immune system produces antibodies (manufactured by differentiated B lymphocytes—‘B’ for ‘bone marrow-

Comprehensive Geriatric Oncology

284

Figure 13.1 Model of the cellular immune system. Ag, antigen; CTL, cytotoxic T lymphocyte; IFN, interferon; IL, interleukin; IL-2R, interleukin-2 receptor; M, macrophage/monocyte; PGE2, prostaglandin E2; TH, T helper (CD4+) lymphocyte; THM, T helper memory lymphocyte; TS, T suppressor (CD8+) lymphocyte; TSM, T suppressor memory lymphocyte; TV, virgin T lymphocyte; TNF, tumor necrosis factor.

Immunological changes of aging

285

Figure 13.2 Model of the humoral immune system. Ag, antigen; B, B lymphocyte; BM, B memory lymphocyte; IFN, interferon; IL, interleukin; M, macrophage/monocyte; PGE2, prostaglandin E2; TH, T helper (CD4+) lymphocyte; TS, T suppressor (CD8+) lymphocyte; TSM, T suppressor memory lymphocyte. derived’), which are the main defense against bacteria and other infectious agents (Figure 13.2). Cells of the monocyte-macrophage series play an important regulatory role in both

Comprehensive Geriatric Oncology

286

humoral and cellular immune responses, and a direct role in ingesting and/or killing foreign material. The distinction between cellular and humoral immunity is somewhat artificial, because both B and T cells can participate in each reaction. While T cells are the effectors of cellular immune responses, they are also required for the great majority of humoral (antibody) responses. B cells can act as antigen-presenting cells (APC) in cellular immune responses, in addition to their antibody-producing function. Antibodies can be major participants in specific cytotoxic responses. As the details of the age-related changes in immunity have become increasingly revealed, it is easier to categorize them as quantitative or qualitative changes in cell populations, and production of or response to macromolecules, rather than as changes in cellular versus humoral immunity. General evidence for the importance of decreased immunity with age One of the major postulated roles of the immune system is protection against the development of malignancy. For example, the concept of ‘immune surveillance’ proposes that the cellular immune system is the first defense against cancer, monitoring the body and eliminating new malignancies that are popping up every day.1,2 A corollary of this theory is that clinical cancer represents a failure of immune surveillance. Thus, elderly persons or other individuals with depressed immune function should have a higher incidence of malignancy. The lack of a generalized increase in most malignancies among immunosup-pressed humans and experimental animals has thrown this theory into relative disrepute. Although the epidemiological data does not support the immune surveillance theory unconditionally, this does not mean that intact immune function is unimportant for continued health. The AIDS epidemic has highlighted the disastrous consequences of impaired immunity. While direct links between decreased immune responses and cancer in elderly persons have not been shown, a relation between depressed immunity and morbidity/mortality has been sought by looking for associations between abnormalities in a particular immune response and health status. For example, Bender et al3 reported that declines in absolute lymphocyte counts predicted mortality after 3 years in aging men participating in the Baltimore Longitudinal Study. Several studies have found a correlation between the response to delayed-type hypersensitivity skin tests and mortality. Elderly subjects who are anergic (responding poorly or not at all to a battery of antigens placed intradermally) have an increased risk of mortality compared with elderly subjects who respond vigorously to one or more of these antigens.4,5 In our studies of healthy elderly individuals in New Mexico, we found about a twofold higher mortality rate and a twofold higher incidence of pneumonia during 8 years of follow-up in the third of the group that was anergic at initial testing.5,6 Ferguson and co-workers found that poor survival over 2 years in a group of adults over the age of 80 was related to the presence of two or more suppressed immune parameters.7 Lymphocyte proliferation in response to mitogens is the in vitro correlate of delayed hypersensitivity skin testing. Decreased lymphocyte proliferation has also been associated with a significantly greater all-cause mortality rate among those with a low degree of response compared with those with a vigorous proliferative response.8,9

Immunological changes of aging

287

Although proliferation in response to mitogen stimulation has been considered an in vitro correlate of delayed hyper-sensitivity skin testing, these studies showed a poor (though significant) correlation between the two assays (r=0.18, p<0.01) and there was poor correlation from year to year for any given individual in mitogen response (r=0.55).9 Another marker for disturbed immune status is the presence of circulating autoimmune antibodies. The presence of autoantibodies in a community-based study of Australian adults was associated with an increased risk of death due to vascular disease and cancer during 6 years of follow-up.10 Changes in immune function with age: Iymphocytes T lymphocytes Although early reports of changes in the number of T cells with aging are variable (reviewed by Miller11), studies using monoclonal antibodies to specific T-lymphocyte receptors have shown consistent increases in the number of ‘memory’ or inert T cells and declines in the number of ‘Virgin’ or reactive T cells in many species with advancing age.11,12 One of the earliest reports of age-related changes in qualitative T-lymphocyte function concerned the decline in proliferative response to mitogens.4,8,13,14 Our study of 300 healthy elderly people showed a substantial decrease in response to all doses of the mitogen phytohemagglutinin (PHA) with age.6 PHA responses measured in 24 chronically ill elderly people were not different from those of the healthy group. Thus, age per se, and not an accompanying illness, was the major determinant of depressed cellular immunity in this population. Hyporesponsiveness to mitogens such as PHA is the sum of at least two deficiencies. First, the number of cells responding to mitogen is reduced in lymphocyte preparations from elderly persons.13 Second, the mitogenresponsive cells do not proliferate as vigorously as lymphocytes from young persons.13 In murine models, smaller percentages of T splenocytes from old mice respond to mitogenic stimulation by entering active phases of cell replication.15 This defect was noted on both CD4+ T helper cells and, to a lesser extent, on CD8+ T suppressor/cytotoxic cells. T helper cells from old mice are less capable of generating cytotoxic effector cells to participate in delayed hypersensitivity reactions.16 Cytotoxic lymphocytes from aged mice are less efficient at binding targets, although they appear to be equally effective in destroying their targets.17 The role of T lymphocytes in supporting antibody production in vitro appears to change with increasing age. Lymphocytes from older subjects produce greater amounts of IgG and IgM when cultured with pokeweed mitogen than lymphocytes from young control subjects,18 and old T cells are more capable than young T cells of

Comprehensive Geriatric Oncology

288

Table 13.1 Changes in T lymphocytes with age Decreased

Increased

• Number of virgin (reactive) T cells

• Number of memory (inert) T cells

• Number of mitogenresponsive cells

• T-cell help for non-specific antibody production

• Stem cell generation of T cells • Proliferative response • Expression of early activation genes • Sensitivity to activating signals • Cytotoxic cell target-binding • Suppressor cell function • Help for generation of cytotoxic effector cells • T-cell help for specific antibody production

supporting immunoglobulin production by either young or old B cells.19,20 This increased helper activity of old T cells is due at least in part to a failure of suppressor cell function.18 Failure of suppressor T cells to provide tonic inhibition is a possible mechanism accounting for the increased incidence of autoimmune antibodies seen in aging.6,19 Healthy humans have circulating B cells that are programmed to differentiate into autoantibody-producing plasma cells (producing antinuclear, antithyroid, antimitochondrial, and other antibodies). Suppressor T cells modulate these normal humoral immune responses and prevent the development of autoimmunity. Many investigators have reported an increase in the prevalence of positive tests for various autoantibodies with age, with a steep rise in prevalence at around age 70.6,21 The presence of elevated autoantibodies in elderly persons has been correlated with decreased T-cell proliferation in response to the mitogen PHA22 (i.e. the greater the proliferation of T cells to mitogens, the lower the level of autoantibodies). Studies of T suppressor cells in aging humans and mice have described decreased proliferation and suppressor function, and enhanced development of oral tolerance.18,23,24 Age-related changes in T lymphocytes are summarized in Table 13.1. B lymphocytes Although the number of circulating B cells does not change appreciably with age,25 the ratios of surface immunoglobulins and major histocompatibility complex (MHC) class II molecule expression are altered.26 Early murine studies showed age-related structural changes in B-cell membranes,27 and an impaired ability to generate B cells.28

Immunological changes of aging

289

The functional ability of B cells to mount appropriate antibody responses does change with age.29 The distinction between antibody responses to T-cell-dependent and T-cellindependent antigens (often made in mice, but less clear in humans) is made on the basis of whether there is an absolute requirement for T-cell help in the antibody response. In experimental animal models, there is an 80% decrease in T-cell-dependent antibodyforming cells in older animals.11 The accumulation of anti-idiotypes (antibodies directed against other antibodies) with increasing age may also interfere with the production of specific antibody.30 The ability to respond to specific challenge with either a novel (primary) or a familiar (secondary) antigen with specific antibody production is decreased with aging.29 When subjects of different ages were immunized with the primary antigen flagellin, both old and young responded with similar levels of anti-flagellin antibody, but the older subjects were unable to maintain the response.31 We studied a group of healthy older adults participating in a larger study of emotions and health behavior, and found they were less likely than a group of healthy young control subjects to mount an in vivo response to immunization with the primary antigen keyhole limpet hemocyanin (KLH) (unpublished data). In contrast, a study by De Greef et al32 utilized aged subjects meeting rigorous inclusion criteria to qualify as healthy.33 Old and young subjects immunized with the primary antigen Helix pomatia hemocyanin had comparable numbers of antibodyproducing cells in culture with in vitro stimulation by the antigen.32 In secondary immune responses, serum antibody levels are significantly lower in older than in younger adults following in vivo immunization with influenza vaccine and tetanus toxoid.34–37 Kishimoto et al35 studied specific anti-tetanus toxoid antibody production, and found that B cells from adults over the age of 65 made significantly less antibody than those from younger subjects. We have also examined in vitro tetanus toxoid-specific antibody production by lymphocytes from elderly humans.36 Old adults had significantly lower serum levels of antibody to tetanus toxoid, regardless of the time elapsed since the last booster immunization. In vitro, old adults had fewer numbers of B cells producing anti-tetanus toxoid antibody, and each cell produced significantly less antibody than the B cells from young adults. The estimated number of anti-tetanus toxoid precursor cells in the peripheral blood of the older subjects was more than a log magnitude lower than in younger subjects. Thus, the lack of precursor cells with the ability to respond to a specific antigen was primarily responsible for the decreased specific antibody production against tetanus toxoid.36 Immunizing the subjects with tetanus toxoid led to an increase in the numbers of B cells producing anti-tetanus toxoid antibody, but the old adults still had significantly fewer B cells producing specific antibody than did

Comprehensive Geriatric Oncology

290

Table 13.2 Changes in B lymphocytes with age • Decreased surface major histocompatibility complex (MHC) class II molecule expression • Decreased proportion of cells capable of clonal expansion • Decreased number of bone marrow precursors • Decreased number of T-cell-dependent antibody-forming cells • Decreased specific antibody production to primary and secondary antigens • Decreased potency • Decreased antigen recognition • Decreased affinity of antibody for targets • Increased anti-idiotypic antibody production

the young adults.37 Booster immunizations did not alter the mean amount of antibody produced per B cell for either age group. Although most of the changes in antibody production described above are the result of declines in T-lymphocyte function, there is some evidence for a decline in intrinsic B-cell function. Findings from our laboratory and others suggest a diminished ability of purified B cells to respond to isolated T helper cells or to T-cell-derived helper factors.19,38,39 This raises the possibility that the age-related changes in helper and suppressor T-cell function might represent a homeostatic mechanism to maintain immunoglobulin production in the face of a failing B-cell compartment. Age-related changes in B-cell function are summarized in Table 13.2 Macrophage function Macrophage function in aging is less well studied than that of other leukocyte subpopulations. Macrophages from old and young adults appear to produce similar levels of cytokines,40,41 and some differences in immune function between age groups may be modulated through changes in T- and B-cell responses to these substances. However, other studies have suggested that macrophage function is indeed altered with aging. Wound healing, a process regulated by macrophages, was shown to take twice as long in old mice as in young mice.42 Adding peritoneal macrophages from young or old animals to wounds on old mice sped healing, but macrophages from young mice accelerated the healing process to a greater degree.42 Bone marrow stem cells in senescence-accelerated mice seem to be defective in their ability to generate granulocyte-macrophage precursor cells.43 Defects in macro-phage-Tcell interactions in old humans have been described by Beckman et al,44 who noted enhanced T-cell responses when macrophages from old adults were replaced with other sources for activation, such as interleukin-2 (IL-2), or an activator such as phorbol 12myris-tate 13-acetate (PMA). Because ‘old’ macrophages effectively supported ‘young’ T cells, the defect was postulated to lie in macrophage-T-cell communication. Monocytes from old adults displayed less cytotoxicity against certain tumor cell lines and decreased

Immunological changes of aging

291

production of reactive oxygen intermediates (H2O2 and NO) than monocytes from young adults,45 and lower IL-1 secretion than monocytes from young adults.46 These findings of decreased secretion were observed when monocytes were stimulated with non-specific mitogens.45,46 Natural killer cells Natural killer (NK) cells differ from cytotoxic T cells in their ability to lyse targets without the need for antigenic sensitization. Lymphokine-activated killer (LAK) cells are highly activated NK cells, able to lyse certain cell lines that are resistant to NK cells. Murine NK cells display an age-related decline in their ability to lyse spleen cells.47,48 Many early studies found no change in NK cytotoxic ability,49 though other studies contradict these findings. The numbers of NK cells appear to increase with age, but NK activity decreases.50,51 Expression of Ly-49 receptors, which downregulates NK activation, is increased in cells from old animals.52 There also may be different requirements for maximal activation of NK cells by interferon-α (IFN-α), with young cells showing maximal responses at lower concentrations.53 Elderly growth hormonedeficient patients have lower NK activity, which can be partially restored in vitro by exposing NK cells to the growth hormone precursor protein.54 The activity of LAK cells also appears to be reduced in aged compared with young humans.49,50 Defects in lymphocyte ability to repair DNA T cells from old adults have X chromosomes that are more fragile than those from young adults, and certain sites on the X chromosome have been shown to be more sensitive to chemical insults.55 Humans over the age of 55 exposed to radiation have lymphocytes that mount poor cellular responses compared with humans exposed to radiation when under the age of 15.56 Such differences may reflect the increased susceptibility of the aging immune system to radiation. When lymphocytes from old adults were exposed to radiation in vitro, there were actually fewer breaks in double-stranded DNA, but the cells had a significantly reduced ability to repair the breaks compared with lymphocytes from young donors.57 The basal frequency of sister chromatid exchange, a measure of DNA damage, was 10 times greater in lymphocytes from healthy old individuals than from newborns.58 Lymphocyte activation, membrane signal transduction, and membrane fluidity A complex set of interactions involving T cells and macrophages or other accessory cells results in a proliferative response of T cells to various stimuli. Mitogens such as PHA activate T cells by binding and crosslinking T-cell antigen receptors. This in turn activates phospholipase C (PLC), leading to cleavage of membrane phosphatidylinositol phosphates and liberation of inositol bisphosphate and diacylglycerol (DAG). Inositol bisphosphate and its metabolites inositol trisphosphate and tetrakisphosphate raise intracellular free calcium concentrations by releasing bound calcium from intracellular stores and opening calcium channels.59–61 DAG binds to and activates protein kinase C

Comprehensive Geriatric Oncology

292

(PKC), which is further activated by the increased free calcium concentration. At least two families of protein kinases—protein phosphate kinases and protein tyrosine kinases—play a role in cell activation. Protein kinase activation leads to increased transcription and subsequent translation of the gene coding for IL-2 (also known as T-cell growth factor) and of IL-2 receptors (IL-2R). IL-2 is an example of an autocrine growth factor, produced by the same cells that respond to it. T cells bearing IL-2R that are exposed to IL-2 will prolifer-

Figure 13.3 Model of T-cell activation. APC, antigen-presenting cell; DAG, diacylglycerol; IL, interleukin; IL-2R, interleukin-2 receptor; IP2, inositol bisphosphate; IP3, inositol trisphosphate; MHC II, major histocompatibility complex class II molecule; N, nucleus; PKC, protein kinase C; PLC, phospholipase C; PPK,

Immunological changes of aging

293

protein phosphate kinase; PTK, protein tyrosine kinase. ate. APC, such as macrophages, secrete a variety of cytokines that provide additional signals necessary for complete T-cell activation (Figure 13.3) Calcium mobilization is an indicator of membrane signal transduction in lymphocytes. Several laboratories have found an association between decreased calcium metabolism and defective proliferation in T cells from some mouse strains with old age.12,62 T lymphocytes that retain the ability to proliferate to mitogen have normal or enhanced mobilization of calcium compared with cells from young animals.63 Studies of human peripheral blood lymphocytes and isolated T cells have shown conflicting results, suggesting that decreased calcium mobilization is a factor in poor proliferation of some cell subpopulations but not others.11,24,64 Jackola and Hallgren65 found decreased cell-cell binding in monocyte-depleted lymphocytes from old compared with young donors, a calcium/magnesium-dependent reaction. This was felt to be secondary to altered activation of the lymphocyte adhesion molecule leukocyte function-associated antigen 1 (LFA-1) in the cells from old adults. Conflicting results have been observed in studies of membrane fluidity of lymphocytes, with no differences seen on comparing cells from young versus old adults,66 in contrast to decreased fluidity of red blood cell membranes correlating with decreased immune responses in old adults.30 Responses to immunoregulatory factors Prostaglandins Arachidonic acid metabolites, particularly the prostaglandins, have been strongly implicated in age-related changes in humoral immunity. Prostaglandin E2 (PGE2) is a feedback inhibitor of T-cell proliferation in humans,67 and T cells from adults aged over 70 are much more sensitive to inhibition by PGE2.14,68 PGE2 may play a role in some of the previously described age-related immune changes by interfering with the expansion of antigen-specific T-cell helper clones. In addition to increased sensitivity to the inhibitory effects of PGE2, studies have shown increases in PGE2 production by splenocytes from old mice compared with young mice.69 Increased sensitivity to PGE2 has been associated with impaired antibody production stimulated by a primary antigen.40 Removing monocytes (the source of PGE2 production) or adding drugs that blocked the PGE2 production partially reversed the depressed response of older subjects.14,40 There does not appear to be a general increase in sensitivity to all immunomodulators with increasing age; for example, lymphocytes from subjects aged over 70 are actually less sensitive to inhibition by histamine and hydrocortisone than are lymphocytes from young control subjects.68 Interleukins

Comprehensive Geriatric Oncology

294

The accessory cells that crosslink T-cell receptors secrete IL-1 and other cytokines that provide additional signals necessary for complete activation of T cells (Figure 13.3). The response to IL-2 has been extensively studied as one mechanism underlying the agerelated defect in cellular immunity. Lymphocytes from old humans and animals demonstrate decreased production of IL-2 after mitogen stimulation, decreased density of IL-2R expression, and decreased proliferation of these cells in response to IL-2.70–74 Additional experiments in rodents suggest that the picture might be more complex, with specific defects in production of or sensitivity to IL-2 depending on the immunological stimulus.75,76 Defects in the expression of mRNA for IL-2 have been described in lymphocytes from aged rats.77 IL-1 and IL-2 are important in the activation, recruitment and proliferation of T lymphocytes. Activated T cells go on to produce a variety of cytokines, including B-cell growth and differentiation factors such as IL-4 and IL-6. Age-related defects in lymphocyte production and response to other cytokines in aging, such as IL-1 and tumor necrosis factor (TNF), have been described.11,78 The stimulatory response seen when IL-4 is added to lymphocytes from young mice is not apparent in lymphocytes from old animals.79 The B-cell proliferative response to IL-4 and anti-IgM is significantly lower in old mice than in young mice.80 We have shown that IL-4 production stimulated by specific antigen is lower in lymphocytes from old adults than in lymphocytes from young adults.81 Lymphocytes from old adults are less sensitive to inhibi- tion of specific antibody production when IL-4 is added early in the course of stimulation with specific antigen.81 Other investigators found no differences between lymphocytes from old and young adults in their ability to produce IL-4 or IL-6 when stimulated with the mitogen PHA.82 However, lymphocytes from the old adults produced significantly less IFN-γ in this model.82 Several investigators have described elevated in vivo levels of IL-6 in old mice, monkeys, and humans.83–85 Urinary levels of IL-6 were increased in old compared with young adults, although circulating levels were similar in both age groups.86 These findings were felt to be due to differential renal production or handling of IL-6 with age. Peritoneal macrophages from old mice produce higher levels of IL-6 than do macrophages from young mice when stimulated with the mitogen lipopolysaccharide (LPS).87 IL-6 levels are elevated in 24-hour unstimulated culture supernates of lymphocytes from murine spleen and lymph nodes, and cultures of peripheral blood mononuclear cells from old humans compared with their young counter-parts.83 Changes in production of the neutrophil chemoat-

Table 13.3 Changes in interleukins with age Decreased

Increased or unchanged

Expression of IL-2 mRNA

In vivo levels of IL-6

Proportion of cells expressing IL-2R

Non-specific stimulation of T-cell IL-4 and IL-6

High-affinity binding sites for IL-2

Non-specific stimulation of T-cell IFN-γ and IFN-γ mRNA

T-cell production/secretion of IL-2

Memory T cell production of IL-2

Immunological changes of aging

295

T-cell proliferative response to IL-2

Lymphocyte production of IL-1 in MLC

Memory T-cell production of IL-4

Lymphocyte production of IL-5 (?)

Sensitivity to IL-4

Lymphocyte production of IL-10

B-cell sensitivity to IL-4 Non-specific stimulation of lymphocyte-produced IL8 Monocyte secretion of IL-1 IL-2-stimulated NK-cell production of IFN-γ IL-12 production in Mycobacterium tuberculosisinfected mouse lungs IL, interleukin; IL-2R, IL-2 receptor; IFN, interferon; MLC, mixed lymphocyte culture.

tractant IL-6 have been described in old compared with young adults. Lymphocytes from old adults produced less IL-6 spontaneously—a difference that appeared to be due primarily to unresponsiveness of cells from old male donors.88 When the lymphocytes were stimulated with LPS, cells from the old men increased IL-8 production over eightfold, while cells from old women showed no increase. Lymphocytes from young subjects of both genders increased production, but to a much smaller degree.88 Old mice displayed increased susceptibility to Mycobacterium tuberculosis infection, associated with lower levels of IL-12 in the lung.89 This defect was postulated to be related to decreased CD4+ T-cell function.89 The old animals had a delay in the emergence of protective, IFN-γ-secreting CD4+ T cells.90 The cells that eventually emerged were slower to express surface adhesion markers that allow migration across endothelial linings to sites of active infection.90 Alterations in other cytokines with aging may also contribute to the increased spread of disease in old animals.91 The major defect seems to lie in the T-cell population, since CD4+ cells from young mice protect old mice from infection, suggesting adequate function of old macrophages.92,93 Age-related changes in interleukins are summarized in Table 13.3. As discussed in other chapters in this volume, many of the macromolecules mentioned above play important roles in regulating tumor growth. Some of the characteristics of malignancies peculiar to older adults may result from altered production and/or sensitivity to these substances. Stress, immunity, and aging The neurohumorally mediated effects of stress on the immune system have been well demonstrated in carefully controlled experiments with animals.94,95 Levels of cortisol and complement factors in primates are profoundly affected by a single stressful event.96 Studies in humans have demonstrated similar effects, although it is impossible to achieve the same degree of control as in animal studies. Clusters of illness (from the common cold to cancer) have been correlated with the occurrence of major life changes.97 Strong

Comprehensive Geriatric Oncology

296

correlations have been demonstrated between loneliness and decreased proliferative responses of lymphocytes to mitogens, decreased NK-cell activity, and impaired DNA splicing and repair in lymphocytes.97,98 We found that healthy old adults with a strong social support system (i.e. a close confidant) had significantly greater total lymphocyte counts and a stronger mitogeninduced proliferation of lymphocytes than those without such a relationship.99 Indeed, being married has been correlated with lower mortality from any cause, in contrast to being single, widowed, or divorced.100 Quasi-experimental observations have also linked stress to depressed immune function and illness.101 Depressed lymphocyte proliferation in response to mitogens has been demonstrated after bereavement,102 although links between depressed immunity and depression are variable.103 The stress of final examinations has been correlated with the recurrence of herpes simplex type I cold sores and rises in serum antibody titers against the virus.104 Persons experiencing the stress of caring for a spouse with dementia have poorer antibody responses to influenza vaccination than age- and sex-matched controls, and their lymphocytes make less IL-1β and IL-2 when exposed to influenza virus in vitro.105 Caregivers also show delayed wound healing after skin punch biopsy compared with controls.106 Correlations have also been found between psycholog- ical factors and tumor progression in adults with cancer. Levy et al107 found that women reporting more depression and apathy in response to breast cancer had poor NK-cell function and were more likely to have positive axillary lymph nodes. Speigel et al108 reported that women with metastatic breast cancer who participated in special emotional support therapy lived significantly longer than individuals with equivalent cancers who did not participate in such groups. Old age is associated with a greater frequency of major life changes, such as loss of spouse or close friends, and changes in lifestyle due to retirement. Because of the decreased reserve in immune function with aging, elderly persons may be more sensitive to the effects of these stressful life events. Underlying mechanisms and reversal of age-related immune decline Many of the age-related changes in immunity that have been described involve different systems and do not appear to be synchronized with each other.11,34 Defects can be seen at varying levels in different systems within a given individual. Immunomodulatory substances may affect only some systems and not others. There are complex interactions between the nervous, endocrine, and immune systems, although no ‘global’ mechanism has yet been found that might be the common underlying cause.109 As suggested by Ershler,110 in situations where immune mechanisms appear important for disease manifestation, age-related immune senescence may be of clinical significance.110 Studies linking disordered immune function with subsequent morbidity and mortality are suggestive but inconclusive. Many hormones appear to influence the immune system, and production of most of these substances declines with age. This has led to investigators studying these hormones as potential causes of age-related declines in immune function. One of the earliest changes occurring in the aging immune system is involution of the thymus, with

Immunological changes of aging

297

subsequent loss of thymic hormone influences and declines in T-cell function. The loss of thymic mass begins in adolescence, with a decrease in mass of up to 90% and a decreased output of thymic hormones.111 In spite of this involutional process, the remaining thymic tissue from old animals maintains its ability to generate new T cells.112 Thymectomy leads to acceleration of normal age-related changes in immune function in mice, suggesting that thymic involution may indeed be a central aspect of age-related immunodeficiencies. Lymphocytes of old individuals exposed to thymic hormones either in vivo or in vitro evidence at least a partial restoration of immunity on a temporary basis.113–117 Thymic hormones have also increased the resistance of aged mice to cutaneous Leishmania infection.118 Several other hormonal substances whose in vivo production declines with age have been studied for their potential to reverse age-related immune changes. Melatonin is a pineal hormone with free-radical-scavenging and antioxidant properties, and its production declines with increasing age.119 Administration of melatonin to old mice increased antibody production, T helper cell activity and IL-2 production.120 Administering IL-2 plus melatonin to humans prior to surgical treatment of gastrointestinal cancer resulted in increased numbers of T cells, T helper cells, and total lymphocytes after surgery.121 The combination of IL-2 and melatonin appeared to result in at least partial tumor regression and enhanced 1 -year survival of patients with some metastatic solid tumors compared with supportive care alone.122 Growth hormone and its precursor, insulin-like growth factor I (IGF-I), have immuneenhancing effects. These substances stimulated phagocytes and production of cytokines, which may help protect against bacterial infection.123 Growth hormone-deficient old patients have lower NK activity, and this can be partially restored by exposing NK cells to growth hormone precursor protein in vitro.50 In contrast, administering growth hormone to non-deficient, healthy old women for 6 months did not change the proliferative responses of lymphocytes or the mean number of virgin T cells compared with untreated controls.124 Dehydroepiandrosterone (DHEA) is the most abundantly produced adrenal steroid, and is another substance whose endogenous levels decline with age. When DHEA is administered in vivo, it augments antibody production by upregulation of T-cell subsets associated with increased antibody production.125 Aged mice pretreated with DHEA display enhanced responses to vaccination with hepatitis B surface antigen (HBsAg) and influenza, as well as increased resistance to infection with influenza.126,127 Old humans who received oral DHEA before influenza vaccination displayed a fourfold increase in hemagglutinin inhibition titers compared with untreated elderly individuals.128 Another potential explanation of age-related immune decline involves the role of cellular oncogenes and tumor suppressor genes. Activation of oncogenes and loss of tumor suppressor genes has been associated with the progression of malignant lesions over long periods of time.110 These genes are postulated to play a role in the development of malignancies through regulation of cell growth and differentiation. Hybrid cells created from senescent cells and immortalized cell lines have finite lifespans, a property felt to be controlled by tumor suppressor genes.129 Thus, the latter genes may play a role in immune senescence and contribute to tumor vulnerability. Often the most intriguing scientific discoveries are those that are without obvious practical consequences. A prime example was the discovery by McCay and his

Comprehensive Geriatric Oncology

298

colleagues130 in 1935 that caloric restriction of experimental animals markedly prolonged their lifespan. Restricting total caloric intake to 50–60% of what was required to maintain normal growth in adolescent mice, rats, and guinea pigs resulted in approximately 50% prolongation of the total lifespan of animals that survived the 6- to 12-month period of starvation. This interesting medical oddity received little attention over the next three decades until other investigators showed that early starvation of experimental animals resulted in a preservation of normal immune function into old age.131 Similar effects have been observed with lesser degrees of caloric restriction.132,133 In contrast to the studies on protein-calorie restriction in animals, nutritional deficiencies in humans are generally associated with poor immune responses.134 In both nutritionally deficient and healthy elderly adults, caloric supplements and supplementation with vitamins and trace elements have been associated with enhanced immune responses, better responses to vaccines, and fewer days of infectious illness.135,136 Older men ingesting a diet high in polyunsaturated fatty acids had significant declines in NK activity, providing ‘reverse’ support for the role of nutrition in immune compromise.137 Antioxidants have been extensively studied as potential anticancer and ‘anti-aging’ treatments. Some of the most intriguing data involve the effects of vitamin E administration on immune function in old experimental animals and, more recently, in older men and women.138,139 For example, supplementation with 400–800 U of vitamin E in healthy elderly subjects resulted in enhanced responses to delayed-type hypersensitivity skin testing, and increased in vitro production of IL-2.140,141 Vitamin E may cause these effects via inhibition of suppressive factors such as PGE2.138 The most dramatic demonstration of the effects of antioxidants on immunity was in a report by Chandra,136 who conducted a placebo-controlled, double-blinded trial of vitamin supplementation in healthy older men and women. Subjects in the experimental group received a multivitamin supplement containing the recommended daily allowance for most vitamins with the exception of vitamin E and β-carotene, which were at about four times the upper quartile of usual intakes. Vitamin supplementation was associated with marked increases in various parameters of immunity, and only half the number of days with infection and 60% of the days taking antibiotics during the 1-year trial.136 If these remarkable results can be reproduced in other populations, it will have major implications for recommendations on appropriate intake of the antioxidant vitamins. Although two large studies looking at antioxidant supplementation found a higher incidence of lung cancer in heavy smokers taking (β-carotene, vitamin E supplementation was not related to an increased incidence of lung cancer.142,143 Other potential pharmacological agents that might stimulate immune function include prostaglandin synthetase inhibitors, such as non-steroidal anti-inflammatory drugs (NSAIDs). By reducing the production of the feedback inhibitor PGE2, NSAIDs stimulate immune responses.67 For example, we found that two completely anergic patients with adult-acquired immunodeficiency became responsive to delayed-type hypersensitivity skin testing when they were treated with the cyclooxygenase inhibitor indomethacin.144 Aspirin administration enhanced specific antibody production to A/Beijing after influenza immunization in adults over the age of 75.145 Such therapeutic strategies might be especially relevant to elderly persons, because their T cells are more sensitive to inhibition by PGE2.14 The use of prostaglandin synthetase inhibitors in aged individuals might also reduce increased autoantibody production,146 while stimulating the

Immunological changes of aging

299

primary antibody response to new antigens.22 The potential benefits of such treatment would have to be weighed against the risk of adverse reactions to NSAIDs, especially since older adults are at higher risk for experiencing such adverse effects. Psychological interventions have been successful in reversing stress-induced suppression of immune function. Writing about traumatic events or participating in simple relaxation exercises has been associated with enhancement of measured immune responses.147,148 The duration of effect has not been explored, and the mechanisms underling such associations are not well understood. The modes of immunostimulation discussed above are representative of the many therapies that have been proposed and/or tested. While it is difficult to justify medical intervention in a healthy individual with a disordered laboratory parameter, studies of nutrition and immunity and of stress and immunity suggest the possibility of benign interventions that may have a significant impact on the health status of elderly individuals.136 Cancer and aging are both characterized by immunosuppression, and the combination of both conditions may have a synergistic effect on the morbidity and mortality associated with malignancy. Continued investigations into the mechanisms of age-associated immune decline, as well as tumor-associated immunosuppression, may well lead to the development of successful interventions to prevent negative effects associated with the disordered immunity of aging. References 1. Burnet FM. The concept of immunological surveillance. Prog Exp Tumor Res 1970; 13:1–27. 2. Thomas L. Reactions to homologous tissue antigens in relation to hypersensitivity. In: Cellular and Humoral Aspects of the Hypersensitivity States (Lawrence HS, ed). New York: HoeberHarper; 1959: 529–32. 3. Bender BS, Nagel JE, Adler WH et al. Absolute peripheral blood lymphocyte counts and subsequent mortality of elderly men. J Am Geriatr Soc 1986; 34:649–54. 4. Roberts-Thompson IC, Whittingham S, Young-Chaiyud U et al. Aging, immune response and mortality. Lancet 1974; ii: 368–70. 5. Wayne S, Rhyne R, Garry P et al. Cell mediated immunity as a predictor of morbidity and mortality in the aged. J Gerontol 1990; 45:45–9. 6. Goodwin JS, Searles RP, Tung KSK. Immunological responses of a healthy elderly population. Clin Exp Immunol 1982; 48:403–10. 7. Hess EV, Knapp D. The immune system and aging: a case of the cart before the horse. J Chronic Dis 1978; 31:647–9. 8. Murasko DM, Weiner P, Kaye D. Association of lack of mitogeninduced lymphocyte proliferation with increased mortality in the elderly. Aging Immunol Infect Dis 1988; 1:1–6. 9. Goodwin JS. Decreased immunity and increased morbidity in the elderly. Nutr Rev 1995; 53: S41–6. 10. Ansbacher R, Keung-Yeung K, Wurster JC. Sperm antibodies in vasectomized men. Fertil Steril 1972; 23:640–3. 11. Miller RA. Aging and immune function. Int Rev Cytol 1991; 124: 187–215. 12. Philosophe B, Miller RA. Diminished calcium signal generation in subsets of T lymphocytes that predominate in old mice. J Gerontol 1990; 45: B87–93. 13. Inkeles B, Innes JB, Kuntz MM et al. Immunological studies of aging, III: Cytokinetic basis for the impaired response of lymphocytes from aged humans to plant lectins. J Exp Med 1977; 145:1176–87.

Comprehensive Geriatric Oncology

300

14. Goodwin JS, Messner RP. Sensitivity of lymphocytes to prostaglandin E2 increases in subjects over age 70. J Clin Invest 1979; 64:434–9. 15. Ernst DN, Weigle WO, McQuitty DN et al. Stimulation of murine T cell subsets with anti-CD3 antibody: age-related defects in the expression of early activation molecules. J Immunol 1989; 142: 1413–21. 16. Vissinga C, Nagelkerken L, Sijlstra J et al. A decreased functional capacity of CD4+ T cells underlies the impaired DTH reactivity in old mice. Mech Ageing Dev 1990; 53:127–39. 17. Gottesman SRS, Edington J. Proliferative and cytotoxic immune functions in aging mice. V. Deficiency in generation of cytotoxic cells with normal lytic function per cell as demonstrated by the single cell conjugation assay. Aging Immunol Infect Dis 1990; 2:19–29. 18. Kishimoto S, Tomino S, Mitsuya H et al. Age-related changes in suppressor functions of human T cells. J Immunol 1979; 123: 1586–92. 19. Rodriguez MA, Cueppens JL, Goodwin JS. Regulation of IgM rheumatoid factor production in lymphocyte cultures from young and old subjects. J Immunol 1989; 128:2422–8. 20. Crawford J, Oates S, Wolfe LA, Cohen HJ. An in vitro analogue of immune dysfunction with altered immunoglobulin production in the aged. J Am Geriatr Soc 1989; 37:1141–6. 21. Delespesse G, Gausset PH, Sarfati M et al. Circulating immune complexes in old people and in diabetics: correlation with autoantibodies. Clin Exp Immunol 1980; 40:96–102. 22. Hallgren H, Buckley C, Gilbertson V et al. Lymphocyte phytohemagglutinin responsiveness, immunoglobulins, and autoantibodies in aging humans. J Immunol 1973; 111:1101–7. 23. Grossmann A, Ledbetter JA, Rabinovitch PS. Reduced proliferation in T lymphocytes in aged humans is predominantly in the CD8+ subset and is unrelated to defects in transmembrane signaling which are predominantly in the CD4+ subsets. Exp Cell Res 1989; 180: 367–82. 24. Kawanishi H, Ajitsu S, Mirabella S. Impaired humoral immune responses to mycobacterial antigen in aged murine gut-associated lymphoid tissues. Mech Ageing Dev 1990; 54:143–61. 25. Makinodan T. Biology of aging: Retrospect and prospect. In: Immunology and Aging (Makinodan T, Yunis E, eds). New York: Plenum Press, 1977:1–8. 26. Subbarao B, Morris J, Kryscio RJ. Phenotypic and functional properties of B lymphocytes from aged mice. Mech Ageing Dev 1990; 51: 223–41. 27. Callard R, Basten A, Blanden R. Loss of immune competence with age may be due to a qualitative abnormality in lymphocyte membranes. Nature 1979; 281:218–21. 28. Zharhary D. Age-related changes in the capability of the bone marrow to generate B cells. J Immunol 1988; 141:1863–69. 29. Delafuente JC. Immunosenescence: clinical and pharmacologic considerations. Med Clin North Am 1985; 69:475–486. 30. Cinader B, Thorbecke GJ. Aging and the Immune System. Report on Workshop #94 held during the 7th International Congress of Immunology in Berlin on August 3, 1989. Aging Immunol Infect Dis 1990; 2:45–53. 31. Whittingham S, Buckley JD, Mackay IR. Factors influencing the secondary antibody response to flagellin in man. Clin Exp Immunol 1978; 34:170–8. 32. De Greef GE, Van Staalduinen GJ, Van Doorninck H et al. Age-related changes of the antigenspecific antibody formation in vitro and PHA-induced T cell proliferation in individuals who met the Senieur protocol. Mech Ageing Dev 1992; 66:1–14. 33. Ligthart GJ, Corberand JX, Fournier C et al. Admission criteria for immunogerontological studies in man: the Senieur protocol. Mech Ageing Dev 1984; 28:47–55. 34. Ershler WB, Moore AL, Socinski MA. Influenza and aging: age-related changes and the effects of thymosin on the antibody response to influenza vaccine. J Clin Immunol 1984; 4:445–54. 35. Kishimoto S, Tomino S, Mitsuya H et al. Age-related decrease in frequencies of B-cell precursors and specific helper T cells involved in the IgG anti-tetanus toxoid antibody production in humans. Clin Immunol Immunopathol 1982; 25:1–10. 36. Burns EA, Lum LG, Giddings BR et al. Decreased specific antibody synthesis by lymphocytes from elderly subjects. Mech Aging Dev 1990; 53:229–41.

Immunological changes of aging

301

37. Burns EA, Lum LG, l’Hommedieu GD, Goodwin JS. Decreased humoral immunity in aging: in vivo and in vitro response to vaccination. J Gerontol 1993; 48:B231–36. 38. Ennist DL, Hones KH, St Pierre RL, Whisler RL. Functional analysis of the immunosenescence of the human B cell system: dissociation of normal activation and proliferation from impaired terminal differentiation into IgM immunoglobulin-secreting cells. J Immunol 1986; 136:99–105. 39. Whisler RL, Williams JW, Newhouse YG. Human B cell proliferative responses during aging. Reduced RNA synthesis and DNA replication after signal transduction by surface immunoglobulins compared with B cell antigenic determinants CD20 and CD40. Mech Ageing Dev 1991; 61:209–22. 40. Delfraissey J, Galanaud P, Wallon C et al. Abolished in vitro antibody response in the elderly: exclusive involvement of prostaglandin-induced T suppressor cells. Clin Immunol Immunopathol 1982; 24:377–85. 41. Delfraissey JF, Galanaud P, Dormont J, Wallon C. Age-related impairment of the in vitro antibody response in the human. Clin Exp Immunol 1980; 39:208–14. 42. Danon D, Kowatch MA, Roth GS. Promotion of wound repair in old mice by local injection of macrophages. Proc Natl Acad Sci USA 1989; 86:2018–20. 43. Izumi-Hisha H, Ito Y, Sugkmoto K et al. Age-related decrease in the number of hemopoietic stem cells and progenitors in senescence accelerated mice. Mech Ageing Dev 1990; 56:89–97. 44. Beckman I, Dimopoulos K, Xaioning X et al. T cell activation in the elderly: evidence for specific deficiencies in T cell/accessory cell interactions. Mech Ageing Dev 1990; 51:265–76. 45. McLachlan JA, Serkin CD, Morrey KM et al. Antitumoral properties of aged human monocytes. J Immunol 1995; 154:832–43. 46. McLachlan JA, Serkin CD, Morrey-Clark KM, Bakouche O. Immunological functions of aged monocytes. Pathobiology 1995; 63: 148–59. 47. Itoh H, Abo T, Sugawara S, Kanno A et al. Age-related variation in the proportion and activity of murine liver natural killer cells and their cytotoxicity against regenerating hepatocytes. J Immunol 1988; 141:315–23. 48. Ho S-P, Kramer KE, Ershler WB. Effect of host age upon interleukin-2-mediated anti-tumor responses in a murine fibrosarcoma model. Cancer Immunol Immunother 1990; 31:146–50. 49. Kutza J, Kaye D, Murasko DM. Basal natural killer cell activity of young versus elderly humans. J Gerontol 1991; 50A:B1 10–16. 50. Facchini AE, Mariani AR, Mariani S et al. Increased number of circulating Leu11+ (CD16) large granular lymphocytes and decreased NK activity during human aging. Clin Exp Immunol 1987; 68:340. 51. Kutza J, Gross P, Kaye D, Murasko DM. Natural killer cell cytotoxicity in elderly humans after influenza immunization. Clin Diagn Lab Immunol 1996; 3:105–8. 52. Dorfman JR, Raulet DH. Acquisition of Ly-49 receptor expression by developing natural killer cells. J Exp Med 1998; 187:609. 53. Kutza J, Murasko DM. Effects of aging on natural killer cell activity and activation by interleukin-2 and IFN-α. Cell Immunol 1994; 155: 195–204. 54. Auernhammer CJ, Feldmeier H, Nass R et al. Insulin-like growth factor I is an independent coregulatory modulator of NK cell activity. Endocrinology 1996; 137:5332–6. 55. Esposito D, Fassina G, Szabo P et al. Chromosomes of older humans are more prone to aminopterin-induced breakage. Proc Natl Acad Sci USA 1989; 86:1302–6. 56. Akiyama M, Shou O-L, Kusunoki Y et al. Age and dose related alteration of in vitro mixed lymphocyte culture response of blood lymphocytes from A-bomb survivors. Radiat Res 1989; 117:26–34. 57. Mayer PJ, Lange CS, Bradley MO, Nichols WW. Age-dependent decline in rejoining of X-rayinduced DNA double-strand breaks in normal human lymphocytes. Mutat Res 1989; 219:95– 100.

Comprehensive Geriatric Oncology

302

58. Melaragno MI, De Arruda Cardoso Smith M. Sister chromatid exchange and proliferation pattern in lymphocytes from newborns, elderly subjects and in premature aging syndromes. Mech Ageing Dev 1990; 54:43–53. 59. Nusbaum NJ. The aging/cancer connection. Am J Med Sci 1998; 315: 40–9. 60. Baylin SB, Herman JG, Graff JR et al. Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv Cancer Res 1998; 72: 142–96. 61. Doria G, Frasca D. Genes, immunity, and senescence: looking for a link. Immunol Rev 1997; 160:159–70. 62. Miller RA, Philosophe B, Ginis I et al. Defective control of cytoplasmic calcium concentration in T lymphocytes from old mice. J Cell Physiol 1989; 128:175–82. 63. Philosophe B, Miller RA. Calcium signals in murine T lymphocytes: preservation of response to PHA and to an anti-Ly-6 antibody. Aging Immunol Infect Dis 1990; 2:11–18. 64. Lustyik G, O’Leary JJ. Aging and the mobilization of intracellular calcium by phytohemagglutinin in human T cells. J Gerontol 1989; 44: B30–6. 65. Jackola DR, Hallgren HM. Diminished cell-cell binding by lymphocytes from healthy elderly humans: evidence for altered activation of LFA-1 function with age. J Gerontol 1995; 50: B368–77. 66. Rivach DAJ, Rosen GM, Cohen HJ. Membrane protein organization of peripheral blood lymphocytes from healthy young and aged adults. Mech Ageing Dev 1988:45:65–74. 67. Goodwin JS, Webb DR. Regulation of the immune response by prostaglandins: a critical review. Clin Immunol Immunopathol 1981; 15:116–32. 68. Goodwin JS. Changes in lymphocyte sensitivity to prostaglandin E, histamine, hydrocortisone, and X-irradiation with age: studies in a healthy elderly population. Clin Immunol Immunopathol 1982; 25: 243–51. 69. Hayek MG, Meydani S, Meydani M et al. Age differences in eicosenoid production of mouse splenocytes: effects on mitogeninduced T cell proliferation. J Gerontol 1994; 49:B197–207. 70. Negoro S, Hara H, Miyata S et al. Mechanisms of age-related decline in antigen-specific T cell proliferative response: IL-2 receptor expression and recombinant IL-2 induced proliferative response of purified Tac-positive T cells. Mech Ageing Dev 1986; 36:223–41. 71. McElhaney JE, Beattie BL, Devine R et al. Age-related decline in interleukin 2 production in response to influenza vaccine. J Am Geriatr Soc 1990; 38:652–58. 72. Vissinga C, Hertogh-Huijbregts, Rozing J et al. Analysis of the age-related decline in alloreactivity of CD4+ and CD8+ T cells in CBA/RIJ mice. Mech Ageing Dev 1990; 51:179–94. 73. Hara H, Tanaka T, Negoro S et al. Age-related changes of expression of IL-2 receptor subunits and kinetics of IL-2 internalization in T cells after mitogenic stimulation. Mech Ageing Dev 1988; 45:167–75. 74. Nagel JE, Chopra RK, Powers DC, Adler WH. Effect of age on the human high affinity interleukin 2 receptor of phytohaemagglutinin stimulated peripheral blood lymphocytes. Clin Exp Immunol 1989; 75:286–91. 75. Ajitsu S, Mirabella S, Kawanishi H. In vivo immunologic intervention in age-related T cell defects in murine gut-associated lymphoid tissues by IL-2. Mech Ageing Dev 1990; 54:163–83. 76. Ernst DN, Weigle WO, Thoman ML. Retention of IL-2 production and IL-2 receptor expression by Peyer’s patch T cells from aged mice. Aging Immunol Infect Dis 1990; 2:1–9. 77. Wu W, Pahlavani M, Cheung HT et al. The effect of aging on the expression of interleukin 2 messenger ribonucleic acid. Cell Immunol 1986; 100:224–31. 78. Bradley SF, Vibhagool A, Kunkel SL, Kauffman CA. Monokine secretion in aging and protein malnutrition. J Leuk Biol 1989; 45:510–14. 79. Udhayakumar V, Subbarao B, Seth A et al. Impaired T cell-induced T cell-T cell interaction in aged mice. Cett Immunol 1988; 116:299–307. 80. Thoman ML, Keogh EA, Weigle WO. Aging Immunol Infect Dis 1988/1989; 1:245–53.

Immunological changes of aging

303

81. Burns EA, FHommedieu GD, Cunning J, Goodwin JS. Effects of interleukin 4 on antigenspecific antibody synthesis by lymphocytes from old and young adults. Lymphokine Cytokine Res 1994; 13: 227–31. 82. Candore G, Di Lorenzo G, Melluso M et al. γ-Interferon, interleukin4 and interleukin-6 in vitro production in old subjects. Autoimmunity 1993; 16:275–80. 83. Daynes RA, Araneo BA, Ershler WB et al. Altered regulation of IL-6 production with normal aging. J Immunol 1993; 150:5219–30. 84. Ershler WB. Interleukin-6: a cytokine for gerontologists. J Am Geriatr Soc 1993; 41:176–81. 85. Sothern RB, Roitman-Johnson B, Kanabrocki EL et al. Circadian characteristics of circulating interleukin-6 in men. J Allergy Clin Immunol 1995; 95:1029–35. 86. Liao Z, Caucino JA, Schniffer SM et al. Increased urinary cytokine levels in the elderly. Aging Immunol Infect Dis 1993; 4:139–53. 87. Foster KD, Conn CA, Kluger MJ. Fever, tumor necrosis factor and interleukin-6 in young, mature and aged Fischer 344 rats. Am J Physiol 1992; 262: R211–15. 88. Clark JA, Peterson TC. Cytokine production and aging: overproduction of IL-8 in elderly males in response to lipopolysaccharide. Mech Ageing Dev 1994; 77:127–39. 89. Krishnaraj R, Bhooma T. Cytokine sensitivity of human NK cells during immunosenescence. 2. IL-2-induced interferon gamma secretion. Immunol Lett 1996; 50:59–63. 90. Goonewardene IM, Murasko DM. Age associated changes in mitogen induced proliferation and cytokine production by lymphocytes of the long-lived brown Norway rat. Mech Ageing Dev 1993; 71:199–212. 91. Faist E, Markewitz A, Fuchs D et al. Immunomodulatory therapy with thymopentin and indomethacin. Successful restoration of interleukin-2 synthesis in patients undergoins major surgery. Ann Surg 1991; 214:264–73. 92. Chopra RK, Holbrook NJ, Powers DC et al. Interleukin 2, interleukin 2 receptor, and interferon-gamma synthesis and mRNA expression in phorbol myristate acetate and calcium ionophore A23187-stimulated T cells from elderly humans. Clin Immunol Immunopathol 1989; 53:297–308. 93. Nagelkerken L, Hertogh-Huijbregts A, Dobber R, Drager A. Age-related changes in lymphokine production related to a decreased number of CD45RBhi CD4+ T cells. Eur J Immunol 1991; 21: 273–81. 94. Ader R, Cohen N. Conditioned immunopharmacologic responses. In: Psychoneuroimmunology (Ader R, ed). Orlando, FL: Academic, 1981:281–317. 95. Borysenko M, Borysenko J. Stress, behavior and immunity: animal models and mediating mechanisms. Gen Hosp Psych 1982; 4: 59–67. 96. Rosenberg LT, Coe CL, Levine S. Complement levels in the squirrel monkey. Lab Anim Sci 1982; 32:371–2. 97. Minter RE, Patterson-Kimball C. Life events and illness onset: a review. Psychosomatics 1978; 19:334–9. 98. Glaser R, Thorn BE, Tarr KL et al. Effects of stress on methyltransferase synthesis: an important DNA repair enzyme. Health Psych 1985; 4:403–12. 99. Thomas PD, Goodwin JM, Goodwin JS. Effect of social support on stress-related changes in cholesterol level, uric acid level and immune function in an elderly sample. Am J Psych 1985; 142:735–7. 100. Goodwin JS, Hunt WC, Kay CR et al. The effect of marital status, treatment and survival of cancer patients. JAMA 1987; 255: 3125–30. 101. Andersen BL, Kiecolt-Glaser JK, Glaser R. A biobehavioral model of cancer stress and disease course. Am Psychol. 1994; 49:389–404. 102. Schleifer SJ, Keller SE, Camerino M et al. Suppression of lymphocyte function following bereavement. JAMA 1983; 250:374–7. 103. Stein M, Miller AH, Trestman RL. Depression, the immune system, and health and illness. Arch Gen Psychiatry 1991; 48:171–7.

Comprehensive Geriatric Oncology

304

104. Glaser R, Kiecolt-Glaser JK, Speicher CE et al. The relationship of stress and loneliness and changes in herpes virus latency. J Behav Med 1985; 8:249–60. 105. Kielcolt-Glaser JK, Glaser R, Gravenstein S et al. Chronic stress laters the immune response to influenza virus vaccine in older adults. Proc Natl Acad Sci USA 1996; 93:3043–7. 106. Kiecolt-Glaser JK, Marucha PT, Malarkey WH et al. Slowing of wound healing by psychological stress. Lancet 1995; 346:1194–6. 107. Levy SM, Herberman RB, Maluish AM et al. Prognostic risk assessment in primary breast cancer by behavioral and immunological parameters. Health Psych 1985; 4:99–113. 108. Speigel D, Bloom HC, Kraemer JR, Gottheil E. Effect of psychosocial treatment on survival of patients with metastatic breast cancer. Lancet 1989; 888–911. 109. Fabris N. A neuroendocrine-immune theory of aging. Int J Neurosci 1990; 51:373–5. 110. Ershler WB. The influence of an aging immune system on cancer incidence and progression. J Gerontol 1993; 48:B3–7. 111. Lewis V, Twomey J, Bealmear P et al. Age, thymic function and circulating thymic hormone activity. J Clin Endocrinol Metab 1978; 47:145–52. 112. Rodewald H Immunology: the thymus in the age of retirement. Nature 1998; 396:630–1. 113. Hirokawa K, Utsuyama M, Kasai M et al. Aging and immunity. Jpn Soc Pathol 1992; 42:537– 48. 114. Effros RB, Casillas A, Walford RL. The effect of thymosin-1 immunity to influenza in aged mice. Aging Immunol Infect Dis 1988:1:31–40. 115. Goso C, Frasca D, Doria G. Effect of synthetic thymic humoral factor (THF-γ2) on T cell activities in immunodeficient ageing mice. Clin Exp Immunol 1992; 87:346–51. 116. Frasca D, Adorini L, Doria G. Enhanced frequency of mitogenresponsive T cell precursors in old mice injected with thymosin alpha 1. Eur J Immunol 1987; 17:727–30. 117. Cillari E, Milano S, Perego R, Gromo G et al. Modulation of IL-2, IFN-γ, TNF-α and IL-4 production in mice of different ages by thymopentin. Int J Immunopharmacol 1991; 14:1029– 35. 118. Cillari E, Milano S, Dieli M et al. Thymopentin reduces the susceptibility of aged mice to cutaneous leishmaniasis by modulating CD4 T-cell subsets. Immunology 1992; 76:362–6. 119. Reiter RJ. Pineal function during aging: attenuation of the melatonin rhythm and its neurobiological consequences. Acta Neurobiol Exp 1994; 54:31S-9. 120. Caroleo MC, Frasca D, Nistico G, Doria G. Melatonin. 1995; 3: 194–7. 121. Lissoni P, Brivio O, Fumagalli L et al. Immune effects of preoperative immunotherapy with high-dose subcutaneous interleukin-2 versus neuroimmunotherapy with low-dose IL-2 plus the neurohormone melatonin in gastrointestinal tract tumor patients. J Biol Regul Homeo Agents 1995; 9:31–3. 122. Lissoni P, Barni S, Fossati V et al. A randomized study of neuroimmunotherapy with lowdose subcutaneous interleukin-2 plus melatonin compared with supportive care alone in patients with untreatable metastatic solid tumour. Support Care Cancer 1995; 3: 194–7. 123. Saito H, Inoue T, Fukatsu K et al. Growth hormone and the immune response to bacterial infection. Hormone Res 1996; 45: 50–4. 124. Bonello RS, Marcus R, Bloch D, Strober S. Effects of growth hormone and estrogen on T lymphocytes in older women. J Am Geriatr Soc 1996; 44:1039–42. 125. Swenson CD, Gottesman SR, Belsito DV et al. Relationship between humoral immunoaugmenting properties of DHEAS and IgD-receptor expression in young and aged mice. Ann NY Acad Sci 1995; 774:249–58. 126. Araneo BA, Woods ML 2d, Daynes RA. Reversal of the immunosenescent phenotype by DHEA: hormone treatment provides an adjuvant effect on the immunization of aged mice with recombinant hepatitis B surface antigen. J Infect Dis 1993; 167:830–40. 127. Danenberg HD, Ben-Yehuda A, Zakay-Rones Z et al. DHEA treatment reverses the impaired immune response of old mice to influenza vaccination and protects from influenza infection. Vaccine 1995; 13:1445–8.

Immunological changes of aging

305

128. Araneo B, Dowell T, Woods ML et al. DHEAS as an effective vaccine adjuvant in elderly humans. Proof-of-principle studies. Ann NY Acad Sci 1995; 774:232–48. 129. Ferluga J. Potential role of anti-oncogenes in aging. Mech Ageing Dev 1990; 53:267–75. 130. McCay C, Crowell M, Maynard L. The effects of retarded growth upon the length of life span and upon the ultimate body size. J Nutr 1935; 10:63–79. 131. Walford RL, Liu RK, Gerbase-Delima M et al. Long-term dietary restiction and immune function in mice: response to sheep red blood cells and to mitogenic agents. Mech Ageing Dev 1973; 2: 447–54. 132. 132.Effros RB, Walford RL, Weindruch R et al. Influences of dietary restriction on immunity to influenza in aged mice. J Gerontol 46:B142–7. 133. Ershler WB, Sun WH, Binkley N et al. Interleukin-6 and aging: blood levels and mononuclear cell production increase with advancing age and in vitro production is modifiable by dietary restriction. Lymphokine Cytokine Res 1993; 12:225–30. 134. Chandra RK. Nutrition is an important determinant of immunity in old age. Prog Clin Biol Res 1990; 326:321–34. 135. Chandra RK, Puri S. Nutritional support improves antibody response to influenza vaccine in the elderly. BMJ 1985; 291:709. 136. Chandra RK. Effect of vitamin and trace-element supplementation on immune responses and infection in elderly subjects. Lancet 1992; 340:1124–7. 137. Rasmussen LB, Kiens B, Pedersen BK et al. Effect of diet and plasma fatty acid composition on immune status in elderly men. Am J Clin Nutr 1994; 59:572–7. 138. Meydani M. Vitamin E. Lancet 1995; 345:170–5. 139. Meydani SN, Hayek M. Vitamin E and immune response. In: Proceedings of International Conference on Nutrition and Immunity (Chandra RK, ed). St John’s, Newfoundland: ARTS Biomedical, 1992:105–28. 140. Meydani SN, Barklund PM, Liu S et al. Vitamin E supplementation enhances cell-mediated immunity in healthy elderly subjects. Am J Clin Nutr 1990; 52:557–63. 141. Meydani, SN, Leka L, Loszewski R. Long-term vitamin E supplementation enhances immune response in healthy elderly. FASEB J 1994; 8:A274. 142. Omenn GS, Goodman GE, Thornquist MD et al. Risk factors for lung cancer and for intervention effects in CARET, the Beta Carotene and Retinol Efficacy Trial. J Natl Cancer Inst 1996; 88: 1550–50. 143. Albanes D, Heinonen OP, Taylor PR et al. α-Tocopherol and β-carotene supplements and lung cancer incidence in the α-Tocopherol, β-Carotene Cancer Prevention Study: effects of base-line characteristics and study compliance. J Natl Cancer Inst 1996; 88:1560–70. 144. Goodwin JS, Bankhurst A, Murphy S et al. Partial reversal of the cellular immune defect in common variable immunodeficiency with indomethacin. J Clin Lab Immunol 1978; 1:197–9. 145. Hsia J, Tang T, Parrott M, Rogalla K. Augmentation of the immune response to influenza vaccine by acetylsalicylic acid: a clinical trial in a geriatric population. Meth Find Exp Clin Pharm 1994; 16:677–83. 146. Cueppens J, Rodriguez M, Goodwin JS. Nonsteroidal anti-inflammatory drugs inhibit the production of IgM rheumatoid factor in vitro. Lancet 1982; i:528–31. 147. Pennebaker JW, Kiecolt-Glaser JK, Glaser R. Disclosure of traumas and immune function: health implications for psychotherapy. J Consult Clin Psych 1988; 56:239–45. 148. Kiecolt-Glaser JK, Glaser R, Williger D et al. Psychosocial enhancement of immunocompetence in a geriatric population. Health Psych 1985; 4:25–41.

14 Biologic characteristics of primary breast cancer Maria Grazia Daidone, Rosella Silvestrini, Aurora Costa, Danila Coradini, Gabriele Martelli, Silvia Veneroni Introduction A progressive increase in average life-expectancy has led to a marked increase in the absolute and relative frequencies of tumors in elderly patients. This increase is mainly evident for specific age-related tumors, such as breast and prostate cancers. It was foreseen, in fact, that by the end of the 20th century about 50% of newly diagnosed breast cancers each year would occur in elderly women,1 and indeed this estimate has been confirmed by data provided by the US National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) program, the nine population-based cancer registries of the USA, which reported an actual increase from 37% to 46.7% in the fraction of women 65 years or older with breast cancer diagnosed in the 22-year interval from 1973 to 1995.2 In the last few decades, studies on breast cancer biology have been progressively intensified, and the resulting information has substantially contributed to improving knowledge of the natural history of the disease, defining the clinical role of biologic markers such as hormone receptors, cell proliferation, ploidy (i.e. nuclear DNA content), functional and structural alterations in oncogenes and tumor suppressor genes (HER2/neu and p53), apoptosis, and angiogenesis-related markers, and giving clinicians information helpful in treatment decision making.3–5 However, such studies have generally been performed on tumors from relatively young patients who entered therapeutic clinical protocols, and, until relatively recently, the biologic features of tumors from elderly patients were only occasionally investigated.6 Two independent studies have evaluated several biologic characteristics7 or the hormonal receptor profile alone8 of primary tumors from 35154 patients aged 55 or more from the San Antonio breast cancer database or from 19541 non-Hispanic White women with node-negative breast cancer from the SEER database. The information presently available confirms the association of advanced age with favorable biologic features and demonstrates that, in elderly women with small and/or node-negative breast cancers, survival is similar to that of the general population, regardless of disease status. Our experience on 14007 patients with primary breast cancer recruited in a single institution (the Istituto Nazionale Tumori of Milan) (3653 cases from women aged 65 or older) confirms our previous findings, as well as those from the San Antonio database, of a reduced expression of unfavorable biomarkers in cancers from elderly patients (absence of steroid receptors, high proliferation rate, aneuploid DNA content, overexpression of p53, and reduced expression of the anti-apoptosis marker Bcl-2). This experience also emphasizes the presence of a pattern of association between the different biologic variables similar to that observed in cancers from younger patients, and demonstrates a

Biologic characteristics of primary breast cancer

307

predictive role of proliferation and apoptosis-related markers on clinical outcome following tamoxifen treatment, even within the subset of steroid receptor-positive cancers. Study design On an overall series of 14007 primary invasive breast cancers from patients admitted to the Istituto Nazionale Tumori of Milan during a 26-year period (1974–2000), we determined some biologic features, including cell proliferation evaluated as the [3H]thymidine labeling index (TLI),9 steroid receptors evaluated using the dextrancoated charcoal technique,9 DNA ploidy evaluated by flow cytometry,10 and p53 and Bcl-2 expression evaluated by immunohistochemistry.11 Biomarkers were considered as dichotomous variables using cut-off values of prognostic relevance in large series of primary breast cancers in different clinical situations, namely 3% for TLI,9–11 10 fmol/mg protein for estrogen receptors (ER), 25 fmol/mg protein for progesterone receptors (PgR),9 5% of positive cells for p53,11and 30% of positive cells for Bcl-2.11 For ploidy determination, human lymphocytes were used as an internal standard (with a median coefficient of variation for the G0/1 peak equal to 1.5%): tumors with a DNA index between 0.95 and 1.05 were defined as diploid, and tumors with lower or higher DNA index values were considered aneuploid if they contained more than 10% aneuploid cells.10 The relations among these biologic variables and between them and conventional pathologic factors were analyzed and compared for the different age classes. Results Basic study The analysis performed on the overall series of 14007 breast cancer patients showed that the fraction of tumor cells in S phase, as indicated by the TLI, progressively and consistently decreased with increasing patient age (Figure 14.1a). In fact, the median TLI value of 5.7%, observed in tumors from the youngest patients, decreased as age increased, and reached a plateau around a value of 2.7% in tumors from patients over 65 (p=0.0001). Such an age-related pattern was mainly evident for breast cancer, since, in our experience, proliferation was unaffected by patient age in other neoplasms, including metastatic melanomas (797 cases), soft tissue sarcomas (128 cases),

Comprehensive Geriatric Oncology

308

Figure 14.1 [3H]thymidine labeling index (TLI) as a function of patient age in: (a) breast cancer; (b) metastatic melanoma and soft tissue sarcoma; (c) renal, thyroid, and bladder carcinomas; (d) colorectal and head and neck

Biologic characteristics of primary breast cancer

309

cancers; (e) hepatocellular carcinoma and non-small cell lung cancer.

Figure 14.2 p53 and Bcl-2 expression as functions of patient age in breast cancer. thyroid carcinomas (123 cases), renal carcinomas (175 cases), and bladder carcinomas (110 cases) (Figure 14.1b,c). A slight decrease of proliferation as patient age increased was observed in head and neck cancers (364 cases) and colorectal cancers (673 cases) (Figure 14.1d). In contrast, a trend in favor of a direct relation between proliferation and patient age was reported in non-small cell lung cancers (277 cases) and in hepatocellular carcinomas (113 cases) (Figure 14.1e). As regards the expression of p53 in primary breast cancers, the older the patients, the lower the likelihood that tumors overexpressed the protein (Figure 14.2). In fact, the fraction of p53-positive tumors decreased from 43% in patients younger than 25 to about 24% in patients aged 35–64 to 17% in patients aged 65 or more (p= 0.001). Expression of the anti-apoptosis protein Bcl-2 (which, in breast cancer, proved to be upmodulated by estrogens and associated with a differentiated phenotype) was weakly directly associated with patient age (Figure 14.2), with an increase from 25% in patients younger than 25 to

Comprehensive Geriatric Oncology

310

50% in patients aged 65 or more (p=0.001). Only a slight decrease in the frequency of aneuploid tumors (i.e. tumors with gross DNA abnormalities) was observed with increasing age (Figure 14.3), with the highest frequency (>80%) in patients younger than 35 and the lowest (65%) in patients older than 85 (p=0.016). As regards steroid receptors, a marked and direct age-related pattern was observed for ER, in terms of receptor presence and concentration (Figure 14.4). In fact, a progressive and relatively constant increase was observed in ER positivity, from 42% in the youngest patients to more than 80% in

Figure 14.3 DNA ploidy as a function of patient age in breast cancer.

Biologic characteristics of primary breast cancer

311

Figure 14.4 Estrogen receptor (ER) content and status as a function of patient age in breast cancer. patients over 65 (p=0.001). Such an increase was paralleled by an increase in ER content. In fact, the median value (which was around 40 fmol in premenopausal patients) dramatically increased from three to more than four times in patients older than 65 and 85, respectively. In contrast, the age-related behavior of PgR was rather discontinuous, with a peak of positivity (60%) and PgR

Comprehensive Geriatric Oncology

312

Figure 14.5 Progesterone receptor (PgR) content and status as functions of patient age in breast cancer. content in tumors from patients aged 35–55, a slight decrease in tumors from patients aged 55–64, and a further increase in PgR positivity and content in tumors from older patients (Figure 14.5). A significant association was observed between the biologic variables, except between ploidy and steroid receptors or apoptosis-related markers, with an association rate ranging from 40% to 80% for the different comparisons (Table 14.1). The agreement was maximum between ER and PgR (direct association), and between steroid receptors and p53 expression (inverse association), intermediate for steroid receptors and Bcl-2 (direct association), for TLI and DNA ploidy or p53 (direct association) and for p53 and Bcl-2 expression (inverse association), and poor for TLI and steroid receptors (inverse association). In particular, cell proliferation was higher in tumors without steroid receptors, with overexpression of p53 or absent/weak Bcl-2 expression, or with an aneuploid DNA content than in tumors with steroid receptors, with no or weak expression of p53 or overexpression of Bcl-2, or with a diploid DNA content. PgR positivity was directly associated with the presence of ER, and both correlated directly with Bcl-2 and inversely with p53 expression. Bcl-2 expression was inversely associated with the expression of p53. These profiles of direct or inverse associations between biologic

Biologic characteristics of primary breast cancer

313

variables were similar in patients younger or older than 65. In particular, for elderly patients generally, the relation between biologic variables gave similar patterns of association, or of lack of an association, regardless of patient age, notwithstanding the relatively low number of cases in some age classes.

Table 14.1 Relation between biologic features according to patient age Percentage agreement in patients ≤49/50–64/≥65 years Proliferation

ER

PgR

p53

ER

53/53/56

PgR

54/53/53

78/73/74

p53

51/51/53

72/75/80

66/63/65

Bcl-2

58/54/56

61/55/61

64/62/59

57/53/58

DNA ploidy

58/60/61

45/43/44

49/52/49

43/39/43

Bcl-2

55/62/50

Table 14.2 Association between biologic and pathologic features according to patient age (pvalues) Tumor size

Nodal involvement

≤49 yr

50–64 yr

≥65yr

≤49 yr

50–64 yr

≥65 yrs

TLI

0.0001

0.0001

0.05

0.0002

ns

ns

ER

0.0001

0.0001

0.0001

0.007

0.0001

ns

PgR

0.0001

0.0001

0.0002

0.0001

0.0001

ns

p53

0.08

0.0003

0.005

ns

0.09

ns

Bcl-2

0.0001

0.004

0.02

ns

ns

ns

ns, not significant.

With regard to the relation between biologic and pathologic factors, biologic markers were independent of nodal involvement at the time of diagnosis in the subset of elderly patients (Table 14.2). This finding was consistent for p53 and Bcl-2 expression also for patients under 65. Conversely, in younger patients, a trend in favor of a direct relation between TLI and nodal involvement was observed, as well as a lower frequency of ERpositive or PgR-positive tumors with an increased degree of nodal involvement in patients aged 49 or less. An overall association was observed between biologic markers and tumor size, regardless of patient age, and such a relation consisted of an increased proliferation and p53 overexpression and a reduced steroid receptor content and Bcl-2 expression in large tumors.

Comprehensive Geriatric Oncology

314

Clinical studies According to the guidelines initially proposed by McGuire12 and later renewed,13 assessment of the clinical relevance of biologic markers should be carried out on substantial series of patients with adequate follow-up, who are homogeneous for tumor stage and clinical treatment. In particular, the prognostic significance of any biologic marker should be evaluated on relapse-free survival for cases subjected to local regional treatment (to avoid the possible interference of systemic treatment) or on survival, regardless of treatment. Conversely, the predictive role of biomolecular markers should be evaluated on case series homogeneously treated, possibly in the context of a clinical protocol. In addition, to provide valuable information on the clinical utility of correlative studies in which patient outcome is analyzed as a function of biomarkers, a level of evidence, from I to V, has been associated with translational studies.13 In particular, the highest levels of evidence are associated with high-powered controlled studies specifically designed to test the clinical utility of a biomolecular marker; with metaanalyses or overviews of translational studies (level of evidence I), or with studies performed in conjunction with randomized treatment protocols in which the determination of the biomolecular marker was planned a priori but did not influence treatment assignment (level of evidence II). Unfortunately, because of the present paucity of clinical treatment protocols on patients aged 65 or more in which the evaluation of biomarkers other than steroid receptors has been prospectively planned, available information on the clinical relevance of biomolecular markers in breast cancer from elderly patients is at a level of evidence III (at best). Within the subset of 3653 patients aged 65 or more admitted to the Istituto Nazionale Tumori of Milan from 1974 to 2000, 1708 were under observation or treatment at the outpatient clinic, with an adequate potential follow-up longer than 5 years. Following local regional therapy (radical or conservative surgery plus radiotherapy), the majority of these patients received hormonal treatment (808 cases; 47.3%) or remained under observation (755 cases; 44.2%). Only 92 and 53 cases were submitted to chemotherapy and to a combination of chemotherapy and endocrine therapy, respectively. Information on DNA ploidy was available on a limited number of cases, and thus was not considered in the successive analyses. Also, information on p53 and Bcl-2 expression was not available for the entire case series, and in this discussion only data on their relation with clinical outcome following tamoxifen treatment are included.

Table 14.3 Six-year relapse-free survival rate (RFS) as a function of pathobiologic variables in patients aged 65 or more subjected to local regional treatment Low-risk categorya No. RFS HRd of (%) cases Univariate 62

84

1.00

Intermediate-risk categoryb

High-risk categoryc

p

No. RFS HRd of (%) cases

p

—

272

0.19 246

75

1.65

No. RFS HRd of (96) cases 70

2.07

P

0.05

Biologic characteristics of primary breast cancer

analysis

315

(0.78– 3.47)

(0.98– 4.33)

Bivariate analysis by: Patient age 65–69 years

42

85

1.00

—

160

77

1.00

—

136

66

1.00

≥70 years

20

82

1.55 0.55 112 (0.37– 6.51)

74

1.11 0.71 110 (0.64– 1.93)

75

0.74 0.29 (0.43– 1.29)

≤3%

27

95

1.00

146

78

1.00

112

64

1.00

>3%

35

75

6.03 0.09 126 (0.74– 49.0)

72

1.60 0.09 134 (0.92– 2.78)

74

0.77 0.32 (0.45– 1.30)

TLI —

—

a

Tumor size≤1 cm. bER-positive, 1–2 cm tumors. cTumors>2 cm or ER-negative. dHazard ratio (95% confidence interval in parentheses).

Table 14.4 Six-year relapse-free survival rate (RFS) as a function of pathobiologic variables in patients aged 65 or more subjected to surgery and adjuvant hormonal therapy Univariate analysis Variable

No. of cases RFS (%) HR

a

Multivariate analysis

P

HRa

P

Patient age: 65–69 years 213

75

1.0

—

1.0

—

70–79 years 383

69

1.36 (0.96–1.94)

0.08

1.45 (1.00–2.10)

0.05

≥80 years

141

65

1.41 (0.89–2.24)

0.14

1.86 (1.11–3.13)

0.019

≤1 cm

41

84

1.0

—

1.0

—

1–2 cm

333

76

1.67 (0.67–4.14)

0.27

1.56 (0.62–3.88)

0.34

>2 cm

363

63

2.92 (1.19–7.17)

0.019

2.17 (0.88–5.37)

0.09

Tumor size:

Positive axillary lymph nodes 0

83

84

1.0

—

1.0

—

1–3

227

80

1.22(0.63–2.38)

0.56

1.57(0.80–3.09)

0.19

>3

167

47

3.88 (2.06–7.31)

0.0001 4.57 (2.40–8.69)

0.0001

nab

260

72

1.68 (0–88–3.22)

0.12

0.06

1.88(0.97–3.66)

Comprehensive Geriatric Oncology

316

ER status: positive

670

72

1.0

—

1.0

—

negative

67

53

2.20 (1.48–3.28)

0.0001 1.86 (1.18–2.94)

0.008

positive

511

73

1.0

—

1.0

—

negative

266

63

1.65 (1.22–2.23)

0.001

1.37 (0.98–1.93)

0.07

≤3%

391

74

1.0

—

1.0

—

>3%

346

66

1.44 (1.07–1.94)

0.016

1.38(1.02–1.87)

0.04

PgR status:

TLI:

a

b

Hazard ratio (95% confidence interval in parentheses). Not assessed.

In the subset of 755 patients subjected to radical or conservative surgery plus radiotherapy without any systemic treatment until relapse, 580 had histologically assessed lymph node-negative resectable breast cancers, with a prevalence of tumors 2 cm or less in diameter (65%; >80% with 1–2 cm tumors). The majority of these cases were ER-positive (83%) and from patients aged 65–69 (58%). A classification of these cases based on conventional pathobiologic factors (tumor size and ER) allowed the identification of low-risk (tumor size ≤1 cm), intermediate-risk (ER-positive tumors 1–2 cm in diameter), and high-risk (tumor size >2 cm or ER-negative) patients, exhibiting a 6-year probability of relapse of 16%, 25%, and 30%, respectively (Table 14.3), with an overall of 115 locoregional or distant relapses. Patient age and proliferative activity, singly, did not provide prognostic information. Conversely, proliferative activity was able to further segregate patients with favorable or unfavorable prognosis within the low- and intermediate-risk categories (Table 14.3). With regard to clinical outcome following systemic treatment, the predictive role of conventional clinical and pathobiologic features, including patient age, pathologic tumor size and lymph node involvement, ER and PgR, and proliferative activity, could be investigated, singly and in association, in 737 of the 808 patients previously identified, treated with endocrine therapy, mainly tamoxifen (20 or 30 mg/day) for at least 1 year, and with a median follow-up of 6 years (177 unfavorable events within 6 years from diagnosis). In univariate analysis, tumor size, lymph node involvement, ER, PgR, and TLI identified patients at low or high risk of relapse, and this predictive role was maintained for all these variables in a multivariate analysis in which patient age also acquired an independent prognostic significance (Table 14.4). Among biologic variables, ER showed the strongest predictive role for response to endocrine treatment, in agreement with the outcome of meta-analyses by the Early Breast Cancer Trialists’ Collaborative Group,14 even in elderly patients. Besides conventional pathobiologic features, an altered expression of p53 or of Bcl-2 also contributed to improve the prognostic resolution for patients treated with adjuvant hormonal therapy. Information on these biomolecular markers was available on a series of 145 patients aged over 70 (median age 74; range 70–88) with node-positive resectable tumors already characterized in terms of ER, PgR, and TLI, treated with tamoxifen (20 or

Biologic characteristics of primary breast cancer

317

30 mg/day) for at least 1 year and with a median follow-up of 7 years.15 In univariate analysis, the probability of relapse was unaffected by tumor size, whereas it was significantly related to the number of involved axillary lymph nodes, ER, TLI, p53, and Bcl-2, although with different discriminating powers. In particular, the hazard ratio (HR) for relapse for patients with ER-negative tumors or for patients with p53-overexpressing tumors was 3.4- and 4.4-fold that of patients with ER-positive or p53-negative tumors, respectively. In addition, the HR for patients with rapidly proliferating or Bcl-2-negative tumors was about 2-fold that of patients with slowly proliferating tumors or those with Bcl-2-overexpressing tumors. The absence of ER or p53 overexpression was associated with the most unfavorable prognosis (80% of patients relapsing within 7 years of diagnosis), whereas a low proliferation rate identified the lowest-risk subgroup of patients (with only 30% of patients relapsing at 7 years). These results held true when adjusted for tamoxifen treatment duration and ER status, and were paralleled by similar findings on overall survival. In a multivariate analysis carried out in the subset of ER-positive tumors, cell proliferation and p53 and Bcl-2 expression maintained their predictive significance. The integration of pathologic and biologic variables significantly improved the predictive resolution of each variable, considered singly, for the identification of either the low-

Figure 14.6 Relapse curves for patients with ER-positive tumors

Comprehensive Geriatric Oncology

318

treated with tamoxifen as a function of the risk profile defined by axillary lymph node involvement, TLI, and p53 and Bcl-2 expression. Low-risk: presence of only one unfavorable factor (>3 positive lymph nodes, high TLI, p53 overexpression, or Bcl-2 absent/weak expression). Intermediate risk: presence of two unfavorable factors. High-risk: presence of three unfavorable factors. risk or the high-risk patients. In fact, within the ER-positive subset (i.e. in women traditionally considered responsive to endocrine treatment and who benefit markedly from adjuvant tamoxifen), the favorable biologic profile, characterized by the presence of only one unfavorable factor (rapid proliferation or p53 overexpression, absent or weak Bcl-2 expression, or more than three involved axillary lymph nodes) allowed the identification of patients with a low probability to relapse at 7 years after starting adjuvant treatment (Figure 14.6). Conversely, an aggressive pathobiologic profile, characterized by the presence of two or three of the four unfavorable factors, identified patients who partially (in 50% of the cases) or totally (in 90% of the cases) escaped tamoxifen control, notwithstanding the presence of ER. The low-risk group includes about 50% of cases, the high-risk group accounts for about 20%, and the remaining 30% were included in the intermediate-risk subset. Although this analysis is exploratory and the data are hypothesis-generating and need to be validated by retrospective or prospective studies on independent series of patients, it could represent a preliminary framework for a biologically tailored therapy even for elderly breast cancer patients. Discussion and conclusions In the past, the interest of clinicians in designing innovative therapeutic protocols has only rarely focused on breast cancer patients aged over 65 or 70. This attitude was due to the exclusion of elderly patients from randomized clinical trials because of comorbid conditions and to spare them from the toxic side-effects of systemic treatment.16 This latter attitude also derived from the common, although still controversial, belief that elderly patients generally develop indolent disease, characterized by a lower responsiveness to treatment. However, against these statements, some reports showed a worse survival rate for elderly patients than for younger patients with metastatic disease,17 and a significant benefit of disease-free survival after treatments using drugs with limited side-effects, such as tamoxifen.18 In considering these demonstrated or only hypothesized findings, there is a case for a renewal of scientific interest in the biologic characterization of breast cancers from elderly patients. In fact, as has already occurred for cancers in younger patients, biologic

Biologic characteristics of primary breast cancer

319

information on this subset of tumors could actually contribute to a better comprehension of the natural history of the disease in elderly patients, and possibly provide prognostic information and guidelines for treatment.19 Overall, in our study, tumors in patients aged 65 or more showed a tendency towards a lower proliferative rate, a lower frequency of p53 expression, a higher ER content, and a slightly more frequent Bcl-2 expression or presence of diploid clones than tumors from younger patients. The PgR positivity in tumors from patients over 65, although higher than that observed in tumors from patients under 35, did not differ from the PgR positivity observed in tumors from patients aged 50–64. It should be investigated whether the pronounced increase in PgR content in patients older than 75 is ascribable only to the presence of free receptors or represents a peculiar feature of very old patients. p53 and Bcl-2 expression were respectively inversely and directly associated with patient age, and their pattern of association, which has an implication for tumor progression and treatment response in younger patients, was maintained even in elderly patients. In general, the relationships between the different biomarkers and the weak or even absent association with clinicopathologic factors observed in tumors from elderly patients are in keeping with results from similar analyses on tumors from younger patients. The absence of steroid receptors, the presence of aneuploid clones, p53 overexpression, and weak or absent Bcl-2 expression were associated with rapid proliferation, and indirectly these findings should indicate that biologic aggressiveness could be defined on the basis of such features, even for tumors from elderly patients. It is worth mentioning that cancers from elderly patients are associated with a more favorable pathobiologic phenotype compared with those from younger patients.6,7 In fact, only 30% of elderly patients presented at diagnosis with three or more unfavorable factors (including the presence of tumors larger than 2 cm, steroid receptor-negative, rapidly proliferating, overexpressing p53, or with absent or weak Bcl-2 expression), compared with about 50% of patients aged 34 or less, and with about 40% of patients aged 35–64. Steroid receptors, proliferation, and apoptosis-related markers proved to be indicators of long-term clinical outcome, following either local regional or hormonal therapy, although their clinical impact was mainly evident for the latter treatment, and we have now validated their predictive role, already assessed in tumors from younger patients subjected to different treatment modalities,9,20–24 including local regional and adjuvant chemotherapy. It should be stressed that the present data were mainly obtained on elderly patients subjected to endocrine treatment, which is known to provide the highest benefit for tumors with hormone receptors14 and low cell proliferation.15,20,25 However, a separate analysis on the subset of ER-positive tumors, conventionally considered hormoneresponsive, again showed that the best prognosis was identified by low TLI, absent or weak p53 expression, or Bcl-2 overexpression in association with a small number of positive nodes.15 Whether these biomolecular markers can be considered to be specifically responsible for a benefit from hormonal therapy or to be only favorable prognostic indicators, associated with a differentiated phenotype, is still an open question. All these data have been derived from retrospective analyses, and need to be prospectively confirmed. For elderly patients, for whom the cost-benefit of treatment should be carefully assessed, it would seem reasonable to use biologic findings as a complement to clinicopathologic features in a ‘risk factor profile system’ for treatment planning. However, this hypothesis should be assessed and validated in prospective

Comprehensive Geriatric Oncology

320

studies, with an associated high level of evidence, even when considering the observation derived from the San Antonio breast cancer database in favor of a decreased impact of breast cancer on survival as patient age increases.7 Notwith-standing the possible limitations and bias of the study, also emphasized by the authors,7 the presence of biologic features characterizing an indolent disease and the favorable outcome of elderly patients regardless of disease status should be taken into consideration when making clinical decisions. References 1. Baranofsky A, Myers MH. Cancer incidence and survival in patients 65 years of age and older. Cancer 1986; 36:26–41. 2. Surveillance, Epidemiology, and End Results (SEER) Program. Public use CD-ROM (1973– 1995). Bethesda, MD: Cancer Statistics Branch, National Cancer Institute, 1998. 3. Bast RC, Ravdin P, Hayes DF et al. 2000 Update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2001; 19:1865–78. 4. National Institutes of Health Consensus Development Conference Statement. Adjuvant Therapy for Breast Cancer, November 1–3, 2000. J Natl Cancer Inst 2001; 93:979–89. 5. Goldhirsch A, Glick JH, Gelber RD et al. Meeting Highlights: International Consensus Panel on the Treatment of Primary Breast Cancer. J Clin Oncol 2001; 19:3817–27. 6. Valentinis B, Silvestrini R, Daidone MG et al. 3H-thymidine labeling index, hormone receptors, and ploidy in breast cancers in elderly patients. Breast Cancer Res Treat 1991; 20:19–24. 7. Diab SG, Elledge RM, Clark GM. Tumor characteristics and clinical outcome of elderly women with breast cancer. J Natl Cancer Inst 2000; 92:550–6. 8. Anderson WF, Chu KC, Chatterjee N et al. Tumor variants by hormone receptor expression in white patients with node-negative breast cancer from the Surveillance, Epidemiology, and End Results database. J Clin Oncol 2001; 19:18–27. 9. Silvestrini R, Daidone MG, Luisi A et al. Biologic and clinicopathologic factors as indicators of specific relapse types in node-negative breast cancer. J Clin Oncol 1995; 13:697–704. 10. Silvestrini R, Daidone MG, Del Bino G et al. Prognostic significance of proliferative activity and ploidy in node-negative breast cancers. Ann Oncol 1993; 4:213–19. 11. Silvestrini R, Benini E, Daidone MG et al. The bcl-2 protein: a prognostic indicator strongly related to p53 protein in lymph node-negative breast cancer patients. J Natl Cancer Inst 1994; 86:499–504. 12. McGuire WL. Breast cancer prognostic factors: evaluation guidelines (editorial, comment). J Natl Cancer Inst 1991; 83:154–5. 13. Hayes DF, Trock B, Harris AL. Assessing the clinical impact of prognostic factors: when is ‘statistically significant’ clinically useful? Breast Cancer Res Treat 1998; 52:305–19. 14. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998; 351:1451–67. 15. Daidone MG, Luisi A, Martelli G et al. Biomarkers and outcome after tamoxifen treatment in node-positive breast cancers from elderly women. Br J Cancer 2000; 82:270–7. 16. Balducci L, Extermann M, Fentiman I et al. Should adjuvant chemotherapy be used to treat breast cancer patients (≥70 years of age)? Eur J Cancer 1997; 33:1720–4. 17. Yancik R, Ries LG, Yates JW. Breast cancer in aging women. A population-based study of contrasts in stage, surgery and survival. Cancer 1989; 63:976–81.

Biologic characteristics of primary breast cancer

321

18. Castiglione M, Gelber RD, Goldhirsch A. Adjuvant systemic therapy for breast cancer in the elderly: completing causes of mortality. International Study Group. J Clin Oncol 1990; 8:519– 26. 19. Silliman RA, Balducci L, Goodwin JS et al. Breast cancer care in old age: what we know, don’t know, and do. J Natl Cancer Inst 1993; 85: 190–9. 20. Daidone MG, Silvestrini R. Prognostic and predictive role of proliferation indices. J Natl Cancer Inst Monogr 2001; 30:27–35. 21. Thor AD, Berry DA, Budman DR et al. ErbB-2, p53 and efficacy of adjuvant therapy in lymph node-positive breast cancer. J Natl Cancer Inst 1998; 90:1346–60. 22. Silvestrini R, Luisi A, Zambetti M et al. Cell proliferation and outcome following doxorubicin plus CMF regimens in node-positive breast cancer. Int J Cancer 2000; 87:405–11. 23. Elledge RM, Green S, Howes L et al. bcl-2, p53, and response to tamoxifen in estrogen receptor-positive metastatic breast cancer: a Southwest Oncology Group study. J Clin Oncol 1997; 15: 1916–22. 24. Daidone MG, Luisi A, Veneroni S et al. Clinical studies of Bcl-2 and treatment benefit in breast cancer patients. Endocrine Rel Cancer 1999; 6:61–8. 25. Scarpi E, De Paola F, Sarti M et al. Biomarker prediction of clinical outcome in operable breast cancer patients treated with tamoxifen. Breast Cancer Res Treat 2001; 68:101–10.

15 Clinical evidence for change in tumor aggressiveness with age: A historical perspective Frederick F Holmes Introduction Age is the most important risk factor for cancer. Cancer incidence at age 80 is nearly 250 times as great as at age 8. While it is trite to say that a group of 80-year-olds is much more diverse than a group of 8-year-olds, nonetheless, uniformity is a characteristic of youth and diversity a characteristic of old age. On this basis alone, it is likely that there is diversity among cancers afflicting the elderly. A critical question, for which there is no answer at present, is whether or not old people have old tumors. Some neoplastic cell lines are immortal, seemingly having escaped aging altogether. Whether or not tumors age, hosts do age, particularly in regard to immunocompetence. Tumor growth is obviously a product of intrinsic cellular factors as well as host factors, some of which may be humoral and thus affect tumors directly. To confound matters, it is difficult to separate the intrinsic properties of any cancer from the defenses of its host. More than 80 years ago, Sistrunk and McCarty1 studied the contributions of cellular differentiation, hyalinization, fibrosis, and lymphocytic infiltration to prolonged survival in breast cancer. They thought that lymphocytic infiltration was not the most important factor but rather cellular differentiation and hyalinization. Even those who have attempted to focus specifically on host factors influencing the growth of tumors in humans have found that the degree of differentiation of tumors is intimately related to expression of host factors.2 Ershler3 has characterized host factors as the ‘soil’ and the tumor itself as the ‘seed’. Let us see if an old seed germinates differently than a young seed. To do this, one can view the tumor in terms of stage and growth, intrinsic aspects of histology, and survival of the host. Stage and growth The relationship between age and cancer stage at the time of diagnosis was described in 1981 by Holmes and Hearne.4 They found increasing age to be significantly related to increased stage at diagnosis in cancers primary to breast, cervix, endometrium, ovary, and urinary bladder, and less significantly related in cancers primary to kidney and stomach. In colorectal cancer, there was no relationship, and in lung cancer, there was a significant

Clinical evidence for change in tumor aggressiveness with age

323

inverse relationship of stage to age. In 1986, Goodwin et al5 studied 15 varieties of cancer, and found melanoma and cancers of breast, cervix, endometrium, ovary, thyroid, and urinary bladder more likely to be diagnosed at an advanced stage with increasing age, with no trend of stage with age for colon, gallbladder/liver, kidney, or prostate cancers. For cancers primary to lung, pancreas, rectum, and stomach, there was an inverse trend, with lung being highly significant. The data for these two studies are shown in Table 15.1. The methods of analysis were not the same, but the results are generally concordant. Another view of the relationship of stage to age may be obtained by reviewing large autopsy studies. An early study cataloged locations of metastases in 1000 consecu-

Table 15.1 Relationship of stage at diagnosis of common cancers to increasing patient age: studies by Holmes and Hearne4 and Goodwin et al5 Site

Holmes and Hearne

Goodwin et al

Breast

Increase

Increase

Cervix

Increase

Increase

Colon

—

Neutral

Colorectum

Neutral

—

Endometrium

Increase

Increase

Gallbladder/liver

—

Neutral

Kidney

Increase

Neutral

Lung

Decrease

Decrease

Melanoma

—

Increase

Ovary

Increase

Increase

Pancreas

—

Decrease

Prostate

—

Neutral

Rectum

—

Decrease

Stomach

—

Decrease

Thyroid

—

Increase

Urinary bladder

Increase

Increase

tive cancer cases in a large metropolitan hospital without more than a general reference to age as a potential factor influencing numbers and distributions of metastases.6 In an autopsy series of 3535 patients aged over 65, Suen et al7 noted that cancer tended to metastasize less frequently in the elderly. They found this in cancers primary to breast, colon, kidney, lung, pancreas, prostate, rectum, stomach, urinary bladder, and uterus. The numbers of cases were small in the oldest age groups and no statistical analysis was reported. Another finding of note from their study was that the number of cancers newly

Comprehensive Geriatric Oncology

324

diagnosed at autopsy increased as a percentage of all cancers by age, from 20.7% in the 66–75 age group to 36.2% in those 86 and older. Studying gastric cancer in Japan, Esaki et al8 found peritoneal involvement to be less in older patients, but no difference in hepatic involvement between the elderly and those younger. More recent studies from Japan have shown that early gastric carcinomas in the very old tend to be well differentiated when compared with the middle-aged, but these cancers do become less differentiated as they grow, eventually matching those of the middle-aged patients.9 This raises the possibility that many cancers in the elderly may be relatively indolent and not cause symptoms during the life of the patient. McFarlane et al10 make this point in their autopsy study. Studying cancers found at autopsy in patients from ages 75 to 106, researchers in Trieste, Italy, found that cancer prevalence declined after age 90, as did mortality from cancer.11 Some think that these autopsy-discovered cancers tend to be more differentiated than those diagnosed during life. In focusing on particular cancers, an autopsy study of 1828 renal adenocarcinomas in Japan found a considerable decrease in the number of metastases with age generally and in organs usually bearing metastases specifically.12 Much the same phenomenon was demonstrated by Ershler et al13 in lung cancer. The magnitude of the trend of decreasing stage with increasing age in lung cancer is considerable. A study of 22 874 lung cancer cases showed local-stage disease in 13.9% of those less than 54 years of age, 19.2% in those aged 55–64, 21.4% in those aged 65–74, and 25.4% in those aged 75 and older.14 Quite apart from other considerations, this makes routine screening for curable lung cancer in the elderly a much more attractive possibility than in the middle-aged. At least part of the reason for the stage-to-age trend in lung cancer is the changing balance of histologies with age shown in a study of 9062 histologically confirmed lung cancer cases by Teeter et al.15 Squamous cell carcinoma increased from 26% to 40% of the total cases between ages 40 and 80, and adenocarcinoma and small cell carcinoma declined proportionately, with large cell carcinoma unchanged. The proportion of staged cases with local disease increased from 27% to 54% for squamous cell carcinoma between ages 40 and 80, with smaller but statistically significant increases for all other histologies except large cell carcinoma. Yancik et al16 focused on data for 125000 women with breast cancer from the US National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) program, in order to study the relationship of age to stage and survival. They found that women presenting with distant disease or unstaged disease were more likely to be elderly. Growth rates for breast cancer are highly variable. Spratt et al17 found an inverse relationship between patient age and tumor size at mammographic diagnosis. Mean tumor diameter for those younger than 70 was 13 mm, while for those older it was 9 mm. There were no age differences in doubling times or growth rates. None of the observations by Spratt et al reached statistical significance. Other studies have shown age-related lead time differences, and Pelikan and Moskowitz18 have created mathematical models to study mammographic screening using numbers that presume slower tumor doubling in older women. One other factor of stage-to-age relationships deserves mention. Where a cancer arises in a particular organ may be of importance. In 1977, Rhodes et al19 described a shift from distal to proximal subsite origin of colorectal cancer during the preceding three decades. In 1985, Butcher et al,20 from this same group, identified increasing age and female

Clinical evidence for change in tumor aggressiveness with age

325

gender as two factors that are at least partly responsible for this interesting phenomenon. In this vein, elderly women are more likely to have medial and central breast cancers than younger women.21 Right-sided colon cancers cause symptoms later than those near the rectum, and medial breast cancers are more likely to spread to lymph nodes within the chest than lateral cancers. Intrinsic aspects of histology Scrutiny of chemically stained small pieces of tumor tissue under the microscope has been common practice for over a hundred years. Yet, even the most clever pathologist cannot determine the age of the patient by microscopic examination of his or her cancer. The relationships of cancer histology to age have not received much attention over the years. In 1949, Lees and Park22 surveyed the extant literature and studied hundreds of cases of their own. They concluded that histologic indicators of cancer aggressiveness or indolence did not appear to be a function of patient age, with the possible exception of carcinoma of the lung. On the other hand, indolent cancers may be more common in the young than the old at sites such as the ovary.23 Carcinoma of the cervix and its precursor states are uniquely available to histologic study through exfoliative cytology. An atypical Papanicolaou cervical smear in a woman aged over 60 is 16 times more likely to lead to a diagnosis of invasive cancer than one in a woman younger than 30.24 Some think that in situ carcinoma of the cervix often has a distinctive cytologic appearance in the elderly, characterized by a large number of keratinizing cancer cells with a variable admixture of lesser numbers of third-type cells of Graham.25 In addition, there is evidence for a slowly evolving cervical cancer in young women and a more rapidly evolving one in older women.26,27 Much of the study of the relationship of cancer histology to age has been pursued with breast cancer. The distributions of the various histologic types of breast cancer are different when older women are compared with middle-aged and younger women.28 Most breast cancers, regardless of age, are infiltrating ductal carcinomas. A higher histologic grade is most common in the youngest breast cancer patients, as are inflammatory and medullary breast cancers. Infiltrating lobular and colloid carcinomas were found to be especially common among the elderly.21,29 Breast cancers in elderly women are more likely to be diploid, and thus relatively slowly growing.30 The very large study of 125000 women with breast cancer conducted by Yancik et al16 found medullary carcinoma to decrease and mucinous carcinoma to increase with age. Other histologies changed little with aging. Identifying cellular components by methods other than microscopy has been a burgeoning field in the past several decades. Perhaps the best example of the utility of these techniques in neoplasia is the quantification of estrogen and progesterone receptors (ER and PgR) in breast cancer cells. Repeatedly, an increasing likelihood of the presence of ER protein has been correlated with increasing age, and the mean concentration increases with age as well. This association is independent of all of the other breast cancer risk factors.31,32 The same seems to be true for PgR, and a higher survival rate in patients with ER and PgR positivity has been demonstrated.33 It seems likely that, at least in part, this phenomenon is related to cellular differentiation.

Comprehensive Geriatric Oncology

326

For many years, it has been known that there is a relationship between histologic grade and survival in cancer.1,34 People with higher-grade cancers (i.e. cancers that are less differentiated) have shorter survivals than those with lower-grade cancers. This has no particular relationship to the size of the primary tumor, but it has great prognostic value when the issues of screening and likelihood of cancer cure are addressed.35 Using unpublished data from the Cancer Data Service, the regional cancer registry for Kansas and western Missouri, it is possible to compare distributions by age for differentiated and undifferentiated histologies for common carcinomas. The results of this simple chi-square analysis are shown in Table 15.2. The numbers of cases are large, so the differences may have more apparent significance than clinical significance. Nonetheless, there does seem to be a trend towards less differentiation with increasing age for

Table 15.2 Relationship of increasing age to increasing histologic grade for common carcinomas: Cancer Data Service, 1982–87 Type of carcinoma

Number

Significance of increasing age/grade trenda

Breast

2303

NS

Colon/rectum

5140

p<0.01

Lung

3660

p<0.001

Ovary

520

NS

Prostate

4596

p<0.001

Stomach

534

NS

Urinary bladder

2037

p< 0.01

a

NS, not significant.

colon/rectum, lung, prostate, and urinary bladder. No difference is seen for breast, ovary, and stomach, but the numbers of cases are smaller in the latter two sites. In thyroid cancer, patient age at diagnosis can be combined with sex and histologic grade to create a highly significant prognostic scoring system. In this system, male gender, greater age, and higher histologic grade were related to decreased survival in papillary thyroid carcinoma.36 Prostate carcinoma is the quintessential cancer of older men—usually indolent but often aggressive and lethal. The contrast between those two extremes has only recently prompted an explanation. Whittemore et al37 believe that the tumor volume of Gleason low-grade latent prostate cancer per patient is directly related to the chance of transformation to Gleason high-grade cancers that will threaten life. They calculate that one may expect 0.024 high-grade cancers per year per cubic centimeter of low-grade latent cancer volume. If true, this observation has great import for the understanding of prostate cancer in older men. Malignancies primary to the brain in the elderly have increased in incidence in recent years—surely due in large part to an increased rate of diagnosis because of the more widespread use of imaging. This has meant that glioblastoma incidence is now

Clinical evidence for change in tumor aggressiveness with age

327

understood to increase directly with increasing age, perhaps implying malignant transformation of low-grade gliomas with aging.38 Survival of the host The final arbiter in the study of the biology or natural history of human cancer is the duration of survival of the patient who bears the cancer. Survival analysis is difficult to do well, particularly in the elderly. By necessity, we compute survival from the time of diagnosis and not from the time the cancer actually started with a cell or cells beginning a course of malignant growth. If one reads only

Table 15.3 SEER 5-year relative survival rates for all sites and stages combined, 1974–8338 Age group

All

Male

Female

All

48.8

42.0

55.0

0–54

59.2

48.3

66.6

55–64

47.9

40.1

55.7

65–74

44.7

40.8

49.2

75+

39.9

38.6

41.1

the last 100 pages of a 400-page novel, can one really understand the story? Computing survival in elderly populations is fraught with considerable hazard. Competing mortalities, a sharply rising mortality curve, inaccuracy of death certificate data, recent improvements in survival in the oldest age groups, and lack of accurate national benchmark statistics conspire to flaw any computation of survival of elderly cancer patients. In spite of this, survival comparisons of elderly with middle-aged and young cancer patients have been attempted. Summary articles tell us that survival in elderly cancer patients varies with the site and that there seems to be little agreement among authors even for specific sites.39,40 SEER 5year relative survival rates for all sites and all stages combined show that there is a general decline by age for both sexes, as shown in Table 15.3.41 This is confounded by the different distributions of cancer sites by age groups and the fact that older people are often treated less aggressively than those younger.42,43 For lung and colon cancer, there are data establishing that elderly patients do just as well as those who are younger if they are acceptable candidates for surgery. Their survival is comparable to that of younger patients. In lung cancer, Kirsh et al44 found a 30% absolute 5-year survival rate in 55 patients aged over 70. Sherman and Guidot45 compared the results of thoracotomy for lung cancer in 64 patients older than 70 with those in 75 patients younger than 70. The operative mortality rate was increased in the older age group (9.4% versus 4.0%), but there was no significant difference in survival between the two age groups. Even the results of chemotherapy of small cell carcinoma of the lung in the elderly are encouraging in one study.46 A study of colon cancer found that

Comprehensive Geriatric Oncology

328

the 5-year survival of 156 patients who were 80 or older at the time of surgical treatment was better than survival in younger patients.47 In the acute leukemias, non-Hodgkin lymphomas, and Hodgkin lymphoma, advanced age is related to a decreased chance of remission and a decreased survival overall.40,48–50 Sadly, this remains true in acute myeloid leukemia, and the paradox of the inverse relationship of age to survival has been examined.51,52 Aged patients with acute leukemia harbor malignant cells of a much more primitive origin that those in younger patients, and their cells typically have the markers of poor survival as well as the greatest likelihood of resistance to drug treatment.53 In myeloma, the aged patient does at least as well, with comparable response rates and survival equal to or better than those in younger patients.54–56 Probably studies of the relationship of age to survival in breast cancer have equaled in number such studies for all other sites of cancer combined. This may be because this is a very common cancer, with long survival also being common. Early studies seemed to indicate that older women survived longer with this disease than those who were middleaged or younger.1,57 Very long survival, even in the untreated state, and very late recurrence make the study of survival in breast cancer difficult.34,58 However, small and occasionally significant differences in survival have been reported on comparing younger and older women in various cohorts over recent decades.28 Although ER-positive cancers are increasingly common with increasing age and ER positivity is associated with improved survival, the survival differential between patients with ER-positive tumors and those with ER-negative tumors seems to lessen as age increases.59 Comparing the extremes of age—those less than 35 with those older than 75—Rosen et al21 found no significant difference in recurrence or survival. In a surgical series of 780 breast cancer patients, Herbsman et al60 found absolute survival to be the same or better with increasing age when patients were stratified by stage, and absolute survival strikingly increased as age at diagnosis increased. In 1978, Mueller et al61 identified age as a significant determinant in the rate of dying and causes of death in 3558 breast cancer cases. Using cancer registry data from an upstate New York hospital and life-table analysis focusing on deaths from breast cancer, they found breast cancer lethality to increase directly with increasing age. The validity of their study was questioned by Newcombe and Hillyard,62 who thought that their estimation of deaths from breast cancer in their greater than 70 age group was inflated by a factor of three. This is illustrative of the difficulty in accurately computing survival from cause-of-death data in the elderly. In 1983, Hibberd et al63 published long-term survival data of 2019 women with histologically proven breast cancer diagnosed in New Zealand between 1950 and 1954, representing an estimated 80% of the breast cancer cohort of those years for that country. They found no apparent relation between age and excess mortality, except that the very youngest cohort (60 women who were aged 20–34 at diagnosis) had virtual flattening of the survival curve after 10 years, whereas none of the other cohorts did. Adami et al64,65 have studied survival in two large breast cancer populations in Sweden: 12319 diagnosed between 1959 and 1963 and 57068 diagnosed between 1960 and 1978. Because cancer registration in Sweden is virtually complete, these data are of high quality. Adami et al found relative survival to decline markedly after age 49, with women older than 75 having the worst survival. Unfortunately, they did not stratify the

Clinical evidence for change in tumor aggressiveness with age

329

data for stage at diagnosis. Analyzing the survival of 78405 White females diagnosed with breast cancer in America between 1974 and 1983, the SEER group found consistently decreased percentage relative survival out to seven years when those younger than 50 were compared with those aged 50 and older. When these patients were stratified by stage, 3- and 5-year survival were apparently better for the older women in stages I and II and the younger women in stages III and IV. However, the only statistically significant difference was at the 0.05 level at 5 years for stages I and II.41 It may be possible to resolve these conflicting results, at least in part. Survival analysis in breast cancer without stratification by stage has limited value. Stage increases with age and thereby worsens survival for older women.4,5 Two studies have identified a subgroup of elderly women with relatively indolent low-stage breast cancer who have reduced excess mortality.66,67 It seems possible that there is heterogeneity in low-stage breast cancer in the elderly, perhaps from more favorable histologic patterns.21,28–30 The meaning and importance of these trends The studies and data presented do not support a simple and single trend for change in tumor aggressiveness with increasing age. Given that cancer is not a single disease but rather a collection of diseases, this should be no surprise. There seems to be diversity even within a single site (e.g. breast). Because cancer incidence rises steeply with age and because there are so many cases in older people (one-half of all cancers diagnosed in the USA are in the one-eighth of the population aged 65 and older), the sheer volume of cases would suggest the possibility of diversity. Beyond this, one must recognize the fact that old people of a given age are far less homogeneous that those who are younger. Thus, although there is a general trend for increasing stage at diagnosis with increasing age for most common cancer sites, colon, gallbladder/liver, prostate, and perhaps kidney show no such trend at all. In lung cancer, there is a strongly significant trend for decreasing stage with age, and this is at least partly explained by changing distributions of common histologies with age. Evidence is not present for increasing histologic grade with age for carcinomas primary to the breast, ovary, and stomach, but it is present for colon/rectum, prostate, urinary bladder, and even lung—although in the lung this seems to contrast with the stage-to-age trend. A study of nearly 5000 prostate cancers showed a highly significant increase in histologic grade with increasing age, even in locally confined disease.68 In relative survival for all sites of cancer, there is a general decline with age, but differences emerge when specific sites are stratified by stage. However, in acute leukemia in the elderly, survival still has not improved much, in striking contrast to the remarkable improvement in survival in children.49,51,69 In many respects, the phenomenon of change in tumor aggressiveness with age can best be illustrated by breast cancer. Although stage at diagnosis increases with age, there is not a corresponding increase in histologic grade with age. However, the distribution of various histologies changes with age, and the proportions of both ER- and PgR-positive tumors increase with age. The meaning of these trends may become clear when one considers the final arbiter—survival, stratified by stage and age. Older women survive longer than younger women when low-stage disease is examined, with the reverse being true for high-stage disease.

Comprehensive Geriatric Oncology

330

So it seems that those who believe that slowly growing tumors are associated with old age are correct, as are those who believe that rapidly growing tumors are associated with old age. Site and stage are two important determinants. It would seem that groups of old tumors are just as diverse as groups of old people. References 1. Sistrunk WE, MacCarty WC. Life expectancy following radical amputation for carcinoma of the breast: a clinical and pathologic study of 218 cases. Ann Surg 1922; 75:61–9. 2. Di Paola M, Angelini L, Bertolotti A et al. Host resistance in relation to survival in breast cancer. BMJ 1974; iv:268–70. 3. Ershler WB. Why tumors grow more slowly in old people. J Natl Cancer Inst 1986; 77:837–9. 4. Holmes FF, Hearne E. Cancer stage-to-age relationship: implications for cancer screening in the elderly. J Am Geriatr Soc 1981; 29:55–7. 5. Goodwin JS, Samet JM, Key CR et al. Stage at diagnosis of cancer varies with the age of the patient. J Am Geriatr Soc 1986; 34:20–6. 6. Abrams HL, Spiro R, Goldstein N. Metastases in carcinoma: analysis of 1,000 autopsied cases. Cancer 1950; 3:74–85. 7. Suen KC, Lau LL, Yermakov V. Cancer and old age. An autopsy study of 3,535 patients over 65 years old. Cancer 1974; 33:1164–8. 8. Esaki Y, Hirayama R, Katsuiku H. A comparison of patterns of metastasis in gastric cancer by histologic type and age. Cancer 1990; 65:2086–90. 9. Inoshita N, Yanagisawa A, Arai T et al. Pathological characteristics of gastric carcinoma in the very old. Jpn J Cancer Res 1998; 89: 1087–92. 10. McFarlane MJ, Feinstein AR, Wells CK et al. The ‘epidemiologic necropsy.’ Unexpected detections, demographic selections, and changing rates of lung cancer. JAMA 1987; 258:331–8. 11. Stanta G, Campagner L, Cavallieri F et al. Cancer in the oldest old: what we have learned from autopsy studies. Clin Geriatr Med 1997; 13:55–68. 12. Saitoh H, Shiramizu T, Hida M. Age changes in metastatic patterns in renal adenocarcinoma. Cancer 1982; 50:1646–8. 13. Ershler WB, Socinski MA, Greene CJ. Bronchogenic cancer, metastases, and aging. J Am Geriatr Soc 1983; 31:673–6. 14. O’Rourke MA, Feussner JR, Feigl P et al. Age trends of lung cancer stage at diagnosis: implications for lung cancer screening in the elderly. JAMA 1987; 258:921–6. 15. Teeter SM, Holmes FF, McFarlane MJ. Lung carcinoma in the elderly population: influence of histology on the inverse relationship of stage to age. Cancer 1987; 60:1331–6. 16. Yancik R, Ries LE, Yates JW. Breast cancer in aging women: a population-based study of contrasts in stage, surgery, and survival. Cancer 1989; 63:976–81. 17. Spratt JA, vonFournier D, Spratt JS, Weber EE. Mammographic assessment of human breast cancer growth and duration. Cancer 1993; 71:2020–6. 18. Pelikan S, Moskowitz M. Effects of lead time, length bias, and false-negative assurance on screening for breast cancer. Cancer 1993; 71: 1998–2005. 19. Rhodes JB, Holmes FF, Clark GM. Changing distribution of primary cancers in the large bowel. JAMA 1977; 238:1641–3. 20. Butcher D, Hassanein K, Dudgeon M et al. Female gender is a major determinant of changing subsite distribution of colorectal cancer with age. Cancer 1985; 56:714–16. 21. Rosen PP, Lesser ML, Kinne DW. Breast carcinoma at the extremes of age: a comparison of patients younger than 35 years and older than 75 years. J Surg Oncol 1985; 28:90–6. 22. Lees JC, Park WW. The malignancy of cancer at different ages: a histological study. Br J Cancer 1949; 3:186–97.

Clinical evidence for change in tumor aggressiveness with age

331

23. Richardson GS, Scully RE, Nikrui N et al. Common epithelial cancer of the ovary. N Engl J Med 1985; 312:415–24. 24. Shingleton HM, Partridge EE, Austin JM. The significance of age in the colposcopic evaluation of women with atypical Papanicolaou smears. Obstet Gynecol 1977; 49:61–4. 25. Gard PD, Fields MJ, Noble EJ et al. Comparative cytopathology of squamous carcinoma in situ of the cervix in the aged. Acta Cytol 1969; 13:27–35. 26. Ashley DJ. Evidence for the existence of two forms of cervical carcinoma. J Obstet Gynaecol Br Comm 1966; 73:382–9. 27. Hakama M, Penttinen J. Epidemiological evidence for two components of cervical cancer. Br J Obstet Gynaecol 1981; 88:209–14. 28. Schottenfeld D, Robbins GF. Breast cancer in elderly women. Geriatrics 1971; 26:121–31. 29. Allen C, Cox EB, Manton KG et al. Breast cancer in the elderly. Current patterns of care. J Am Geriatr Soc 1986; 34:637–42. 30. von Rosen A, Gardelin A, Auer G. Assessment of malignancy potential in mammary carcinoma in elderly patients. Am J Clin Oncol 1987; 10:61–4. 31. McCarty KS, Silva JS, Cox EB et al Relationship of age and menopausal status to estrogen receptor content in primary carcinoma of the breast. Ann Surg 1983; 197:123–7. 32. Elwood JM, Godolphin W. Oestrogen receptors in breast tumors: associations with age, menopausal status and epidemiological and clinical features in 735 patients. Br J Cancer 1980; 42:635–44. 33. S/akacs JG, Arroyo JG, Girgenti AJ. Assessment of results of estrogen and progesterone receptor assays performed in a community hospital. Ann Clin Lab Sci 1986; 16:266–73. 34. Bloom HJG, Richardson WW, Harries EJ. Natural history of untreated breast cancer (1805– 1933). Comparison of untreated and treated cases according to histological grade of malignancy. BMJ 1962; ii:213–21. 35. Meyers FJ. Tumor biology in explanation of the failure of screening for cancer and in determination of future strategies. Am J Med 1986; 80:911–16. 36. Akslen L. Prognostic importance of histologic grading in papillary thyroid carcinoma. Cancer 1993; 72:2680–5. 37. Whittemore AS, Keller JB, Betensky R. Low-grade, latent prostate cancer volume: predictor of clinical cancer incidence? J Natl Cancer Inst 1991; 83:1231–5. 38. Fernandez P, Brem S. Malignant brain tumors in the elderly. Clin Geriatr Med 1997; 13:327– 38. 39. Peterson BA, Kennedy BJ. Aging and cancer management. Part I: Clinical observations. CA Cancer J Clin 1979; 29:322–32. 40. Lipschitz DA, Goldstein S, Reis R et al. Cancer in the elderly: basic science and clinical aspects. Ann Intern Med 1985; 102:218–28. 41. Sondik EJ, Young JL, Horm JW. 1986 Annual Cancer Statistics Review. NIH Publication 87– 2789. Bethesda, MD: US Department of Health and Human Services, 1987. 42. Samet J, Hunt WC, Key C et al. Choice of cancer therapy varies with age of patient. JAMA 1986; 255:3385–90. 43. Mor V, Masterson-Allen S, Goldberg RJ et al. Relationship between age at diagnosis and treatments received by cancer patients. J Am Geriatr Soc 1985; 33:585–9. 44. Kirsh MM, Rotman H, Bove E et al. Major pulmonary resection for bronchogenic carcinoma in the elderly. Ann Thorac Surg 1976; 22: 369–73. 45. Sherman S, Guidot CE. The feasibility of thoracotomy for lung cancer in the elderly. JAMA 1987; 258:927–30. 46. Clamon GH, Audeh MW, Pinnick S. Small cell lung carcinoma in the elderly. J Am Geriatr Soc 1982; 30:299–302. 47. Calabrese CT, Adam YG, Volk H. Geriatric colon cancer. Am J Surg 1973; 125:181–4. 48. Sorensen JT, Gerald J, Bodensteiner D, Holmes FF. Effect of age on survival in acute leukemia. Cancer 1993; 72:1602–6.

Comprehensive Geriatric Oncology

332

49. Baudard M, Marie JP, Cadiou M et al. Acute myelogenous leukaemia in the elderly: retrospective study of 235 consecutive patients. Br J Haematol 1994; 86:82–91. 50. Peterson BA, Pajak TF, Cooper MR et al. Effect of age on therapeutic response and survival in advanced Hodgkin’s disease. Cancer Treat Rep 1982; 66:889–98. 51. Stone RM,, Berg DT, George SL et al. Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. N Engl J Med 1995; 332:1671–7. 52. Hamblin TJ. Disappointments in treating acute leukemia in the elderly. N Engl J Med 1995; 332:1712–13. 53. Extermann M. Acute leukemia in the elderly. Clin Geriatr Med 1997; 13:227–44. 54. Ludwig H, Fritz E, Friedl HP. Epidemiologic and age-dependent data on multiple myeloma in Austria. J Natl Cancer Inst 1982; 68:729–33. 55. Holmes FF. Aging and Cancer. Berlin: Springer-Verlag, 1983. 56. Cohen HJ, Silberman HR, Forman W et al. Effects of age on responses to treatment and survival of patients with multiple myeloma. J Am Geriatr Soc 1983; 31:272–7. 57. Daland EM. Untreated cancer of the breast. Surg Gynecol Obstet 1927; 44:264–8. 58. Sutton M. Late recurrence of carcinoma of breast. BMJ 1960; ii: 1132–4. 59. Croton R, Cooke T, Holt S et al. Oestrogen receptors and survival in early breast cancer. BMJ 1981; 283:1289–91. 60. Herbsman H, Feldman J, Seldera J et al. Survival following breast cancer surgery in the elderly. Cancer 1981; 47:2358–63. 61. Mueller CB, Ames F, Anderson GD. Breast cancer in 3,558 women: age as a significant determinant in the rate of dying and causes of death. Surgery 1978; 83:123–32. 62. Newcombe RB, Hillyard JW. Age and death in breast cancer. Surgery 1980; 87:599–600. 63. Hibberd AD, Horwood LJ, Wells JE. Long term prognosis of women with breast cancer in New Zealand: study of survival to 30 years. BMJ 1983; 286:1777–9. 64. Adami H-O, Malker B, Meirik O et al. Age as a prognostic factor in breast cancer. Cancer 1985; 56:898–902. 65. Adami H-O, Malker B, Holmberg L et al. The relation between survival and age at diagnosis in breast cancer. N Engl J Med 1986; 315:559–63. 66. Langlands AO, Pocock SJ, Kerr GR et al. Long-term survival of patients with breast cancer: a study of the curability of the disease. BMJ 1979; ii:1247–251. 67. Christiansen HD, Holmes FF, Scott TE et al. Age and survival in breast cancer. In: Proceedings of the Annual Meeting of the American Geriatric Society, 1983. 68. Borek D, Butcher D, Hassanein K, Holmes F. Relationship of age to histologic grade in prostate cancer. Prostate 1990; 16:305–11. 69. Whitely R, Hannah P, Holmes F. Survival in acute leukemia in elderly patients, no improvement in the 1980s. J Am Geriatr Soc 1990; 38:527–30.

16 Morbid anatomy of aging Giorgio Stanta Introduction There has been great interest in the morbid anatomy of aging, and many studies have been performed on autopsies of elderly people over the last two decades and more, with particular attention to the extreme ages of life.1–10 However, it is the belief of the present author that the relevance of many of these studies has been underestimated. Today, the ever-increasing proportion of elderly people in industrialized countries makes these studies more and more important. This renewed interest is connected with difficulties in making a precise diagnosis in elderly people, in spite of recently available sophisticated techniques. Diseases in elderly patients often lack those symptoms and signs that usually guide physicians. Sometimes, even after autopsy, it is difficult to precisely define the cause of death in an elderly person. In this age of molecular biology, morbid anatomy can still be an important tool to answer questions concerning the aging process and to provide a more comprehensive picture of the problem. In this chapter, attention will be focused on the pathological patterns of the extreme ages of life and on malignant tumors. However, it is not meant to be a review of geriatric pathology, but rather will focus on some of the relevant issues. Non-neoplastic pathology of the aging In the elderly, the presence of a basic and characteristic pathology causes specific lesions in different organs and apparatus through systemic changes (Table 16.1). Distinct lesions of different organs result from a single multisystemic process. For example, arteriosclerosis is involved in myocardial fibrosis, nephrosclerosis, and atrophy of many organs. Most of these lesions are degenerative and chronic, and obviously increase in frequency and severity in the elderly. Acute diseases are present at any age, and cannot be considered characteristic of the elderly. Nevertheless, some of these characteristics are more common among the elderly, and are especially severe in the extreme ages of life, when they become relevant causes of death (e.g. bronchopneumonia). Cardiovascular system Most octogenarians and nonagenarians present an evident atherosclerosis of the major arteries, with atheromas and thrombi that sometimes obstruct most of the vessel lumen. These lesions are a common finding at autopsy of the elderly, usually being localized at

Comprehensive Geriatric Oncology

334

the level of the aorta,11–13 but their severity varies from case to case, and two-thirds of examined nonagenarians present a severe atherosclerosis.3 In a few cases, the lesions, even when present, are only slightly evident. The degree of intimal fibrous thickening with stenosis of the coronary vessels has been reported to be related to the same kind of lesion in the aorta,3 but from our experience and that of others,5

Table 16.1 Chronic and degenerative lesions commonly found at autopsy of the oldest old Cardiovascular lesions •

The coronary arteries are less sclerotic than in the younger old11

•

Severe myocardial fibrosis1,3

•

Cardiac amyloid deposition1

Pulmonary lesions •

Emphysematous panacinar changes5

•

Bronchiectatic changes5

Urinary system lesions •

Nephrosclerosis3

•

Chronic pyelonephritis6

•

Renal infarctions6

Digestive system lesions •

Sigmoid diverticulosis3

•

Atrophy of the liver without fibrosis and specific lesions6

Osseous system lesions •

Osteoporosis7

Morbid anatomy of aging

335

Figure 16.1 Myocardial fibrosis. this cannot be found in centenarians: the degree of sclerosis of coronary vessels is usually lower than that of the aorta. The same can be shown by autopsy examination of cerebral vessels. On the other hand, the severity of atherosclerosis of femoral arteries in centenarians seems to be linked to that of the aorta. Myocardial fibrosis is one of the most important pathological findings in aging (Figure 16.1) and is an extremely important condition contributing to death in octogenarians and nonagenarians1,3,11,13 In our centenarians case study, myocardiosclerosis was moderate in 35% of the cases, marked in 42%, and severe in 12%. Fibrosis was confined to the left ventricle, mostly localized to the anterior and posterior wall and to the septum. The localization of fibrosis and the concomitance of coronarosclerosis prove the lesion to be connected with ischemia of myocardium. Also, the wall of the right ventricle of the elderly shows anatomic signs of a decreased contractile efficiency, with the presence of adipocytes between the muscle fibers, sometimes with the pattern of so-called right ventricle lipomatosis.5 Myocardial scars from a previous myocardial infarction are often seen, and can also contribute to a cardiac failure. Amyloidosis of the heart is another characteristic of the elderly. We found amyloid in 12% of our cases (Figure 16.2), but other studies report the presence of cardiac amyloidosis in over 30% of centenarians.5 Myocardial atrophy was evident in 23% of our centenarian cases, and even the apparently hypertrophic hearts did not show any increased cardiac weight.5 As experienced by other authors,5 we did not find a real case of brown atrophy, which should be considered to be connected with severe malnutrition rather than directly with the aging process. In addition to the above-reported lesions, degeneration of the cardiac valves can also contribute to chronic heart

Comprehensive Geriatric Oncology

336

Figure 16.2 Amyloidosis of the heart. failure. A calcified ring or fibrous thickening at the mitral or aortic level is a frequent finding in the elderly.5 Respiratory system Bronchopneumonia is the final cause of death in only 2.5% of people aged over 65, but it represents 20% of the causes in people aged over 95 and 30% in centenarians. Usually, pneumonia can be considered the final cause of death, as a complication of other evident contributory diseases, such as a hip fracture with immobilization of the patient; sometimes, it is apparently the only cause of death. The lesion is usually focal, but it can involve an entire pulmonary lobe or more. It is often reported that most pneumonias of the elderly are ‘ab ingestis’ lesions. The rare occurrence of foreign body granulomas in our study and in other case studies5 does not confirm this hypothesis. Perhaps the reason for the high frequency of bronchopneumonia is, besides immunodeficiency, stagnation of secretions and air. The frequent emphysematous and bronchial changes could also play an important role in the occurrence of pneumonia.5 The presence of emphysema (Figure 16.3) was described in over 70% of the nonagenarians examined3 but in only 20% of centenarians.5 This discrepancy could be related to the use of different diagnostic criteria rather than to a real difference in occurrence. Together with bronchiectatic changes, the lesions vary in severity, and tend to increase in frequency, particularly among people aged over 80. A fibrous pleuritis with pleural adhesions is present in more than onethird of people over 90. Pulmonary tuberculosis caused the death of 3 centenarians out of 99 examined. In 1 more case, the disease was detected, but it was not related to the cause of death. None of the cases was suspected before death.

Morbid anatomy of aging

337

Figure 16.3 Emphysema. Digestive tract The most frequent lesion of the digestive tract in the elderly is diverticulosis of the large bowel, which involves the sigmoid colon in about 40% of people aged over 80.3,14 Complications of diverticulosis in the very old are not very frequent. In our case study of centenarians, only 1 case out of 99 showed perforation of a diverticulus. The peritonitis that followed caused the death of the patient. In the very old, the liver is characterized by a peculiar lack of lesions. In centenarians, the liver appears moderately atrophic, but always with a normal histologic structure (Figure 16.4).6 The microscopic finding of a high number of binucleated cells and the alteration of the nucleus-to-cytoplasm ratio are considered specific histologic changes of the senile liver.15 Fatty changes and congestion are frequently observed as a consequence of final respiratory and cardiac failure. Chronic primary lesions of the liver, such as chronic hepatitis and cirrhosis, are quite frequent autopsy findings in the younger age groups of the elderly, but they are uncommon in the extreme ages of life. We found a marked atrophy of the pancreas in onethird of centenarians, and lithiasis of the gallbladder in 15% of cases. Genitourinary lesions Most of the very old have atrophic kidneys with macroscopic scars and multiple retention cysts. Atrophy mainly involves the cortex, while the medulla presents interstitial fibrosis (Figure 16.5). The renal arterioles show hyaline thickening. Signs of chronic pyelonephritis and previous infarctions are often present. All of these lesions generally worsen with age.

Comprehensive Geriatric Oncology

338

In 253 autopsy examinations of the prostate gland in the elderly (males aged over 80), 92 hyperplastic glands,

Figure 16.4 Normal histologic structure of the liver in a centenarian.

Figure 16.5 In the aging kidney, the cortex is atrophied while the medulla presents interstitial fibrosis.

Morbid anatomy of aging

339

21 latent adenocarcinomas, and 16 aggressive tumors were found.1 The testes show atrophy of the spermatic ducts and moderate hyperplasia of the Leydig cells. In females, there is a marked atrophy of the uterus and ovaries, with loss of germinal follicles. Other organs Aging is characterized by diseases of other organs and apparatus, such as those of the bones and joints and the chronic degenerative lesions of the brain, but the occasional autopsy findings cannot add information regarding these well-studied pathologies. On the other hand, acute cerebrovascular accidents, such as strokes and hemorrhages, are frequently found as main or contributory causes of death at autopsy. Also, the aging process of the skin and pressure ulcers contribute significantly to pathology in the elderly. Characteristic patterns of non-neoplastic pathology in the extreme ages of life There are many autopsy studies of pathology in the extreme ages of life.2,3,5–9 Chronic lesions, characteristic of the aging process, are more frequent and severe in nonagenarians and centenarians. Among chronic degenerative diseases, arteriosclerosis in particular characterizes the aging process. The localization of atheromas in the elderly is not uniform. In centenarians, the lesions in the aorta and the femoral arteries are more severe than in the cerebral and coronary vessels.5 Many of the characteristic pathologies found in extremely old people are related to arteriosclerosis of the major and the small arteries. The consequent chronic ischemic damage contributes to the degeneration of other organs that is associated with the aging process. Myocardial fibrosis, nephrosclerosis, and atrophy of organs are the outcomes. The heart’s efficiency as a pump is decreased by fibrosis and the possible association with myocardial atrophy and amyloidosis. The respiratory system is damaged by a panacinar emphysema, with which are associated bronchiectatic changes and stagnation of secretions. In such a critical situation, bronchopneumonia and cardiac failure are frequent fatal outcomes. Atrophic and fibrotic changes involving most organs and the consequent hypofunction, together with frequent leanness, contribute to define the usual pattern of the extremely old. An absence of pathologic changes in the liver is also characteristic of centenarians.6 No signs of chronic hepatitis or fibrosis of any origin are usually detected in very old people, even after microscopic examination. In contrast, these lesions are common findings in autopsies of the younger age groups. Cardiac and pancreatic fibrosis is on average more severe in centenarians than in people aged between 75 and 85. The prevalence of arteriolosclerosis of kidney and brain vessels is also different in the two age groups. The walls of the kidney arterioles are clearly thicker in centenarians than in people aged 75– 85, as expected. The opposite can be found in the brain, where the vessels are on average thicker in people aged 75–85 at the time of death than in centenarians.

Comprehensive Geriatric Oncology

340

Causes of death in the elderly Many differences can be found in a comparison of the main causes of death between the elderly and younger age groups. There are also many differences among subgroups of the elderly, particularly on comparing people aged over 65 with those in the extreme ages of life (Table 16.2). Malignant neoplasms are the number one cause of death among people aged under 65, but they become the number two cause after cardiovascular diseases in people

Table 16.2 Causes of death in the oldest old in the Trieste areaa Over 95

Over 65

Causes of death

Rank

%

Rank

%

Cardiovascular disease

1

21.4

1

31.6

Pneumonia

2

20.0

9

2.4

Cerebrovascular disease

3

19.1

3

13.3

Malignant neoplasm

4

9.5

2

26.1

Accidents (hip fracture)

5

10.2

6

3.4

Atherosclerosis

6

8.4

4

4.0

Digestive tract disease

7

3.7

8

2.7

Tuberculosis

8

1.8

13

0.1

Urinary system disease

9

1.8

12

0.6

Septicemia

10

0.5

14

0.1

Chronic pulmonary obstruction

11

0.5

5

3.4

a

Data from the Trieste Tumor Registry.

over 65, the number four cause in nonagenarians, and only the number five cause in centenarians.16 Cardiovascular diseases are the number two cause of death in younger people, but they become the number one cause in the elderly, including nonagenarians. In centenarians, cardiovascular diseases are the number two cause, while bronchopneumonia is by far the most common cause, accounting for one-third of all deaths.7,10 In some cases, bronchopneumonia is the only evident cause of death, while in others, it is the final cause associated with other contributory causes. One of the most frequent contributory causes is hip fracture with immobilization of the patient and final bronchopneumonia. Cerebrovascular diseases are the number three cause of death in the elderly in any age subgroup, but they again decrease in frequency in centenarians. In our experience,

Morbid anatomy of aging

341

cerebral diseases account for almost 20% of the deaths among nonagenarians, but for only 10% in centenarians. Another condition deserving of some attention, cirrhosis is one of the most frequent causes of death in the area of Trieste in people aged under 65. It is in fourth place in order of causes of death, and is mostly related to alcohol abuse. In contrast, in people over 65, cirrhosis is tenth, and its frequency decreases more and more with age; it becomes extremely rare in those over 95. In the extreme ages of life, contributory causes of death must be considered in addition to the main causes.7,10 In In the extreme ages of life, contributory causes of death fact, in this group, death cannot be ascribed to just one final cause. Heart, pulmonary, and renal conditions contribute together to a critical situation, and any change such as cardiac failure, infectious disease, hemorrhage, encephalic ischemia, and hip fracture can take the patient rapidly to death. Sometimes there are so many contributory factors that even autopsy fails to identify a well-defined cause of death.7,9,10 In these cases, a pattern of a general atrophy of the organs with moderate myocardial fibrosis and nephrosclerosis and with a limited focal inflammation of the lung is found. Agreement between clinical diagnosis and autopsy diagnosis for the main causes of death is quite good, even in centenarians, with a correspondence of about 70%.17 The correspondence is lower for malignant tumors and acute diseases. Latent and undiagnosed tumors Latent and undiagnosed tumors are more frequent in the elderly than in younger people. This is because tumors of any anatomic site are more common in people aged over 65 and also because, in the oldest age groups, diagnosis is more difficult. The lower aggressiveness of malignant tumors in the very old also contributes to the latency. A well-known biological problem is latent cancer of the prostate, which shows a very high prevalence in the glands removed at autopsy in the elderly.18 In our necropsy series, we discovered more than 2 early (but macroscopically evident) gastric cancers in every 1000 autopsies in people aged over 70.19 The incidence of undiagnosed colorectal cancers increases from about 3 cases per 1000 autopsies in people aged between 60 and 70 to 9 cases in every 1000 in those over 80.20 In contrast, for breast cancer, the cases discovered only at autopsy seem to decrease in the more advanced ages.21 Studies of comparisons between death certificate and autopsy show that false-negative death certificates for malignant tumors are more common in the elderly. In males, the agreement for lung cancer decreases from 70% in people aged under 60 to 40% in those over 85. In females over 85 with lung cancer, there is complete agreement in only 17% of cases.22 The same trend is present for many other tumors. Correspondingly, for ovarian tumors, for example, agreement is complete in almost 80% of cases in the younger age groups, but decreases to 30% in women aged over 80.23 Considering all the malignant tumors of any anatomic site in people aged over 75, the false-negative death certificates are around 40% in all the compared cases.24

Comprehensive Geriatric Oncology

342

Malignant tumors in the extreme ages The frequency of malignant tumors increases in the elderly, but not with the same frequency for every tumor. Reports from tumor registries can give a clear idea of the incidence of neoplasms in the different age groups. For

Table 16.3 Comparison of cancer incidences in young and oldest old (>85/<65 incidence ratio)a Males

Ratio

Prostate

Females 203.0 Pancreas

Ratio 49.3

Pancreas

50.1 Urinary bladder

34.8

Stomach

31.6 Colon

34.4

Colon

28.4 Stomach

34.1

Kidney

21.4 Gallbladder

32.8

Liver

18.3 Rectum

15.8

Esophagus

16.7 Kidney

13.2

Rectum

16.6 Lung

11.9

Urinary bladder

16.4 Non-Hodgkin

Non-Hodgkin

15.8 lymphoma

lymphoma

7.9

Breast

4.5

Pleura

14.6 Ovary

2.9

Lung

10.5 Corpus uteri

2.7

Melanoma

10.5 Melanoma

2.4

Larynx

0.0 Cervix uteri

1.9

a

Data from the Trieste Tumor Registry.

the very old, however, as reported above, this analysis is usually defective. To calculate the occurrence of malignant tumors in the oldest ages, it is necessary to estimate the possibility of false-negative diagnosis. This can be done using data supported by autopsy studies in the elderly. The Tumor Registry of Trieste has been able to obtain information about cancer from autopsy reports in over 60% of all the deaths in the area,25 so the occurrence of tumors in a very old population can be evaluated (Table 16.3). The median age for all the tumors in both sexes is 71 years, this is higher than that calculated using the US National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) data (67.9 years). There is a higher median age for cancers of the large bowel,

Morbid anatomy of aging

343

stomach, kidney, liver, gallbladder, and pancreas. For males, prostate cancer has a median age of 76 years, and for females, pancreatic cancer has a median age of 78 years. In a series of 99 autopsies of centenarians, 17 cases of malignant tumor were found.16 Only 5 of these cases were correctly diagnosed, and in only 7 out of 17 was the tumor the main cause of death. Among the 7 fatal tumors, in only 4 was the cause of death related directly to the metastatic spreading of the neoplasm (a rectal adenocarcinoma, a pancreatic tumor, and two breast cancers). In the other 3 tumors, no distant metastases were found, and the causes of death were a hemorrhage in a gastric cancer, obstruction of the extrahepatic biliary ducts in a gallblad- der tumor, and a bronchopneumonia ‘ab ingestis’ in a destructive carcinoma of the nasal sinuses. Surprisingly, other infiltrative (usually aggressive) tumors, including three stomach cancers, a colic adenocarcinoma, two small-intestinal tumors, two adenocarcinomas of the gallbladder, a ductal carcinoma of the breast, a small cell carcinoma of the lung, a melanoma, and a hepatocarcinoma, did not give any macroscopically evident metastatic localization. In the tumors with metastatic spread, the number of anatomic sites involved by the metastases was always low (from one to three) and always localized only to the liver, the lung, or the distant lymph nodes. Causes of death and comorbidity in cancer Sometimes establishing the cause of death in the elderly with cancer can be a very complicated problem. The contributory effect of multiple comorbidities is often very important. Elderly people treated for a tumor can die with a recurrence, but this recurrence may not be the main cause of death. An infection, a stroke, a cardiac failure, or even a second primary malignant tumor can be the final cause of death. In the death certificate, the initial neoplasm is very often considered the main cause, even when it is contributes to death only in a marginal way or is completely unrelated. When a second primary cancer is present in the elderly, it is often diagnosed as a metastasis of the first one. In our experience, there is a clear difference in the causes of death between women aged under and over 65 who underwent mastectomy for breast cancer (Stanta G, Campagner L, Cavallieri F, unpublished data). In the under-65 group, over 60% of the women died directly from the tumor, while in the over-65 group in only 36% of the autopsies was the cause of death related directly to the cancer recurrence. In the other cases, the main cause of death was unrelated to the tumor. A prudent analysis is necessary in the evaluation of the contributory effect of recurrences or of therapy in causing death.26 The survival rate is quite different in the two age groups. In our case study, only 9% of the women who underwent mastectomy for cancer aged under 65 died in the first year after surgery, while the percentage increased to 38% in women over 65. On the other hand, 52% of women in the younger group died more than 5 years after the intervention, but only 24% of those over 65 survived 5 years and more. The differences in survival are also related to the high frequency of comorbidity in the elderly.27 In the older group, bronchopneumonia was the main cause of death in over 16% of cases and pulmonary embolism in over 10%, heart failure in 9%, and stroke in 6%. Surprisingly, a

Comprehensive Geriatric Oncology

344

second primary tumor was the cause of death in around 10% of cases, regardless of the age at mastectomy (Stanta et al, unpublished data). The contribution of concurrent non-neoplastic causes to death in the elderly with cancer is even more evident in centenarians. As described above, only 7 out of 17 cancers found in a group of centenarians were the cause of death. In the remaining 10 cases, the cause was related to non-neoplastic diseases such as bronchopneumonia, stroke, and heart failure. The role of the malignant tumor was judged to be only contributory in most cases. Cancer spread Frequency and localization of metastases can change for a given tumor type, depending on the age of the patient. The number of anatomic sites found at autopsy in women who died from breast cancer depends on the age at mastectomy.28 The average number of metastasized sites is over 3 in women mastectomized under 55 years of age; it becomes 2.5 in those aged between 55 and 65, 1.9 in the group aged 65–75, and 1.6 in those over 75. The localization pattern of the metastases also changes with age.26 Localization to the endocrine organs is more frequent in the younger group. Involvement of the skin and lymph nodes in the metastatic process is more common among women who underwent mastectomy at an advanced age. In our case study, the average age at mastectomy was 52 for those with a metastasis to the ovary and almost 70 for those with skin metastases. Even the frequency of metastases to the classic anatomic sites changes with age. In women mastectomized aged under 65, liver metastases are found in over 55% of cases, lung metastases in 42%, and pleural metastases in 33%. In women who were treated for breast cancer aged over 65, the frequencies of metastases in the same sites were 27%, 29%, and 22%, respectively. Conclusions At the macroscopic level of autopsy, aging seems to be a process mainly related to chronic degenerative vascular alteration and to atrophic, fibrotic changes in the parenchyma of the organs. Arteriosclerosis of the vessels connected with cardiac and renal fibrosis and severe emphysematous and bronchiectatic changes of the lung together determine a critical situation that can lead to death when associated with any other contributory cause. This is why in centenarians bronchopneumonia becomes the most common cause of death. Vascular alterations are not uniformly distributed in the oldest old. In the brains of centenarians, sclerotic thickening of the walls of small arterioles is less evident than in the younger old, whereas in the kidney, the lesions are more evident in centenarians. Also, coronary arteries are less affected by sclerosis in the oldest old than in younger age groups. Another peculiarity of the oldest old is the absence of hepatic lesions. The distribution of vascular lesions and sparing of the liver suggest that the oldest old, and particularly centenarians, are a select group of people, probably on a genetic basis.

Morbid anatomy of aging

345

References 1. Mulligan RM. Geriatric pathology: autopsy findings in three hundred fifty-six persons eighty years of age and older. AMA Arch Pathol 1960; 69:9–42. 2. Howell TH. Causes of death in nonagenarians. Gerontol Clin 1963; 5:139–43. 3. Howell TH. Multiple pathology in nonagenarians. Geriatrics 1963; 18:899–902. 4. Hofman WI. The pathologist and the geriatric autopsy. J Am Geriatr Soc 1975; 23:11–13. 5. Ishii T, Sternby NH. Pathology of centenarians. I. The cardiovascular system and lungs. J Am Geriatr Soc 1978; 26:108–15. 6. Ishii T, Sternby NH. Pathology of centenarians. II. Urogenital and digestive system. J Am Geriatr Soc 1978; 26:391–6. 7. Ishii T, Sternby NH. Pathology of centenarians. III. Osseus system, malignant lesions, and causes of death. J Am Geriatr Soc 1978; 26: 529–33. 8. Ishii T, Hosoda Y, Maeda K. Cause of death in the extreme aged. Age Ageing 1980; 9:81–9. 9. Kohn RR. Cause of death in very old people. JAMA 1982; 247: 2793–7. 10. Puxity JAH, Horan MA, Fox RA. Necropsies in the elderly. Lancet 1983; i:1262–4. 11. Pomerance A. Pathology of the heart in the tenth decade. J Clin Pathol 1968; 21:317. 12. Howell TH, Piggot AP. Morbid anatomy of old age. Geriatrics 1951: 6:85. 13. Howell TH, Piggot AP. Morbid anatomy of old age. Part VII. Cardiovascular lesions. Geriatrics 1955:10:428. 14. Manousos ON, Truelove SC, Lumbsden K. Prevalence of colon diverticulosis in general population of Oxford area. BMJ 1967; iii: 762. 15. Tauchi H. On the fundamental morphology of senile changes. Nagoya J Med Sci 1961; 24:97. 16. Stanta G, Cavallieri F, Campagner L. Cancer of the oldest old: what we have learned from autoptic studies. Clin Geriatr Med 1997; 13: 55–68. 17. Paterson DA, Dorovitch MI, Farquhar DL et al. Prospective study of necropsy audit of geriatric inpatient deaths. J Clin Pathol 1992; 45: 575–8. 18. Guileyardo JM, Johnson WD, Welsh RA et al. Prevalence of latent prostate carcinoma in two U.S. populations. J Natl Cancer Inst 1980; 65:311. 19. Stanta G, Sasco AJ, Riboli E et al. Prevalence of gastric cancer in a large necropsy series. Lancet 1986; i:624. 20. Delendi M, Gardiman D, Riboli E, Sasco AJ. Latent colorectal cancer found at necropsy. Lancet 1989; i:1331–2. 21. Gorilla L, Stanta G, Delendi M et al. Prevalence of female breast cancer observed in 517 unselected necropsies. Lancet 1986; ii:864. 22. Daysland M, Riboli E, Peruzzo P et al. Comparison of diagnoses of cancers of the respiratory system on death certificates and at autopsy. In: Autopsy in Epidemiology and Medical Research (Riboli E, Daysland M, eds). Lyon: IARC Press, 1991:55–62. 23. Di Bonito L, Stanta G, Daysland M et al. Comparison between diagnoses on death certificates and autopsy reports in Trieste: gynecological cancers. In: Autopsy in Epidemiology and Medical Research (Riboli E, Daysland M, eds). Lyon: IARC Press, 1991:63–71. 24. Stanta G, Cavallieri F, Peruzzo P et al. Death certificate autopsy diagnosis comparison in elderly with malignant tumors. In: Recent Advances in Aging Acience (Baregi E, Gergely IA, Rajczi K, eds). Bologna: Monduzzi, 1993. 25. Parkin DM, Muir CS, Whelan SL et al. Cancer Incidence in Five Continents, Vol VI. Lyon: IARC Press, 1992:120. 26. Cho SY, Choi HY. Causes of death and metastatic patterns in patients with mammary cancer. Am J Clin Pathol 1980; 73:232–4. 27. Mueller CB, Ames F, Anderson GD. Breast cancer in 3,558 women: age as a significant determinant in the rate of dying and causes of death. Surgery 1978; 83:123–32.

Comprehensive Geriatric Oncology

346

28. Viadana E, Cotter R, Pickren JW, Bross IDJ. An autopsy study of metastatic sites of breast cancer. Cancer Res 1973; 33:179–81.

17 Natural history and epidemiology of monoclonal gammopathies Harvey Jay Cohen, Daniel Nikcevich Introduction This chapter will explore the linkage that exists between the aging process and the development of cancer, and will highlight the monoclonal gammopathies as an example of this connection. It will focus on three areas relative to this discussion: (i) the natural history and epidemiology of monoclonal gammopathies; (ii) the relationships that exist between aging and the development of a monoclonal gammopathy; (iii) some aspects of the pathophysiology of monoclonal gammopathies, with an emphasis on the role of aging. Natural history and epidemiology of monoclonal gammopathies The hematologic malignancies, as with most types of cancer, demonstrate an increased incidence with age. Among the various leukemias, myelomas, and lymphomas, the overall incidence will rise with age, and furthermore the incidence rises with each recorded age increment, with the highest incidence being found among the oldest ages (Figure 17.1). The monoclonal gammopathies are an excellent example of the connection between aging and malignancy, and represent a spectrum of clinical presentations that range from the presence of a monoclonal gammopathy of unknown significance to that of a plasma cell dyscrasia or lymphoproliferative disorder such as acute myeloid leukemia, amyloidosis, chronic lymphocytic leukemia, multiple myeloma, non-Hodgkin lymphoma, solitary plasmacytoma, or Waldenström’s macroglobulinemia. The overall differential diagnosis of monoclonal gammopathy is protean, and includes both benign and malignant conditions (Table 17.1). Most monoclonal gammopathies are benign. The appearance of monoclonal proteins in a serum or urine protein electrophoresis assay without clinical or laboratory evidence for an underlying plasma cell dyscrasia has often been referred to as a monoclonal gammopathy of unknown significance (MGUS). Formerly known as benign monoclonal gammopathy,1 the name was changed since this label was misleading and suggested that the benign monoclonal gammopathy will not transform or evolve into a malignant process. The definition of MGUS, nevertheless, remains a clinical problem, and ultimately MGUS is a diagnosis of exclusion. MGUS is defined as an M-spike of less than 3.0 g/dl or trace light-chain deposition in a 24-hour urine collection, less than 10% plasma cells in the bone marrow, no lytic bone

Comprehensive Geriatric Oncology

348

lesions, and absence of anemia, hypercalcemia, and renal failure.2,3 In addition, the Mspike of MGUS must remain relatively stable over time. The monoclonal protein of MGUS is most commonly IgG (73%), and this is followed in frequency by IgM (14%) and IgA (11%).

Figure 17.1 Age-specific incidence of hematologic malignancies. Table 17.1 Clinical conditions associated with monoclonal gammopathiesw Malignant conditions • Multiple myeloma • Lymphoma

Natural history and epidemiology of monoclonal gammopathies

349

• Acute and chronic leukemias • Myeloproliferative disorders • Melanoma • Breast cancer • Lung cancer • Prostate cancer • Liver cancer • Ovarian cancer • Kaposi sarcoma Non-malignant conditions • Autoimmune disorders (systemic lupus erythematosus, scleroderma, rheumatoid arthritis, primary biliary cirrhosis, polyarteritis nodosa, polymyositis) • Organ transplantation (solid organ, bone marrow) • Chronic infection (tuberculosis, cytomegalovirus, hepatitis C, human immunodeficiency virus) • POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes) • Pyoderma gangrenosum • Discoid lupus • Porphyria • Sarcoidosis • Hyperparathyroidism • Paget’s disease of the bone • Gaucher’s disease

Light-chain MGUS most commonly involves κ molecules (62%).2 The initial investigation of a monoclonal gammopathy should include a complete history and physical examination, complete blood count and blood film, serum electrolytes, blood urea nitrogen, creatinine, and calcium. Occasionally, the initial workup will include a bone marrow aspirate and biopsy, a radiologic skeletal survey, a 24-hour urine collection for protein quantitation and electrophoresis, and quantitative serum immunoglobulins. If the clinical investigation results in the diagnosis of MGUS, then patients with this diagnosis should be examined and the M-spike measured every 3–6 months for 1 year to assess for progression. If the patient remains clinically well and the M-spike remains stable, then clinical follow-up may be reasonably extended to annual visits. The relatively indolent nature of MGUS and the presence of an easily measured clinical marker of disease such as a serum or urine paraprotein has allowed for landmark studies of the natural history of monoclonal gammopathies to be conducted. In a prospective study of 241 patients with monoclonal gammopathy, the initial 10-year follow-up period revealed that the M-spike remained stable in 38% of cases, increased in

Comprehensive Geriatric Oncology

350

9%, and progressed to a B-cell malignancy (predominantly multiple myeloma) in 18%. The remaining patients (34%) died of unrelated causes.4 Subsequently, Kyle5 has published a longer-term follow-up (range of 20–35 years, median 22 years), and has demonstrated that 19% remained with a stable MGUS, 10% developed indolent multiple myeloma, 24% developed overt multiple myeloma or other plasma cell dyscrasias, and 47% died of unrelated causes. Of the 59 patients who developed active disease, 39 had multiple myeloma, 8 had primary amyloidosis, 7 had Walden-strom’s macroglobulinemia, and 5 had non-Hodgkin lymphoma. Multiple myeloma was diagnosed at a median of 10 years after diagnosis of MGUS. Remarkably similar results were reported by Pasqualetti et al6 in their series of 263 patients with MGUS. At a median follow-up of 11.5 years, 18% had a stable MGUS, 4% developed an increase in the monoclonal paraprotein, 18% developed a plasma cell proliferative disease, and 60% died of unrelated causes. The actuarial rate of malignant transformation was approximately 15% at 10 years and 31% at 20 years. Likewise, the Mayo Clinic group has estimated the rate of transformation to multiple myeloma, primary amyloidosis, Waldenström’s macroglobulinemia, or non-Hodgkin lymphoma after diagnosis of MGUS to be 16% at 10 years, 33% at 20 years, and 40% at 25 years.2 A separate retrospective analysis has revealed that 59% of patients newly diagnosed with multiple myeloma carried a prior diagnosis of MGUS,7 but in at least three different studies, no differences were observed in the median survival of patients regardless of an antecedent diagnosis of MGUS.7 While the presence of an MGUS may be considered a pre-myelomatous condition, one of the most vexing clinical issues with MGUS is predicting if transformation to a plasma cell dyscrasia or lymphoproliferative disorder will indeed occur. Most patients with an MGUS do not transform, and the incidence of MGUS is remarkably high, particularly in patients aged over 65. In a retrospective review of serum samples from more than 6000 patients, a monoclonal gammopathy was present in 3% of patients older than 70.8 A prospective analysis of 111 well patients living in a retirement home revealed that almost 10% possessed an MGUS,9 and it has been estimated that the prevalence of MGUS may exceed 20% for patients over age 90.10 Careful review of the literature reveals that there is no shortage of controversies regarding the natural history of MGUS. Indeed, different studies will report the propensity of MGUS to undergo malignant transformation to be low-risk,11 intermediate-risk,12 or high-risk.4,5 These differences are most likely a reflection of the heterogeneity of the studies with respect to patient population, diagnostic criteria and staging, and length of follow-up. Pasqualetti et al6 pooled data from several large North American and European studies, and concluded that despite the heterogeneity of the studies, 15% of patients with MGUS will eventually undergo transformation to a plasma cell proliferative disease. The incidence of multiple myeloma per se also exhibits a characteristic increase with age. For example, a seminal study of the epidemiology of multiple myeloma in Sweden discovered no cases in patients younger than 40.13 Younger patients with multiple myeloma have been described. However, these reports have indicated that 1% or less of patients with multiple myeloma are below the age of 40.14,15 In two series of patients followed in the USA and the UK, the incidence of multiple myeloma increased from under 1 to over 20–30 per 100 000 in the older age groups.16 Interestingly, the same age relationship with multiple myeloma is present in Japan, despite the fact that the overall

Natural history and epidemiology of monoclonal gammopathies

351

incidence of B-cell neoplasms is lower than in Western countries. Additionally, while the incidence of multiple myeloma in male Chinese and male Japanese is lower than that for White males living in the same geographic area, all groups nevertheless display an increased incidence of multiple myeloma with age.17 Aging and monoclonal gammopathy relationships The prevalence findings discussed above suggest that some fundamental change is occurring during the aging process that, if not intrinsically linked to aging, is at least heavily conditioned by the aging process and contributes to the development of a monoclonal gammopathy. Animal models have provided new clues for understanding the pathophysiology of age-related monoclonal gammopathies. For example, in aging C57BL/KaLwRij mice, 80% of aged animals will develop a monoclonal gammopathy that is essentially indistinguishable from an MGUS in humans.18,19 On the other hand, plasma cell dyscrasias such as MGUS, multiple myeloma, or Waldenström’s macroglobulinemia are rarely seen in C57BL/KaLwRij mice less than 2 years old. One hypothesis for the development of a monoclonal gammopathy in C57BL/KaLwRij mice is that these animals may have a dysregulated immune system. Radl18 has explained the findings in C57BL/KaLwRij mice as an imbalance between a failing or faltering T-cell compartment (due to an involuted thymus) with an otherwise intact B-cell compartment. The loss of a balanced T-cell/B-cell dichotomy in the immune system may lead to a restriction of the B-cell repertoire and thus to excessive B-cell clonal proliferation, excessive immunoglobulin production, and ultimately to the development of a monoclonal gammopathy. Another interesting discovery from the C57BL/KaLwRij story is that B-cell clones from mice that develop benign monoclonal gammopathies may be transplanted into naive animals for only a few passages before clonal B-cell growth will cease, possibly suggesting the presence of an intact T-cell regulatory role in the recipients that may have been absent in the older animals from which the transplanted cells were obtained. In contrast, similar transplantation experiments with B-cell clones from mice that develop a malignancy such as multiple myeloma or Waldenstrom’s macroglobulinemia revealed that these clones may be passaged indefinitely, suggesting an immortal phenotype of these cells. When viewed in a clinical context, the transplantation experiments with C57BL/KaLwRij mice seem to contradict the clinical observations by Kyle2,4,5 that MGUS may be a pre-myelomatous condition. Instead, the murine data would suggest that malignancies such as multiple myeloma and Waldenstrom’s macroglobulinemia did not arise from a formerly benign MGUS clone, but rather that MGUS and multiple myeloma/Waldenström’s macroglobulinemia may represent distinct biological entities, if not distinct clinical conditions or diseases. One way to possibly reconcile the C57BL/KaLwRij murine data of Radl18,19 with the longitudinal clinical data of Kyle4,5 is to consider that some of the MGUS patients observed by Kyle to transform to multiple myeloma/Waldenström’s macroglobulinemia may actually have had a smoldering myeloma instead of MGUS. Clinically, this distinction may be irrelevant, however, since there presently exists no uniformly accepted means to distinguish age-related MGUS

Comprehensive Geriatric Oncology

352

from smoldering myeloma. This apparent clinical ambiguity between MGUS and smoldering myeloma underscores the necessity to closely follow patients with MGUS. Another major clinical issue regarding the relationship between age and monoclonal gammopathies is that age is often invoked as a prognostic factor in multiple myeloma. In fact, a few studies have suggested that multiple myeloma in younger patients (<40 years) may have a more indolent course and longer survival than when the disease presents in older patients.14,20,21 These studies are limited by the small numbers of patients studied, and thus may inaccurately portray age as a negative prognostic variable. Table 17.2 lists a few of the trials that have investigated age as a prognostic factor in patients with multiple myeloma. Basically, the conclusions of the studies are mixed as to whether age influences prognosis. These discrepancies may be explained by careful scrutiny of the trial design and patient inclusion criteria. For instance, trials that enrolled patients in community-based studies often included a wide variety of patients representing a spectrum of myeloma stages and disease comorbidities. Accordingly, these studies included an overall sicker group of patients. On the other hand, patients enrolled in multiinstitutional studies performed at tertiary care centers tended to have lower disease stage, better performance status, and less comorbid disease. The results summarized in Table 17.2 reveal that community-based studies suggest that age is a negative prognostic factor, while those studies reported from tertiary care centers suggest that age has a neutral effect

Table 17.2 Selected studies examining the influence of greater age on prognosis in multiple myeloma (adapted from Gautier and Cohen91) Study

No. of patients

Mean age

Effect of greater age on prognosis

Accrual pattern

Cavo et al92

163

60

Worse

Singleinstitution

Hannisdal et al93

92

70

Worse

Multiinstitution

Froom et al94

59

68

Worse

Singleinstitution

Rayner et al95

141

65

Worse

Singleinstitution

Corrado et al96

410

NA

Slightly worse

Multiinstitution

Cohen et al97

280

62

None

Multiinstitution

Palva et al98

110

74

None

Multiinstitution

Cohen and Bartolucci22

374

NA

None

Multiinstitution

Natural history and epidemiology of monoclonal gammopathies

353

NA, not available.

on disease prognosis. Indeed, age is a variable to view in the context of a patient’s overall clinical status, since when patients with multiple myeloma are matched on the basis on disease comorbidity, age does not influence prognosis.22 Likewise, Corso et al23 reviewed the outcomes of multiple myeloma from a single institution in 61 patients younger than 50 compared with 295 patients aged 50 or older. In this study, the groups were evenly matched according to presenting clinical and laboratory features, and response rates to initial alkylating agent-based therapy were similar. Hypercalcemia, poor performance status, and elevated creatinine were all independent negative prognostic factors. With respect to observed survival rates, however, younger patients fared better than older patients, but this observation was actually reversed when a separate analysis was performed that considered the expected mortality of the corresponding population. Age is also not a prognostic factor in patients receiving autologous stem cell transplants for multiple myeloma. The University of Arkansas group has reviewed the outcomes of patients receiving tandem autologous stem cells.24 In a comparison of 49 patients younger than 65 with 49 patients aged 65 or older, age was not found to be of prognostic value with respect to stem cell collection, hematopoietic recovery, treatment toxicity, or median duration of event-free survival or overall survival. Instead, the clinical variables that predicted outcome for event-free survival and overall survival included favorable cytogenetics and low β2-microglobulin. On the basis of this retrospective analysis, these investigators have concluded that age should not constitute an exclusion criterion for treatment of multiple myeloma with high-dose therapy and autologous stem cell transplantation. In short, healthy older patients fare as well as healthy younger patients. Multiple myeloma is an incurable disease characterized by a monoclonal proliferation of plasma cell cells and excessive production of monoclonal immunoglobulins. A substantial body of evidence supports the notion that its pathogenesis involves a multistep process of evolution from MGUS to myeloma. The next section will discuss some of the data regarding the role of viral oncogenes, growth factors, cytokine interactions, and the bone marrow stroma in the spectrum of disease from MGUS to multiple myeloma. Interleukin-6 The function, differentiation pattern, and survival of hematopoietic cells are governed by the presence of pleiotropic cytokines in the local tissue milieu. Likewise, the effect(s) exerted by a particular cytokine is dependent upon cellular expression of appropriate cytokine receptors, many of which share common molecular signaling subunits, which only serves to multiply the pleiotropic effects of the cytokine ligand. Plasma cells in the bone marrow develop after antigen stimulation of B cells in peripheral lymphoid tissue. These B cells differentiate into plasmablastic cells and eventually migrate to the bone marrow. After arrival in the bone marrow, the plasmablastic cells proliferate and then differentiate into immunoglobulin-secreting plasma cells.

Comprehensive Geriatric Oncology

354

The development of multiple myeloma is dependent upon a variety of different cytokines that support the proliferation and differentiation of myeloma cells. Cytokines described as supporting the growth of freshly isolated myeloma cells or cell lines include granulocyte colony-stimulating factor (G-CSF), interferon-α (IFN-α), leukemia inhibitory factor (LIF), interleukin-11 (IL-11), and IL-6. Among these molecules, IL-6 has been the most thoroughly investigated and may possess the greatest biologic and clinical importance. The primary function of IL-6 is to stimulate the differentiation of mature B cells into plasma cells, but it is also the primary proliferation factor for plasmablastic cells in the bone marrow.25,26 The evidence that IL-6 may function as a myeloma growth factor was suggested initially by the clinical observation that increased serum IL-6 levels correlated with advanced disease, presence of chemotherapy refractoriness, and the observation that patients with aggressive plasma cell leukemias have elevated serum IL-6 levels.27,28 The evidence to support a role for IL-6 in the pathogenesis of monoclonal gammopathies has been revealed in multiple elegant studies that have detailed IL-6-stimulated proliferation of myeloma cells in vitro, inhibition of IL-6-stimulated growth of myeloma cells in vitro by anti-IL-6 antibodies, IL-6 transgenic mouse models, both autocrine and paracrine functions for IL-6 in myeloma, expression of IL-6 receptors (IL-6R) by myeloma cells, and clinical responses detected in patients treated with anti-IL-6 antibodies.25,29,30 During the short-term culture of bone marrow cells from patients with multiple myeloma, numerous cytokines are detectable, but only the addition of anti-IL-6 monoclonal antibodies will inhibit myeloma cell proliferation.31,32 In one study of patients with advanced multiple myeloma or plasma cell leukemia, growth of myeloma cell cultures from all 30 patients studied was inhibited by anti-IL-6 monoclonal antibodies.28 IL-6 dependence has been documented for cell lines derived from patients with multiple myeloma as well as ex vivo cultures.33 Addition of IL-6 antisense oligonucleotides blocks the growth of human myeloma cells.34 IL-6 supports the growth of myeloma cells both through stimulation of cellular proliferation and through antiapoptotic effects. The latter function of IL-6 has been noted in myeloma cell cultures in which addition of exogenous IL-6 abrogates the apoptosis otherwise induced by suramin or serum.35–37 An anti-apoptotic role for IL-6 is also supported by experiments with IL6R antagonists that block IL-6 function and thus act to induce apoptosis.38 Interestingly, BALB/c IL-6 transgenic mice will develop monoclonal plasmacytomas.39 However, IL-6 transgenic mice (C57BL6 background) develop a massive oligoclonal plasmacytosis that is fatal, but these mice do not develop monoclonal plasmacytomas,39 suggesting that the development of a monoclonal gammopathy may not always be a consequence of excessive or dysregulated IL-6 production. Conversely, plasmacytomas cannot be induced in IL-6 knockout mice.40 These knockout mice are also noted to have major defects in immunoglobulin production, but this defect is correctable with administration of exogenous IL-6.41 There have been some reports that IL-6 may function in an autocrine fashion during active mutiple myeloma.42 Additionally, an autocrine activity of IL-6 was suggested by data from patients with IgM monoclonal gammopathy in whom spontaneous in vitro Bcell differentiation into plasma cells was inhibited either by anti-IL-6 monoclonal antibodies or by retinoic acid blockade of IL-6 production.43 In general, however, most

Natural history and epidemiology of monoclonal gammopathies

355

investigators would agree that while autocrine IL-6 production exists in monoclonal gammopathies, the contribution of IL-6 autocrine production to clinically relevant disease is minimal. The paradigm that has emerged is that paracrine secretion of IL-6 is a major factor in the pathogenesis of multiple myeloma and other monoclonal gammopathies.44–46 The cell that produces IL-6 remains a matter of debate, and IL-6 production has been detected in Th2 T cells, monocytes, endothelial cells, fibroblasts, and bone marrow stromal cells (reviewed by Treon and Anderson29 and Kleis et al47). IL-6 production by bone marrow stromal cells is probably the major source of IL-6 in monoclonal gammopathies. For example, co-culture of myeloma cells with bone marrow stromal cells from patients with multiple myeloma and from normal individuals results in excess IL-6 production in the former, but not the latter.45,48 Furthermore, in patients with multiple myeloma, IL-6 mRNA has been is expressed in monocytic and myeloid cells obtained from bone marrow, but is not expressed in purified plasma cells.49 Despite a wealth of data supporting a paracrine role for IL-6 in monoclonal gammopathies, the regulation of IL-6 paracrine secretion may be related to other cytokines produced by malignant plasma cells, but the precise mechanisms are unknown. IL-6 delivers its signals via the heterodimer IL-6 receptor. This receptor is composed of the ligand-binding 80 kDa α-chain (IL-6R), which after IL-6 binding then complexes with the signal-transducing β-chain (glycoprotein 130, gp130) to form a multimer of two IL-6R chains and two gp130 chains. One of the fascinating aspects of the biology of monoclonal gammopathies is that soluble IL-6 receptors (sIL-6R) exist and function to bind IL-6. This complex, in turn, may bind to gp130 and deliver activating signals in the same manner as membrane-bound IL-6R. This agonist behavior of sIL-6R is unique inasmuch as most soluble cytokine receptors that have been described act to bind excess cytokine and therefore act as antagonists to cytokine function. It remains unknown why patients with multiple myeloma overexpress sIL-6R (sIL-6R is undetectable in normal, healthy individuals), but significantly elevated IL-6R levels have been measured in patients with high tumor burdens and have been recognized as an indicator of poor prognosis.50–52 The gp130 molecule does not possess intrinsic kinase activity, but instead binds to members of the Jak and STAT kinase families in order to transduce intracellular signals. The gp130 molecule is also promiscuous inasmuch as it functions as the signal transduction molecule for other cytokines such as IL-11, G-CSF, LIF, and ciliary neurotropic factor (CNTF), all of which have described as being growth factors for myeloma cells in vitro.47 Mutations in the cytoplasmic domain of gp130 isolated from myeloma cells have been described,53 and while it is unknown if these mutations are clinically relevant, it is tempting to speculate that mutations present in this molecule lead to transduction of dysregulated signals and thus contribute to the pathogenesis of a monoclonal gammopathy. Additional studies on gp130 signal transduction hold the promise to lead to novel therapeutics, especially since gp130 is a molecule employed by many plasmablastic growth factors for signal transduction Clinically, manipulation of IL-6 has been disappoint ing. Bataille et al54 treated nine patients with advanced multiple myeloma or plasma cell leukemia with murine anti-IL-6 monoclonal antibodies. Reductions in the M-spike and serum calcium were noted, but none of the patients achieved a remission. Other problems have included the development of human anti-murine antibodies (HAMA), an inability to achieve adequate antibody levels to bind circulating IL-6, and even upregulation of IL-6R.54,55 Planned future studies

Comprehensive Geriatric Oncology

356

using IL-6 constructs that interfere with IL-6 binding and gp130 signaling or using IL-6diphtheria toxin fusion proteins may allow for more elegant, biologic-based therapies for monoclonal gammopathies, but will likely find application in combination with cytoreductive chemotherapy or in the setting of bone marrow purging or minimal residual disease. Human herpesvirus 8 Human herpesvirus 8 (HHV-8; also known as Kaposi sarcoma-associated herpesvirus, KSHV) was originally described after isolation from a patient with Kaposi sarcoma,56 and has also been isolated from a patient with multicentric Castleman’s disease.57 In patients with Kaposi sarcoma, HHV-8 has been isolated from primary sarcoma cells as well as B cells, macrophages, and dendritic cells. Perhaps the most intriguing finding was that HHV-8 viral DNA contains an IL-6 homologue.58 The viral IL-6 gene product possesses biologic activity and supports the growth of IL-6-dependent B9 murine plasmacytoma cells and human myeloma cell lines,58,59 and also blocks apoptosis of a murine myeloma cell line.60 In addition, viral IL-6 has been shown to bind directly to gp130, suggesting that this molecule may directly activate IL-6R signal transduction without binding to the IL-6R α-chain.61 HHV-8 also contains the viral homologue for interferon regulatory factor (vIRF). Viral gene expression for vIRF and its protein product have been detected in bone marrow from patients with multiple myeloma.62,63 Fibroblasts transfected with vIRF will develop a transformed phenotype and will develop into stromal cell tumors after injection into nude mice.64 Additionally, the HHV-8 genome also encodes for a viral homologue of IL-8R (vIL-8R), a molecule recognized as important in angiogenesis since it induces the production of vascular endothelial growth factor (VEGF). Transcripts of vIL-8R have been detected in bone marrow samples from myeloma patients.65 Similar to vIRF, transfection of fibroblasts with vIL-8R leads to transformation and growth of stromal cell tumors after injection into nude mice.65 Collectively, these data on vIRF and vIL-8R have led to speculation that HHV-8 infection of bone marrow stromal cells may lead to a competitive advantage over uninfected stromal cells, and thus foster the growth of a malignant plasma cell clone.66 HHV-8 has been isolated from long-term bone marrow cultures established from patients with multiple myeloma and also in 85% and 56% of fresh bone marrow and peripheral blood, respectively, of such patients.67 In contrast, HHV-8 has not been detected in bone marrow from normal patients, patients with lymphoma, or patients with myelophthisic infiltration of the bone.68 In patients with MGUS, 30% of bone marrow samples and 26% of peripheral blood samples have been positive for HHV-8 by polymerase chain reaction (PCR).67 What is unclear at present, however, is if MGUS patients with HHV-8 infection will progress to develop overt multiple myeloma. Interestingly, HHV-8 cannot be detected in the sexual partners of patients with multiple myeloma (known to be HHV-8-positive), but it can be detected in the partners of patients with HIV infection and Kaposi sarcoma.69 What has not been observed, however, is an increased incidence of multiple myeloma in patients with concomitant HIV and HHV-8 infections. This would suggest that HHV-8 may not play a direct causal role in

Natural history and epidemiology of monoclonal gammopathies

357

the development of multiple myeloma, but rather is just one factor involved in the spectrum of disease from MGUS to multiple myeloma. HHV-8 infection of bone marrow dendritic and stromal cells may play a more prominent role in sustaining the malignant plasma cell clone after multiple myeloma has developed into full-blown clinical disease. Cytogenetic abnormalities Knowledge of the biology of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) has advanced significantly over the past decade as various cytogenetic abnormalities have been identified, and clinical prognostic features have been attached to these chromosomal changes. Furthermore, the BCR-ABL gene product (the t(9; 22) translocation) in CML and the retinoic acid receptor (t(15; 17)) in M3 AML (acute promyelocytic leukemia, APL) are now manipulated therapeutically in the clinic. Monoclonal gammopathies are also characterized by complex cytogenetic abnormalities, but the relatively low proliferative rate for multiple myeloma has slowed the rate of understanding of abnormal mitoses. Several reports have provided comprehensive descriptions of cytogenetic abnormalities in patients with multiple myeloma.70–74 Characteristic chromosomal abnormalities detected in patients with multiple myeloma include trisomies of chromosomes 3, 5, 7, 9, 11, 15, and 19.70 Monosomy 13 is also a characteristic finding. Recent advances in molecular cytogenetic technology, including fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH), have revealed that many patients with multiple myeloma possess chromosomal abnormalities.70 Two of the most common and best studied chromosomal abnormalities include translocations involving 14q32 and partial deletion of chromosome 13 (del(13) (q14)). During normal B-cell differentiation, plasmablasts will undergo immunoglobulin heavychain switch recombination from the IgM of a primary immune response to the IgG or IgA of a secondary immune response. The molecular mechanism of this switch involves the juxtaposition of 14q32 (the immunoglobulin heavy-chain gene locus) with the switch regions of the genes for IgG or IgA. In multiple myeloma, illegitimate switch recombinations occur resulting in the juxtapostion of 14q32 with DNA on other chromosomes that do not encode for immunoglobulin gene sequences. These illegitimate recombinations have been observed in cell lines established from patients with multiple myeloma as well as from primary myeloma cells.75,76 A wide variety of illegitimate recombination partners have been described (reviewed by Drach et al77), including bcl-1 (cyclin D1), bcl-2, and c-myc, but the biological and overall clinical consequences of these translocations remain unknown. del(13) (q14) has been detected in 20–50% of patients with multiple myeloma, depending on the method of detection.75,78 Currently, it is unknown what gene is inactivated due to this chromosomal abnormality, but whatever is silenced undoubtedly has a major function in the homeostasis of plasma cells. del(13) (q14) is an extremely important independent prognostic parameter in patients with multiple myeloma treated with convential chemotherapy, since its absence confers a low-risk prognosis (median overall survival 102 months) while its presence in the absence or presence of elevated β2microglobulin confers an intermediate-risk prognosis (median overall survival 45

Comprehensive Geriatric Oncology

358

months) or high-risk prognosis (median overall survival 11 months), respectively.79 del(13)(q14) confers similar poor-risk features to patients with multiple myeloma who are treated with highdose chemotherapy and autologous stem cell support.80 While the oncogenes (and the functions of their protein products) that are involved with cytogenetic abnormalities in multiple myeloma are poorly understood, what is evident is that across the spectrum of monoclonal gammopathies, cytogenetic abnormalities will accumulate and reflect disease stage. For example, one group has described a series of patients with multiple myeloma, more than 50% of whom had detectable cytogenetic abnormalities. However, none of the stage I or II patients had detectable abnormalities, while over 90% of patients with stage III disease had cytogenetic abnormalities.81 In two series of patients with MGUS (none of whom developed multiple myeloma), the use of FISH detected at least one numerical chromosomal abnormality (trisomy 3, monosomy 7, trisomy 9, or monosomy 11) in more than 50% of the patients studied.82,83 Furthermore, some of these patients exhibited different plasma cell subclones that possessed different cytogenetic abnormalities.83 In another study comparing cytogenetic abnormalities between a group of 100 patients with MGUS or smoldering multiple myeloma (SMM) and a group of 102 patients with overt multiple myeloma, translocations of 14q32 were detected in similar numbers of patients with MGUS/SMM and overt multiple myeloma, while del(13) (q14) was detected in plasma cell clones in 41 of 102 patients with overt multiple myeloma, but only 7 of 100 patients with MGUS/SMM.84 These data may suggest that whereas acquisition of translocations of 14q32 occurs early in the spectrum of monoclonal gammopathies, del(13) (q14)—wherever it may acquired in the spectrum of disease—is linked closely to the development of overt multiple myeloma. An important caveat to the interpretation of these cytogenetic data is that the observation of chromosomal abnormalities is limited to what is present at presentation or progression of disease, but how these data may apply to the initiation or promotion of a monoclonal gammopathy is unknown. Overall, karyotypic instability in monoclonal gammopathies appears to develop with MGUS and then progress steadily with the development of overt multiple myeloma. Some of these chromosomal abnormalities (such as del(13) (q14)) may be linked tightly to overt multiple myeloma, and therefore may be similar to chromosomal abnormalities seen in leukemia or lymphoma, while others accumulate and eventually the sum of these accumulated cytogenetic abnormalities results in overt multiple myeloma. Multidrug resistance Multiple myeloma is a disease whose natural history is characterized by initial responsiveness to chemotherapy, but, with relapse, the clinical situation is often manifested by disease that is less responsive or even refractory to treatment. Likewise, plasma cell leukemia often presents initially as aggressive disease that is refractory to treatment. While the etiology of relapsed/refractory disease is pleiotropic, the acquisition of a multidrug-resistant phenotype has become increasingly recognized as a major clinical problem in patients with multiple myeloma. Multidrug resistance in multiple myeloma and other monoclonal gammopathies is a clinical phenomenon that may be

Natural history and epidemiology of monoclonal gammopathies

359

categorized as a function of altered drug concentration in the target dcell, alterations in drug-induced apoptosis, and alterations in the expression of drug targets, although the latter category is the least understood. The multidrug-resistance gene (MDR1) encodes for an ATP-dependent drug-efflux pump known as P-glycoprotein (P-gp). Cells that overexpress P-gp have the ability to pump out substrates of P-gp such as doxorubicin, vincristine, and glucocorticoids. Essentially, as the expression of P-gp in a cell increases, the multidrug-resistance phenotype of that cell becomes more robust. Indeed, overexpression of P-gp has been detected in myeloma cells from patients who have drug-resistant disease.85,86 Overexpression of P-gp has also been described in patients with MGUS. While it is unclear if these patients will develop multiple myeloma, it is tempting to speculate that MGUS patients who overexpress P-gp are at increased risk for transformation into frank multiple myeloma. Inhibition of P-gp is being studied in ongoing clinical trials as a means to prevent the development of a multidrug-resistance phenotype in patients with multiple myeloma. Another transporter protein that may confer a multidrug-resistance phenotype is the lung-resistance protein (LRP). At least one report has described that overexpression of LRP in patients with multiple myeloma may allow for resistance to alkylating agents such as melphalan, and therefore predict poor clinical response.87 Many chemotherapeutic agents will activate mechanisms of apoptosis.88 Resistance to this type of killing may be present in multiple myeloma. Drug-resistant myeloma cells that are resistant to Fas (CD95)-mediated apoptosis have been described.89 Resistance to Fas-mediated apoptosis may be a function of reduced Fas expression and/or alterations in downstream Fas signaling targets. Additionally, IL-6 has been shown to promote protection from Fas-mediated apoptosis in myeloma cell lines, suggesting that new therapies that block IL-6R signaling may prevent escape from apoptotic stimuli and thus improve clinical response and outcome. IL-6R signaling includes the Jak and STAT pathways, and activated STAT3 molecules have been detected in bone marrow from patients with active multiple myeloma.90 Exploitation of weaknesses in signaling pathways (Fas and IL-6R) that control apoptosis in myeloma cells or the surrounding bone marrow stroma is the area that will likely lead to the most therapeutic gain in the treatment of multiple myeloma and other monoclonal gammopathies. Summary The monoclonal gammopathies are an excellent example of the connection between aging and malignancy. Clearly, a fundamental change is occuring during aging that, if not intrinsically linked to the latter, is influenced by it, and contributes to the development of a monoclonal gammopathy. A biological model of monoclonal gammopathy is shown in Figure 17.2. Various host resistance factors that prevent neoplasia may decline with age. Over time, there

Comprehensive Geriatric Oncology

360

Figure 17.2 Relationship between age and pathogenesis of multiple myeloma (MM). HHV-8, human herpesvirus 8; IL-6, interleukin-6; MGUS, monoclonal gammopathy of unknown significance. may exposures to various initiating factors that give rise to the initial monoclonal gammopathy. As these events accumulate or new promotion events occur, the accumulated weight of these acquired changes results in the clinical emergence of a malignancy. References 1. Waldenström J. Studies on conditions associated with disturbed gammaglobulin formation (gammopathies). Harvey Lect 1961; 56: 211. 2. Kyle RA. Monoclonal gammopathy of undetermined significance and solitary plasmacytoma. Implications for progression to overt multiple myeloma. Hematol Oncol Clin North Am 1997; 11:71–87. 3. Gautier M, Cohen HJ. Hematologic malignancies. In: Geriatric Medicine (Cassel CK, Cohen HJ, Larson EB et al, eds). New York: Springer-Verlag, 1997. 4. Kyle RA. Monoclonal gammopathy of undetermined significance. Natural history in 241 cases. Am J Med 1978; 64:814–26. 5. Kyle RA. ‘Benign’ monoclonal gammopathy after 20 to 35 years of follow-up. Mayo Clin Proc 1993; 68:26–36. 6. Pasqualetti P, Festuccia V, Collacciani A, Casale R. The natural history of monoclonal gammopathy of undetermined significance. Acta Haematol 1997; 97:174–9.

Natural history and epidemiology of monoclonal gammopathies

361

7. Kyle RA, Beard CM, O’Fallon WM, Kurland LT. Incidence of multiple myeloma in Olmstead County, Minnesota: 1978 through 1990, with a review of the trend since 1945. J Clin Oncol 1994; 12:1577–83. 8. Axelsson U, Hallen J. A population study on monoclonal gammopathy. Follow-up after 5 and one-half years on 64 subjects detected by electrophoresis of 6995 sera. Acta Med Scand 1972; 191:111–13. 9. Crawford J, Eye MK, Cohen HJ. Evaluation of monoclonal gammopathies in the ‘well’ elderly. Am J Med 1987; 82:39–45. 10. Cohen HJ. Monoclonal gammopathies and aging. Hosp Pract 1988; 23:75–100. 11. Axelsson U. A 20-year follow-up study of 64 subjects with M-components. Acta Med Scand 1986; 219:519–22. 12. Blade J, Lopez-Guillermo A, Rozman C et al. Malignant transformation and life expectancy in monoclonal gammopathy of undetermined significance. Br J Haematol 1992; 81:391–4. 13. Turesson I, Zettervall O, Cuzick J et al. Comparison of trends in the incidence of multiple myeloma in Malmo, Sweden, and other countries, 1950–1979. N Engl J Med 1984; 310:421–4. 14. Hewell GM, Alexanian R. Multiple myeloma in young persons. Ann Intern Med 1976; 84:441– 3. 15. Blade J, Kyle RA, Greipp PR. Multiple myeloma in patients younger than 30 years. Report of 10 cases and review of the literature. Arch Intern Med 1996; 156:1463–8. 16. Cohen HJ. Multiple myeloma in the elderly. Clin Geriatr Med 1985; 1:827–55. 17. Devesa SS. Descriptive epidemiology of multiple myeloma. In: Epidemiology and Biology of Multiple Myeloma (Obrauns GI, Potter M, eds). Berlin: Springer-Verlag, 1991. 18. Radl J. Age-related monoclonal gammopathies: clinical lessons from the aging C57BL mouse. Immunol Today 1990; 11:234–6. 19. Radl J. Aging and proliferative homeostasis: monoclonal gammopathies in mice and men. Lab Anim Sci 1992; 42:138–41. 20. Blade J, Kyle RA, Greipp PR. Presenting features and prognosis in 72 patients with multiple myeloma who were younger than 40 years. Br J Haematol 1996; 93:345–51. 21. Lazarus HM, Kellmeyer RW, Aikawa M, Herzig RH. Multiple myeloma in young men. Clinical course and electron microscopic studies of bone marrow plasma cells. Cancer 1980; 46:1397–400. 22. Cohen HJ, Bartolucci A. Age and the treatment of multiple myeloma. Southeastern Cancer Study Group Experience. Am J Med 1985; 79: 316–24. 23. Corso A, Klersy C, Lazzaruno M, Bernasconi C. Multiple myeloma in younger patients: the role of age as prognostic factor. Ann Hematol 1998; 76:67–72. 24. Siegal DS, Desikan KR, Mehta J et al. Age is not a prognostic variable with autotransplants for multiple myeloma. Blood 1999; 93:51–4. 25. Hallek M, Bergsagel PL, Anderson KC. Multiple myeloma: increasing evidence of a multistep transformation process. Blood 1998; 91: 3–21. 26. Lotz M. Interleukin-6: a comprehensive review. Cancer Treat Res 1995; 80:209–93. 27. Zhang XG, Klein B, Bataille R. Interleukin-6 is potent myeloma-cell growth factor in patients with aggressive multiple myeloma. Blood 1989; 74:11–13. 28. Zhang XG, Bataille R, Widjenes J, Klein B. Interleukin-6 dependence of advanced malignant plasma cell dyscrasias. Cancer 1992; 69: 1373–6. 29. Treon SP, Anderson KC. Interleukin-6 in multiple myeloma and related plasma cell dyscrasias. Curr Opin Hematol 1998; 5:42–8. 30. Chen Y-H, Shiao R-T, Labayog J-M et al. Modulation of interleukin-6/interleukin-6 receptor cytokine loop in the treatment of multiple myeloma. Leuk Lymphoma 1997; 27:11–23. 31. Sonneveld P, Schoester M, deLeeuw K. In vitro Ig-synthesis and proliferative activity in multiple myeloma are stimulated by different growth factors. Br J Haematol 1991; 79:589–94. 32. Kawano M, Hiramo T, Matsuda T, Taga T. Autocrine generation and essential requirements of BSF-2/IL-6 for human multiple myeloma. Nature 1988; 332:83–5.

Comprehensive Geriatric Oncology

362

33. Anderson KC, Jones RM, Morimoto C et al. Response patterns of purified myeloma cells to hematopoietic growth factors. Blood 1989; 73:1915–24. 34. Levy Y, Tsapis A, Brouet JC. Interleukin-6 antisense oligonucleotides inhibit the growth of human myeloma cell lines. J Clin Invest 1991; 88:696–9. 35. Shiao RT, Miglietta L, Khera SY et al. Dexamethasone and suramin inhibit cell proliferation and interleukin-6-mediated immunoglobulin secretion in human lymphoid and multiple myeloma cell lines. Leuk Lymphoma 1995; 17:485–94. 36. Hardin J, MacLeod S, Grigorieva I et al. Interleukin-6 prevents dexamethasone-induced myeloma cell death. Blood 1994; 84: 3063–70. 37. Lichtenstein A, Tu Y, Fady C et al. Interleukin-6 inhibits apoptosis of malignant plasma cells. Cell Immunol 1995; 162:248–55. 38. Demartis A, Bernassola F, Savino R et al. Interleukin-6 receptor superantagonists are potent inducers of human multiple myeloma cell death. Cancer Res 1996; 56:4213–18. 39. Suematsu S, Matsuda T, Aozasa K et al. IgG1 plasmacytosis in interleukin 6 transgenic mice. Proc Natl Acad Sci USA 1989; 86:7547–51. 40. Hilbert DM, Kopf M, Mock BA et al. Interleukin 6 is essential for in vivo development of B lineage neoplasms J Exp Med 1995; 182:243–8. 41. Kopf M, Baumann H, Freer G et al. Impaired immune and acutephase responses in interleukin6-deficient mice. Nature 1994; 368: 339–42. 42. Kawano M, Hiraro T, Matsuda T et al. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature 1988; 332:83–5. 43. Levy Y, Fernand JP, Navarro S et al. Interleukin 6 dependence of spontaneous in vitro differentiation of B cells from patients with IgM gammopathy. Proc Natl Acad Sci USA 1990; 87:3309–13. 44. Klein B, Zhang XG, Jourdan M et al. Paracrine rather than autocrine regulation of myelomacell growth and differentiation by interleukin-6. Blood 1989; 73:517–26. 45. Caligaris-Cappio F, Bergui L, Gregoretti MG et al. Role of bone marrow stromal cells in the growth of human multiple myeloma. Blood 1991; 77:2688–93. 46. Bataille R, Chappard D, Marcelli C et al. Recruitment of new osteoblasts and osteoclasts is the earliest critical event in the pathogenesis of human multiple myeloma. J Clin Invest 1991; 88:62–6. 47. Klein B, Zhang XG, Lu ZY. Bataille R. Interleukin-6 in human multiple myeloma. Blood 1995; 85:863–72. 48. Uchiyama H, Barut BA, Mohrbacher AF et al. Adhesion of human myeloma-derived cell lines to bone marrow stromal cells stimulates interleukin-6 secretion. Blood 1993; 82:3712–20. 49. Portier M, Rajzbaum G, Zhang XG et al. In vivo interleukin 6 gene expression in the tumoral environment in multiple myeloma. Eur J Immunol 1991; 21:1759–62. 50. Gaillard JP, Bataille R, Brailly H et al. Increased and highly stable levels of functional soluble interleukin-6 receptor in sera of patients with monoclonal gammopathy. Eur J Immunol 1993; 23:820–4. 51. Greipp PR, Gaillard JP, Kalish LA et al. Independent prognostic value for serum soluble interleukin-6 receptor (sIL-6R) in Eastern Cooperative Group (ECOG) myeloma trial E9487. Proc Am Soc Clin Oncol 1993; 12:404. 52. Papadaki H, Kyriakou D, Foudoulakis A et al. Serum levels of soluble IL-6 receptor in multiple myeloma as indicator of disease activity. Acta Haematol 1997; 97:191–5. 53. Rodriguez C, Theillet C, Portier M et al. Molecular analysis of the IL-6 receptor in human multiple myeloma, an IL-6-related disease. FEBS Lett 1994; 341:156–61. 54. Bataille R, Barlogie B, Lu ZY et al. Biologic effects of anti-interleukin-6 murine monoclonal antibody in advanced multiple myeloma. Blood 1995; 86:685–91. 55. Klein B, Lu ZY, Gaillard JP et al. Inhibiting IL-6 in human multiple myeloma. Curr Top Microbiol Immunol 1992; 182:237–44.

Natural history and epidemiology of monoclonal gammopathies

363

56. Chang Y, Cesarman E, Pessin MS et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma Science 1994; 266:1865–9. 57. Soulier J, Grollet L, Oksenhendler E et al. Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman’s disease Blood 1995; 86:1276–80. 58. Nicholas J, Ruvolo V, Zong J et al. A single 13-kilobase divergent locus in the Kaposi sarcomaassociated herpesvirus (human herpesvirus 8) genome contains nine open reading frames that are homologous to or related to cellular proteins. J Virol 1997; 71:1963–74. 59. Burger R, Neipel F, Fleckenstein B et al. Human herpesvirus type 8 interleukin-6 homologue is functionally active on human myeloma cells Blood 1998; 91:1858–63. 60. Moore PS, Boshoff C, Weiss RA, Chang Y. Molecular mimicry of human cytokine and cytokine response pathway genes by KSHV. Science 1996; 274:1739–44. 61. Molden J, Chang Y, You Y et al. A Kaposi’s sarcoma-associated herpesvirus-encoded cytokine homolog (vIL-6) activates signaling through the shared gp130 receptor subunit. J Biol Chem 1997; 272: 19625–31. 62. Ma H, Vescio R, DerDanielian M et al. The HHV IL-8R homologue and interferon regulatory genes are frequently expressed in myeloma bone marrow biopsies whereas the vIL-6 is rarely found. Blood 1998; 92(Suppl 1):515a. 63. Zimring JC, Goodbourn S, Offermann MK. Human herpesvirus 8 encodes an interferon regulatory factor (IRF) homolog that represses IRF-1-mediated transcription. J Virol 1998; 72:701–7. 64. Gao SJ, Boshoff C, Jayachandra S et al. KSHV ORF K9 (vIRF) is an oncogene which inhibits the interferon signaling pathway. Oncogene 1997; 15:1979–85. 65. Bais C, Santomasso B, Coso O et al. G-protein-coupled receptor of Kaposi’s sarcomaassociated herpesvirus is a viral oncogene and angiogenesis activator Nature 1998; 391:86–9. 66. Berenson JR. Etiology of multiple myeloma: what’s new. Semin Oncol 1999; 26(5 Suppl 13):2– 9. 67. Anderson K. Advances in the biology of multiple myeloma: therapeutic applications. Semin Oncol 1999; 26(5 Suppl 13):10–22. 68. Said JW, Rettig MR, Heppner K et al. Localization of Kaposi’s sarcoma-associated herpesvirus in bone marrow biopsy samples from patients with multiple myeloma. Blood 1997; 90:4278–82. 69. Martin JN, Ganem DE, Osmond DH et al. Sexual transmission and the natural history of human herpesvirus 8 infection. N Engl J Med 1998; 338:948–54. 70. Zandecki M, Lai JL, Facon T. Multiple myeloma: almost all patients are cytogenetically abnormal. Br J Haematol 1996; 94:217–27. 71. Dewald GW, Kyle RA, Hicks GA, Greipp PR. The clinical significance of cytogenetic studies in 100 patients with multiple myeloma, plasma cell leukemia, or amyloidosis. Blood 1985; 66:380–90. 72. Gould J, Alexanian R, Goodacre A et al. Plasma cell karyotype in multiple myeloma. Blood 1988; 71:453–6. 73. Lai JL, Zandecki M, Mary JY et al. Improved cytogenetics in multiple myeloma: a study of 151 patients including 117 patients at diagnosis. Blood 1995; 85:2490–7. 74. Sawyer JR, Waldron JA, Jagannath S, Barlogie B. Cytogenetic findings in 200 patients with multiple myeloma. Cancer Genet Cytogenet 1995; 82:41–9. 75. Avet-Loiseau H, Li JY, Morineau N et al. Monosomy 13 is associated with the transition of monoclonal gammopathy of undetermined significance to multiple myeloma. Blood 1999; 94:2583–9. 76. Nishida K, Tamura A, Nakazawa N et al. The Ig heavy chain gene is frequently involved in chromosomal translocations in multiple myeloma and plasma cell leukemia as detected by in situ hybridization. Blood 1997; 90:526–34. 77. Drach J, Kaufmann H, Urbauer E et al. The biology of multiple myeloma. J Cancer Res Clin Oncol 2000; 126:441–7.

Comprehensive Geriatric Oncology

364

78. Chang H, Bouman D, Boerkoel CF et al. Frequent monoallelic loss of D13S319 in multiple myeloma patients shown by interphase fluorescence in situ hybridization. Leukemia 1999; 13:105–9. 79. Konigsberg R, Zojer N, Ackermann J et al. Predictive role of interphase cytogenetics for survival of patients with multiple myeloma. J Clin Oncol 2000; 18:804–12. 80. Tricot G, Barlogie B, Jagannath S et al. Poor prognosis in multiple myeloma is associated only with partial or complete deletions of chromosome 13 or abnormalities involving 11q and not with other karyotype abnormalities. Blood 1995; 86:4250–6. 81. Smadja NV, Louvet C, Isnard F et al. Cytogenetic study in multiple myeloma at diagnosis: comparison of two techniques. Br J Haematol 1995; 90:619–24. 82. Drach J, Angerler J, Schuster J et al. Interphase fluorescence in situ hybridization identifies chromosomal abnormalities in plasma cells from patients with monoclonal gammopathy of undetermined significance. Blood 1995; 86:3915–21. 83. Zandecki M, Lai JL, Genevieve F et al. Several cytogenetic subclones may be identified within plasma cells from patients with monoclonal gammopathy of undetermined significance, both at diagnosis and during the indolent course of this condition. Blood 1997; 90:3682–90. 84. Avet-Loiseau H, Facon T, Daviet A et al. 14q32 translocations and monosomy 13 observed in monoclonal gammopathy of undetermined significance delineate a multistep process for the oncogenesis of multiple myeloma. Intergroupe Francophone du Myelome. Cancer Res 1999; 59:4546–50. 85. Epstein J, Xiao HQ, Oba BK. P-glycoprotein expression in plasma-cell myeloma is associated with resistance to VAD. Blood 1989; 74: 913–17. 86. Sonneveld P, Durie BG, Lokhorst HM et al. Analysis of multidrug-resistance (MDR-1) glycoprotein and CD56 expression to separate monoclonal gammopathy from multiple myeloma. Br J Haematol 1993; 83:63–7. 87. Lokhorst HM, Izquierdo MAI, Raajmakers HGP et al. Lung-resistance protein expression is a negative predictive factor for response to alkylating chemotherapy and survival in multiple myeloma Blood 1996; 88(Suppl 1):640a. 88. Hannun YA. Apoptosis and the dilemma of cancer chemotherapy. Blood 1997; 89:1845–53. 89. Landowski TH, Qu N, Buyuksal I et al. Mutations in the Fas antigen in patients with multiple myeloma. Blood 1997; 90:4266–70. 90. Catlett-Falcone R, Landowski TH, Oshiro MM et al. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 1999; 10:105–15. 91. Gautier M. Cohen HJ. Multiple myeloma in the elderly. J Am Geriatr Soc 1994; 42:653–64. 92. Cavo M, Galieni P, Zuffa E et al. Prognostic variables and clinical staging in multiple myeloma. Blood 1989; 74:1774–80. 93. Hannisdal E, Kildahl-Andersen O, Grottum KA, Lamvik J. Prognostic factors in multiple myeloma in a population-based trial. Eur J Haematol 1990; 45:198–202. 94. Froom P, Quitt M, Aghai E. Multiple myeloma in the geriatric patient. Cancer 1990; 66:965–7. 95. Rayner HC, Haynes AP, Thompson JR et al. Perspectives in multiple myeloma: survival, prognostic factors and disease complications in a single centre between 1975 and 1988. Q J Med 1991; 79:517–25. 96. Corrado C, Santarelli MT, Pavlovsky S, Pizzolato M. Prognostic factors in multiple myeloma: definition of risk groups in 410 previously untreated patients: a Grupo Argentino de Tratamiento de la Leucemia Aguda study. J Clin Oncol 1989; 7:1839–44. 97. Cohen HJ, Silberman HR, Forman W et al. Effects of age on responses to treatment and survival of patients with multiple myeloma. J Am Geriatr Soc 1983; 31:272–7. 98. Palva JP, Ahrenberg P, Ala-Harja K et al. Treatment of multiple myeloma in old patients. Finnish Leukaemia Group. Eur J Haematol 1989; 43:328–31.

PART 4 Influence of aging on prevention, diagnosis, and treatment of cancer

18 Physiology of aging: Relevance to symptoms, perceptions, and treatment tolerance Edmund H Duthie, Jr Introduction Aging is associated with anatomic and structural changes, which have implications for physiologic function. Clinicians need to be aware of the physiologic changes that occur in association with the aging process. Since disease occurrence is so ubiquitous in late life, physiologic changes may be the result of disease (pathophysiology), and this can further confound the care of the elderly patient. When reviewing the topic of aging physiology, a few principles need to be kept in mind. First, most physiologic processes change gradually over time. Figure 18.1 is a classic depiction of physiologic decrement over time in groups of subjects.1 Decline in physiologic function can be shown to begin in early adulthood and gradually progress into the middle years and beyond. It is also noteworthy that, for some of the measures shown in Figure 18.1, re-evaluation of physiologic function in more recent years, using stricter criteria for health, can sometimes show that previously described decrements are no longer found. The decline in cardiac output with age may be a case in point. Early reports noted a decline in cardiac output,2 but later studies3,4 have not verified this result. Subjects with occult non-detectable heart disease could account for the earlier findings.

Comprehensive Geriatric Oncology

368

Figure 18.1 Age decrements in physiological performance. Average values for 30-year-old subjects are taken as 100%. Decrements shown are schematic. (a) Fasting blood glucose. (b) Nerve conduction velocity and some cellular enzyme activities. (c) Resting cardiac index. (d) Vital capacity and renal blood flow. (e) Maximum breathing capacity. (f) Maximum work rate and maximum oxygen uptake.1 Another important point about aging physiology is the variability of measures. In older subjects, it appears that a wider range for the variable being measured will be found compared with younger subjects. As a corollary, although the mean value of a measure may decline, among individual subjects the value may decline, remain static, or even increase over time. This has been shown most impressively for changes in creatinine clearance.5 Lipsitz and Goldberger6 have expanded further on the analysis of physiologic changes in senescence to point out that even beyond genetic background, diet, and activity, there are factors at work that militate toward variability in physiologic function

Physiology of aging: Relevance to symptoms, perceptions

369

in later life. Also, key to aging appears to be the reduced capacity to adapt to stress. Therefore, measurements of a variable at rest (e.g. heart rate or serum glucose) may not show much difference among subjects of varying ages, but with stress (exercise or glucose infusion) impressive differences can be noted to occur. This has led to the suggestion that with age there is a loss of complexity among organ system functions, leading to an impairment in the ability of the organism to adapt to stress. This chapter will review physiologic changes occurring in later life and highlight the relevance these changes have for oncologic practice. The approach will be to follow the order of the usual physical examination and comment upon changes in the systems as they are examined. Some changes (e.g. eyesight/hearing) will be commented upon under neurosensory changes rather than during the ‘head and neck’ examination. Some areas of physiologic change (e.g. immunology or hematopoietic system) will not be addressed in this chapter, since they are covered elsewhere in this volume.

Figure 18.2 Mean regression slopes of height and weight on age determined from serial measurements on the same subjects (normal males) over a period

Comprehensive Geriatric Oncology

370

of 8 years. The vertical line represents±1 standard deviation of the mean value.1 Body composition and aging At the beginning of the clinical encounter, the clinician will obtain a height and weight and inspect the body habitus of the patient. Serial measurements of weight are particularly important in oncologic practice. Both crosssectional analyses (point-in-time assessment of subjects of varying ages) and longitudinal analyses (serial measurement of the same subject over time) show changes in height and weight with age (Figure 18.2).1 Loss of height is likely related to changes in the intervertebral discs. Buckwalter et al7 note that ‘no musculoskeletal tissue undergoes more dramatic age-related changes than the intervertebral disc’. Table 18.1 lists the changes that are seen in aged subjects and that contribute to height loss with age. From age 30 to 80, a man may lose 5 cm of height and a woman 8 cm.8 Calculations for body surface area should rely on measured height, since older patients

Table 18.1 Intervertebral disc changes with age • Fissure and cracking of disc • Decrease in proteoglycans and water concentration • Increase in non-collagenous protein concentration • Loss of viable cells in central regions • Decrease in the number of arteries supplying the disc region

may not be aware of height loss and will report heights that are erroneous, based upon what they recall their height to have been when younger. Excessive loss of height in late life may be the result of osteoporosis, with compression of vertebral bone causing pathologic height loss. With regard to body weight, Figure 18.2 does demonstrate a weight plateau through mid-adult life, with a gradual decline in weight in the later decades (age 70 and beyond). Associated with this weight change are important changes in body composition. With age, there appears to be a decline in the percentage of body mass that is lean mass.9,10 Body water seems to remain constant or decline slightly with age, and there is a shift of water from intra- to extracellular space. Body fat mass and the percentage of body weight that is composed of fat increase through adulthood into senescence. Studies using computed tomographic (CT) scanning suggest that fat is ‘internalized’ in older persons, i.e. it is not subcutaneous in the extremities but rather is intraabdominal and infiltrated within and between muscles.11 Mechanisms to explain these changes have included diet, sedentary lifestyles, and hormonal changes. For example, exercise programs have been shown to increase muscle mass even in frail older nursing home residents.12 Growth hormone replacement in growth hormone-deficient older subjects has resulted in some

Physiology of aging: Relevance to symptoms, perceptions

371

loss of fat and gain in lean mass.13 This suggests that age-related changes in body composition may be due to loss of growth hormone with advancing age in some people. No matter what the precise mechanism is for changes in body composition with advancing age, the implications for clinical practice are important. For example, lipidsoluble drugs will have a greater volume of distribution and altered pharmacokinetics, just as water-soluble agents will have a smaller volume of distribution, higher concentration for a given drug dose, and changed pharmacokinetics. Vital signs and autonomic function Histologic studies of the myocardium show that there is a decrement of pacemaker cells in older subjects and connective tissue infiltration in the area of the sinoatrial node.14 Likewise, a loss of Purkinje fibers is seen in the bundle of His.14 These anatomic changes do not seem to produce major changes in resting heart rate. Data are conflicting whether resting heart rate remains constant or declines with aging.15 From the clinical perspective, even if heart rate does decline with age, the decline is modest. Detection of bradycardia, particularly symptomatic bradycardia, should not be attributed to aging, but rather to

Figure 18.3 Heart rate plotted by age decade at rest and at peak exercise in males (filled symbols) and females (open symbols).

Comprehensive Geriatric Oncology

372

*Significant age regressions within gender at rest or peak effort. The pvalues indicate gender differences by analysis of variances.16 cardiac disease. Respiratory variation of heart rate and spontaneous variations in heart rate over a 24-hour period are diminished with aging. Even more impressive is the reduction of heart rate in response to catecholamine stimulation or exercise as subjects age (Figure 18.3).16 The reduction of maximal heart rate with aging is not due to a decline of circulating catecholamines or excessive vagal tone. Rather, there appears to be severe blunting of β-adrenergic receptor response in healthy older individuals.17 The oncologist caring for the geriatric patient may find, therefore, that stress or fear will not produce the same degree of pulse elevation among older patients as occurs in younger patients. Blood pressure is known to change with aging. Arteriosclerosis is the age-related change in the arterial blood vessels. In the aorta and other large vessels, elastic fibers are fractured and unrolled with aging. Simultaneously, calcium is deposited along with collagenous matrix.18 These changes cause vessels to become ‘stiff’. As a result, the arterial pulse is forceful in the geriatric patient. This can be true even in conditions where one might expect a reduction of pulse amplitude, such as significant aortic stenosis. Smaller arteries and arterioles demonstrate hyaline degeneration within the media and a decrease in the lumen-to-wall ratio and overall cross-sectional area of the lumen with aging.18 The effect of these changes is to produce an increase in systemic vascular resistance with aging. Table 18.2 outlines the various influences on blood pressure and changes seen with aging. When populations are studied to examine the changes in blood pressure with age, it appears that systolic pressure

Table 18.2 Determinants of blood pressure and changes with aging Factor

Age-related change

Peripheral vascular resistance

Increase

Plasma catecholamines

No change/increase

α-receptor response

No change

β-receptor response

Decrease

Baroreceptor response

Decrease

Plasma renin

Decrease

Sodium retention/excretion

Decrease/decrease

rises steadily throughout adult life, while the diastolic pressure reaches a mid-life plateau. Interestingly, these changes have not been documented in all human populations, but seem to be true for Western Europe, North America, and other industrialized nations. In later life, blood pressure normals are the same as for middle-aged or younger adults.

Physiology of aging: Relevance to symptoms, perceptions

373

Blood pressure elevation continues to be a risk factor for cardiovascular morbidity and mortality in geriatric patients. One troublesome area in the clinical assessment of blood pressure in the geriatric patient in the issue of ‘pseudohypertension’. This entity is felt to be the false measurement of an elevated blood pressure in the face of a normal intraarterial pressure.19 Pseudohypertension may be the result of excessive arteriosclerosis that causes the brachial artery to be poorly compressible when the sphygmomanometer is applied, so that a falsely elevated reading is obtained. Patients with pseudohypertension may show little target organ change from their elevated blood pressure and be very sensitive to the blood pressurelowering effect of antihypertensive agents. Attempts to clinically differentiate pseudohypertensives from true hypertensives without resorting to the direct measurement of intraarterial blood pressure have not been particularly successful. Also important in blood pressure determination of geriatric patients is the measurement of orthostatic blood pressure. Despite factors that might predispose to orthostasis (Table 18.2: e.g. decrease in baroreceptor sensitivity, decreased arterial compliance, decreased renal sodium conservation, and decreased renin), studies indicate that blood pressure should not decline significantly (≥20 mmHg systolic) when geriatric patients go from the supine to the upright position.20 Orthostatic blood pressure drop is found commonly in geriatric patients and requires an explanation. It is good practice to measure orthostatic blood pressure in all geriatric oncology patients at baseline. Abnormalities need to be pursued, and follow-up examination can be indexed against the baseline determination. Temperature is another key vital sign assessed in geriatric medicine practice. Core body temperature does not appear

Table 18.3 Age-associated skin changesa Component

Anatomic or functional change

Impacted function

Keratinocytes

Decreased proliferation

Wound healing; vitamin D3

Melanocytes

Decreased by 10% per decade

Photoprotection; color

Langerhans cells

Decreased by up to 40%

Delayed hypersensitivity reactions; immune recognition

Flattens, reducing the dermoepidermal interface

Epidermal-dermal adhesion

Fibroblasts

Decreased collagen elastin synthesis

Tensile strength elasticity

Microvasculature

Decreased vascular area

Thermoregulation and inflammatory response

Mast cells

Decreased

Immediate hypersensitivity reactions

Neural elements

Decreased by one-third

Sensation; pain threshold

Epidermis:

Basement membrane zone Dermis:

Comprehensive Geriatric Oncology

374

Subcutis: Fat

Decreased

Insulation and mechanical protection

Eccrine glands

Decreased number and output

Thermoregulation

Apocrine glands

Decreased number and output

Unknown

Sebaceous glands

Increased size and decreased output

Unknown

Hair follicles

Decreased number and growth rate

Cosmetic

Appendages:

a

From: Chuttani, Gillcrest BA. Skin. In: Handbook of Physiology, Section 11: Aging. Oxford: Oxford University Press, 1995:309–24.

to change as a function of age.21 Heat or cold stress may not be as well tolerated by older subjects, and older patients are more prone to heat illness or hypothermia during times of environmental stress.22 Debate exists whether it is generalizable that older patients have less ability to mount a febrile response to an infection.23 There certainly are older patients who show little or no temperature elevation from infection or in the presence of a tumor. Respiratory rate is the other vital sign measured routinely on patient assessments. There is no clear evidence that resting respiratory rate changes as a function of age. With hypoxia or hypercapnic stress, however, older subjects respond with a diminished respiratory response.24 Skin Although not traditionally viewed as a physiologic system, the skin is one of the areas of the body where aging is clinically manifest. The barrier function of the skin is particularly important in oncologic practice. Yaar and Gilchrest25 have reviewed this topic in great detail. Table 18.3 is a summary of age-associated skin changes with the anatomic or functional changes and the implications for function. Clearly, wrinkling of the skin occurs with aging. There is hair loss, and graying of the hair is seen as the result of melanocyte loss and decreased melanocyte activity. The impact of these changes on chemotherapy- or radiotherapy-induced alopecia and recovery in geriatric patients is not well studied. Wound healing is reported to be affected by age, and may be due to a muted inflammatory response, changes in skin metabolic responses, and diminished rates of capillary ingrowth. This has important implications for the surgical patient or patient receiving radiation with secondary skin involvement. Age-related skin changes affect the endocrine function of the skin. Less vitamin D3 is present in the skin of older subjects, and the skin of older people is less able to produce vitamin D3 than the skin of younger people. These changes in vitamin D production as well as the reduced sunlight exposure of some older patients may presage the occurrence of vitamin D deficiency among certain older patients, with resultant osteomalacia.

Physiology of aging: Relevance to symptoms, perceptions

375

Cellular and biochemical changes of the skin affect the skin’s tensile strength and elasticity. As a result, the assessment of skin turgor as a measure of hydration in geriatric patients is not as valid as it might be in younger patients. Microvascular changes of skin blood vessels may relate to the ability to dissipate or conserve heat in late life. Additionally, thinning of blood vessel walls and loss of subcutaneous fat in areas such as the dorsum of the hand can predispose to easy bruisability in some older patients. Furthermore, loss of subcutaneous fat in areas such as the heel of the foot results in less mechanical protection to that area and propensity to injury (i.e. pressure ulceration).

Figure 18.4 The effect of age on subdivision of lung volume: TLC, total lung capacity; FRC, functional residual capacity; RV, residual volume. From: Tockman MS. Aging of the respiratory

Comprehensive Geriatric Oncology

376

system. In: Principles of Geriatric Medicine and Gerontology, 3rd edn (Hazzard WR, Bierman EL, Blass JP et al, eds). New York: McGraw-Hill, 1994:557. Respiratory system The bedside examination of the chest and lungs does not change much with aging. Older persons who are dyspneic or have a cough generally have underlying pathology to account for their symptoms. There are, however, important anatomic changes in the chest wall, lung, and central nervous system (CNS) that have implications for respiratory physiology and clinical practice. Figure 18.4 summarizes the physiologic changes that occur with aging. Total lung capacity remains constant. Residual volume (the amount of air in the lung at maximal expiration) increases with age, as does the functional residual capacity (the amount of air in the lung after a quiet expiration). Since vital capacity (the maximum amount of air expired after maximal inspiration) is the difference between total lung capacity and residual volume, it is inevitable that vital capacity will decline with age as the residual volume increases. The closing volume (the volume of the lung at which the dependent airways begin to close) is also higher in older subjects. These changes have been detailed and reviewed by Janssens et al.26 Changes in airflow rates occur with

Physiology of aging: Relevance to symptoms, perceptions

377

Figure 18.5 Arterial PO2 as a function of age from birth to 80 years. From: Murray JF. The Normal Lung. Philadelphia: WB Saunders, 1976. advancing age. The forced vital capacity (FVC), forced expiratory volume in one second (FEV-1) and forced expiratory flow between 25% and 75% of the vital capacity (FEF 25– 75) all decline with age. Regression equations have been developed and published so that pulmonary function laboratories may use the appropriate reference values when testing aged subjects.27 These changes in physiologic function relate in part to declining strength in respiratory muscles with age, an age-related increase in pleural elastin leading to increased elastic load on respiratory muscles, stiffening of the chest wall due to changes in the ribcage (e.g. calcification of rib articulations), and loss of lung elastic recoil with increase in lung compliance. Measurement of blood gases is important in oncologic practice. Figure 18.5 depicts the decline in the arterial partial pressure of oxygen (PO2) in adulthood. One regression equation that has been employed to calculate the impact of aging on PO2 is the following:26 PO2=100.0−0.323 (age)

Comprehensive Geriatric Oncology

378

Since alveolar PO2 remains constant with age, the alveolar-arterial gradient widens as patients grow older. The partial pressure of carbon dioxide (PCO2) does not appear to undergo any significant age-related change, but the diffusing capacity for carbon monoxide (DLCO) does decrease. These blood gas changes may result from observed distributional changes in ventilation with age and a mismatch of ventilation and perfusion. A decline in alveolar capillary surface area with increasing age also plays a role. As mentioned above, hypoxia and hypercapnia fail to elicit the same response in respiratory rates in older subjects as compared with the young, i.e. the old seem to be less sensitive. It has also been reported that older subjects perceive shortness of breath less intensely than the young. Other changes with age in the respiratory system include a decline in cough and laryngeal reflexes and a slowing of mucous velocity. It remains speculative whether these changes result in a predisposition to aspiration or pneumonia in aged patients. Cardiac function and exercise Aging results in changes in the heart and vascular system. Blood vessel changes have been described above. In the heart, the interventricular septum thickens, as well as the left ventricular free wall, with greater thickening of the septum. The heart mass as indexed against the body mass increases in older women.28 These findings can be seen on echocardiography as well as at autopsy. This change in muscle mass may be the result of increased aortic impedance, due to structural changes in the aorta. On microscopic examination, pigment deposition (lipofuscin) within myofibrils has been reported, as well as an increase of connective tissue at localized sites.29 Valvular changes have also been noted with aging. The mean circumferences for each of the four cardiac valves increase progressively throughout life.28 Valve leaflet thickness increases with aging. Calcifications of the aortic valve, mitral annulus, and mitral valve are seen commonly in the hearts of older people. Mitral annulus calcification is more prevalent among elderly women. Although these valvular changes are evident on echocardiography, it is not clear that they result in any functional disturbance. Changes in the conducting system were alluded to above in the discussion of pulse. Lakatta15 has detailed the functional properties of the senescent myocardium Although early reports note a decline in cardiac performance with advancing age, more recent studies do not support this finding. The more recent reports probably reflect better ability to screen for subclinical cardiac disease and exclude affected subjects from research studies. Figure 18.6 shows results from a series of studies examining subjects of different ages and various physiologic parameters at rest, with exercise and by gender16 In men, the end-systolic volume index (ESVI), the end-diastolic volume index (EDVI), and the stroke volume index (SVI) increase with age at rest; this is not seen in women. Resting ejection fraction (EF) and cardiac index (CI) show no change in men; in women, the EF is stable, but the CI declined 16% from the third to eighth decade. Peripheral vascular resistance at rest does increase in both genders with aging, while the resting heart rate declines slightly. The gender differences appear to be the result of differences in fitness levels. It is interesting, therefore, that since cardiac output is the product of stroke volume and heart rate, older men maintain cardiac output by compensating for a mild heart rate

Physiology of aging: Relevance to symptoms, perceptions

379

reduction with increased stroke volume, which is due to an increase of end-diastolic volume (EDV) (‘preload’). Table 18.4 summarizes these changes.

Figure 18.6 Systemic hemodynamic variables plotted by age decade at rest and peak exercise in males (filled symbols) and females (open symbols). *Significant age regressions within gender at rest or peak effort. The pvalues indicate gender differences of variance. †Significant gender differences for individuals decades adjusted for multiple comparison. (a, b) Left ventricular volume indices at rest (a) and peak exercise (b): EDVI, end-diastolic volume index; SVI, stroke volume index; ESVI, endsystolic volume index. (c) Cardiac

Comprehensive Geriatric Oncology

380

index (CI). (d) Systemic vascular resistance. (e) Ejection fraction (EF).16 Table 18.4 Seated rest: changes in cardiac output regulation between 20 and 80 years of age in healthy humans15 Parameter

Age-related change a

Cardiac index

No change

Heart rate

Decrease (10%)

Stroke volume

Increase (10%)

Preload: End-diastolic volumea

Increase (12%)

Early filling

Decrease

Late filling

Increase

Afterload: Compliance

Decrease

Reflected waves

Increase

Inertance

Increase

Total peripheral vascular resistance

Increase

Contractility

No change

Ejection fraction

No change

Left ventricular mass

Increase

a

Women differ from men: there is no increase in end-diastolic volume and a decrease in cardiac index with age in women.

Figure 18.6 also examines cardiac functional changes with aging during exercise. In older men with exercise, the EDVI rises compared with the young. For men and women, the SVIs are comparable with exercise and age, while the ESVI is greater for older subjects of both genders with exercise compared with the young. The EF with exercise increases markedly in younger subjects. This increase is not seen in exercising older men and women. Similarly, although heart rate and CI increase in both old and young with exercise, older men and women do not have the same degree of heart rate or CI elevation that is seen in the young. Table 18.5 summarizes these exercise-related differences between young and old. In summary then, at-rest cardiac function does not appear to change much with aging. With the stress of exercise, older subjects are less able to augment cardiac function as much as younger subjects. This lack of comparable response to exercise is the result of age-associated decreases in heart rate, a relative reduction in myocardial contractile

Physiology of aging: Relevance to symptoms, perceptions

381

reserve, and a relatively greater increase in impedance of left ventricular ejection. All of these factors could be related to blunted adrenergic responsiveness that is seen with aging.17 Maximum oxygen consumption (VO2max) achieved during exercise reflects cardiac and pulmonary factors as well as local tissue oxygen delivery, extraction, and utilization. When measured in subjects of different ages, VO2max declines with advancing age.15 This remains true when the data are controlled for weight, lean body mass, and training effects. This decline is likely the result of changes in cardiac output, respiratory reserve, and loss of skeletal

Table 18.5 Exhaustive upright exercise: changes in aerobic capacity and cardiac regulation between the ages of 20 and 80 in healthy men and women15 Parameter

Age-related change

Oxygen consumption

Decrease (50%)

(A-V)O2

Decrease (25%)

Cardiac index

Decrease (25%)

Heart rate

Decrease (25%)

Stroke volume

No change

Preload: EDV Afterload:

Increase (30%) Increase

Vascular (PVR)

Increase (30%)

Cardiac (ESV)

Increase (275%)

Cardiac (EDV)

Increase (30%)

Contractility

Decrease (60%)

Ejection fraction

Decrease (15%)

Plasma catecholamines

Increase

Cardiac and vascular responses to β-adrenergic stimulation

Decrease

(A-V)02, arterio-venous oxygenation difference; ESV, end-systolic volume; EDV, end-diastolic volume; PVR, total peripheral vascular resistance.

muscle fitness with aging. Skeletal muscle metabolism does not appear to account for the decline in VO2max. Although maximal performance with exercise is greater in young adulthood than in senescence, older patients can exercise and should exercise to minimize decrements in physiologic function with aging. Symptoms of cardiac dysfunction in late

Comprehensive Geriatric Oncology

382

life are the result of disease, and need evaluation and explanation. Cardiac disease remains the number one cause of death, even into the ninth decade. Gastrointestinal function The evaluation of the gastrointestinal system begins at the mouth. This is particularly important in oncologic practice, since geriatric cancer patients may have mucositis or other oral complaints. The teeth and gums do undergo aging changes, with gingival recession, pulp recession inside individual teeth, and an increase in tooth brittleness.30 The ability to efficiently chew food declines with aging.31 Salivary function, on the other hand, is preserved into late life.32 Xerostomia (dry mouth) is generally the result of drugs, radiation therapy, or disease (e.g. Sjogren syndrome). Studies of taste sensation show that the threshold for detecting taste is greater in late life, i.e. older subjects do not have as acute a sense of taste as younger subjects. However, the meaning of these studies for clinical practice is unclear, since the stimuli for taste are present in much greater concentrations in the routine diet than experienced in the laboratory environment where thresholds are being examined. Overall, the ability to taste is preserved with advancing age in ordinary day-to-day life. Therefore, disturbance in taste should suggest some pathologic process in the geriatric patient.33 It should be noted, however, that the same is not true for olfaction. The identification and recognition of odor decline dramatically with age. A decline in olfaction is more difficult to sort out with regard to whether the change is due to disease (e.g. upper respiratory infection). Complete loss of smell (anosmia) should not be attributed to aging, although defining a precise etiology may be elusive. Swallowing is a complex function requiring intact sensory, voluntary motor, and involuntary motor functions. Shaker and Staff34 have reviewed the effect of aging on swallowing and esophageal motor function. Data are lacking regarding consistent changes in oromotor function that occur with age. Measurement of upper esophageal sphincter pressure has yielded conflicting results, making generalizations difficult. In the pharynx, the peristaltic pressure wave amplitude and duration seem to be greater in elderly subjects compared with young subjects. These changes in pressure may be needed to overcome a reduced cross-sectional area of the deglutitive upper esophageal sphincter opening in elderly patients. Older studies suggested changes in esophageal motor function termed ‘prebyesophagus’. More recent data suggest that primary esophageal peristalsis induced by swallowing does not necessarily change with age. Secondary peristalsis (initiated in response to local esophageal stimuli) is either absent or inconsistent, and significantly less frequent in old subjects compared with the young.35 This loss of secondary peristalsis may result in impairment of esophageal volume clearance, and predispose to esophageal and supraesophageal complications of reflux among older patients. Also noted in this study was less relaxation of the lower esophageal sphincter in response to esophageal distention among the old subjects.35 Resting lower esophageal sphincter pressure has been reported to be stable with aging, but in response to swallowing, the sphincter may not completely relax consistently in the oldest subjects (those aged 90 and above).

Physiology of aging: Relevance to symptoms, perceptions

383

Symptoms of dysphagia, choking, or odynophagia in older patients need evaluation and should not be attributed to aging. With regard to gastric function, it has been traditionally thought that acid production declines with age. On closer scrutiny, investigators excluding subjects with diseases such as atrophic gastritis and Helicobacter pylori infestation, and controlling for body composition, have found that basal acid output and maximal/stimulated acid outputs are preserved into later years.36 It may even be the case that there is a significant increase of acid output with aging. The clinician must keep in mind, however, that diseases such as atrophic gastritis are exceedingly common in late life (they may affect 40% or more of persons aged 80 and over) and result in decreased secretion of acid.37 Evaluation of the literature on gastric motility and aging is plagued with the same problems of subject selection as acid output. Motility is affected by acid, and studies must control for achlorhydria since this condition has been shown to delay gastric emptying. Many reports do not comment on whether achlorhydria is present or absent among subjects. Therefore, there are contradictory reports on gastric motility and age. Holt36 has summarized this motility literature, and states that ‘overall, these studies lead to the conclusion that by the best nuclear medicine techniques that examine passage of both solid and liquid meals, gastric emptying of food is little reduced as a function of age, though gastric emptying of the liquid part of a meal may be slightly delayed’. In clinical practice, the ability of the gastric mucosa to protect itself is important. Arthritis is the number one chronic illness seen in older persons, and is frequently treated with aspirin and non-steroidal anti-inflammatory agents, which can influence gastric mucosal protection. Data on prostaglandin concentration and synthesis in the upper gastrointestinal tract support a decline with aging. Animal studies do suggest that experimentally induced gastric injury causes more severe injury and reduced healing in senescent research animals.36 Older patients do have an appreciable risk of gastrointestinal hemorrhage when treated with non-steroidal agents. Small-intestine physiology in humans represents a challenge to investigators because of the inaccessibility of the small bowel. Controversy exists as to whether any significant morphologic changes occur in the intestinal mucosa with aging. With regard to absorption, carbohydrate digestion seems unimpaired by aging. However, intestinal monosaccharide absorption does seem to be reduced with age.36 This may be due to a change in intestinal receptor density or affinity for actively absorbed substrates. This reduction in carbohydrate absorption is unlikely to result in malnutrition in healthy older patients. Protein absorption is less well studied than carbohydrate absorption and data from humans are not sufficient enough to make generalizations. For fat absorption, there is little evidence that major changes in intestinal lipid transport occur with age.36 Sodium, potassium, zinc, and copper appear to be absorbed effectively into late life. Iron has been reported to have altered absorption, but this finding has been called into question, and it is believed that iron absorption is intact in healthy older subjects.36 Calcium, on the other hand, does have impaired absorption with advancing age. Since achlorhydria, vitamin D deficiency, and dietary calcium or fiber intake can all influence calcium intake, these must be factored into interpretation of studies examining calcium absorption. When these factors are considered, it still does appear that aging is associated with a reduced calcium

Comprehensive Geriatric Oncology

384

Table 18.6 Effects of aging on liver physiology37 Liver variable

Age-related changes

Liver size

Decreased

Hepatic blood flow

Decreased

BSP, galactose elimination

Decreased

Microsomal drug metabolism

Normal to decreased

Glucuronidation

Probably unchanged

Glutathione

May be decreased

Serum albumin

Slightly decreased

Routine liver chemistries

Normal

absorption.36 As a result, recommendations have been made for older persons to increase dietary calcium intake. Vitamin absorption has been examined as a function of age. Thiamine, niacin, folate, vitamin B12, vitamin K, and vitamin A all seem to be absorbed without difficulty in healthy older persons. Vitamin D absorption does appear to be impaired.36 Smallintestinal transit time appears to be unaffected by age. As far as colonic structure and function are concerned, it is well known that colonic diverticuli are seen with increasing frequency as patients age. Although constipation is common in later life, it does appear that this is a pathologic state and that colonic transit time is not affected by aging. Manometric anorectal study shows that rectal distention may be associated with higher pressures and decreased basal and squeeze anal pressures in elderly volunteers compared with young volunteers. These findings might contribute to the risk of fecal incontinence among geriatric patients.38 Pancreatic function has been assessed closely in animals and humans. A number of physiologic changes, such as reduced responsiveness of secretion to exogenous stimuli, a delay in responsiveness of pancreatic growth to proliferative signals, and an impaired or delayed response of pancreatic enzyme synthesis to changes in nutrient substrate uptake, have all been reported to occur with aging.36 None of these, however, is sufficient to cause clinical manifestations of pancreatic exocrine dysfunction in geriatric patients. Table 18.6 outlines the influence of age on hepatic structure and function. The clinical examination is not sensitive enough to reliably demonstrate the decline in hepatic size/weight in geriatric patients. The reduction of hepatic blood flow in older patients may result in diminished first-pass metabolism of drugs. Hepatic synthetic capacity is well maintained into late life and changes in serum albumin are modest. Serologic measures of enzymes found in liver cells appear to have similar reference ranges for younger and geriatric patients.

Physiology of aging: Relevance to symptoms, perceptions

385

Endocrine aspects of aging After consideration of the abdomen and gastrointestinal system, the clinician will often examine the genitalia. This raises issues of endocrine aspects of aging as well as renal physiology. The endocrine system will be dealt with first, followed by consideration of the kidneys and urinary tract. Elderly women have evidence of estrogen loss, with vaginal, uterine, ovarian, and breast atrophy. Bone loss is accelerated with estrogen depletion. Although menopause is initially associated with marked elevation of folliclestimulating hormone (FSH) and luteinizing hormone (LH), data are conflicting whether these gonadotropins remain elevated or decline, particularly after age 60.39 After menopause, FSH increases to a greater extent than LH. Therefore, the ratio of FSH to LH is greater than 1 in the postmenopausal state—as opposed to premenopause, when it is less than 1.40 The administration of luteinizing hormone-releasing hormone (LHRH) to older women still produces a surge of LH and to a lesser extent FSH.40 Estradiol levels are, of course, markedly depressed in elderly postmenopausal women. Estrone levels, which in premenopausal women are lower than estradiol levels, exceed estradiol levels in late life.41 The source of estrone appears to be the extraglandular aromatization of adrenal androstenedione by adipose tissue, bone, muscle, skin, and brain. Studies are ongoing to examine the risks and benefits of estrogen replacement therapy in older women. Physical examination of the older man’s genitalia does not show significant changes from earlier in life. Pubic hair thins and grays. The prostate gland enlarges. Although testicular size may not change with age, histologic examination shows a drop in the percentage of seminiferous tubules containing sperm, atrophy of the seminiferous tubules with thickening of the tunica propria and basement membrane, loss of Sertoli cells and spermatids per Sertoli cell, and a loss of Leydig cells.42 Serum total testosterone declines with advancing age in men. Sex hormone-binding globulin (SHBG) is known to rise. As a result, when a free testosterone index (total testosterone/SHBG) is examined, the decline of male androgen is even more impressive.43 It is estimated that 20% of men aged 60 and over are hypogonadal using total testosterone measurements. This rises to 50% of men aged 80 and over. These estimates would be even higher if the free testosterone index were used. Androgen replacement in aging men will likely become more prevalent as data accumulate regarding the benefits and risks. Estradiol levels have been reported to generally decrease less with age in men than serum testosterone. This means that the estradiol-totestosterone ratio may increase with age.39 There is speculation that this ratio shift may relate to prostatic hyperplasia in late life. Estradiol may also drive the rise in SHBG in men with age. Analysis of gonadal function naturally leads to a consideration of general pituitary function with aging. The ability of the pituitary to secrete gonadotropins has been described for men and women. Growth hormone (GH) has been extensively studied and reviewed as a function of aging.44 GH decrement between the ages of 20 and 80 ranges between 25% and 66%. A parallel decline in insulin-like growth factor I (IGF-I) has also

Comprehensive Geriatric Oncology

386

been reported. IGF-I is a hepatic protein whose synthesis is dependent upon GH. A significant number (40–50%) of patients aged 70 and over have evidence of profound GH depletion. Studies continue to examine the risks and benefits of replacing GH in deficient elderly people. Beneficial effects might include improved lean body mass content, decreased body fat mass, increased muscle mass/strength, improved exercise capacity, and improved bone density.13 The pituitary does seem to be able to respond to growth hormone-releasing hormone (GHRH) in older subjects, although there are conflicting results whether the response is as brisk as that seen in younger subjects.45 Regarding prolactin secretion and aging, studies are variable in their results, showing no change, decreased serum levels, or increased basal/stimulated levels of the hormone in older subjects.46 Also produced in the pituitary gland is adrenocorticotropic hormone (ACTH). ACTH secretion is pulsatile and complex. Human studies have not always taken this into full consideration, but secretion appears to be unchanged with aging.47 The pituitary remains responsive to corticotropin-releasing hormone (CRH) in late life.48 At the level of the adrenal gland, Nelson,39 in a review of 19 studies, notes that plasma cortisol levels are generally unchanged in late life, although occasional reports do note increased plasma levels in aging individuals. When these increases are noted, they are relatively small. The most plentiful adrenal steroid found in the serum is dehydroepiandrosterone (DHEA) and its sulfate. Although abundant, the precise role of this weak androgen is unknown in human physiology. What is noteworthy for the care of geriatric patients is a marked decline of plasma DHEA concentration with aging.39 Epidemiologic studies have linked depressed DHEA levels to a higher risk of breast cancer, a higher risk of cardiovascular disease, and a higher all-cause mortality. This has led to an interest in human trials of DHEA to assess the benefits and side-effects of this agent. Yet another pituitary hormone is thyroid-stimulating hormone (TSH). TSH levels seem to be stable throughout life. Basal pituitary secretion of TSH increases somewhat in older persons, and pituitary response to thyrotropin-releasing hormone (TRH) has yielded conflicting results, with decreased, unchanged, or increased TSH responses.48 With aging, there is fibrosis, decreased follicular cellularity and size, and increased microscopic nodularity of the thyroid gland. Despite these anatomic changes, serum levels of thyroxine and triiodothyronine generally appear to be stable with advancing age. Both hyper- and hypothyroidism have increased frequency in geriatric patients, and can be difficult to diagnose due owing atypical manifestations and non-specific symptoms. In close anatomic proximity to the thyroid gland are the parathyroid glands. Throughout life, the reference range for serum calcium level determination does not change appreciably. Careful research studies indicate that there may be a slight decline in serum calcium with aging.49 Whether this is the result of a slight decline in serum albumin with age or a true decline due to depression of ionized calcium is disputed. Serum parathyroid hormone (PTH) has been shown to be higher in older persons (particularly older women) than in younger persons.48 This elevation may be due to diminished clearance of PTH associated with declining glomerular filtration rate with aging. Reduced calcium absorption due to intestinal effects of aging as well as slight reduction in serum albumin may cause a decline in ionized serum calcium in late life, which in turn results in increased secretion of PTH.

Physiology of aging: Relevance to symptoms, perceptions

387

Since the prevalence of diabetes is known to increase with advancing age, any consideration of endocrine function and aging must include some mention of pancreatic endocrine function. Modest anatomic changes of the pancreas have been described with aging, and include some atrophy, an increased incidence of tumors, and deposition of amyloid material and lipofusion granules.50 Halter51 has reviewed carbohydrate metabolism and aging in depth. From this review, a number of important points about aging and pancreatic endocrine function emerge. When fasting levels of glucose are measured in healthy subjects of varying ages, values appear to be stable and perhaps a minor clinically insignificant rise may occur. With the administration of glucose either orally or intravenously, significant differences are seen among subjects of differing age. In young adulthood, the rise in plasma glucose is not as high or sustained for as long as seen in late life. This impairment in glucose homeostasis is not due to defective insulin release, since measured insulin levels are comparable for the young and old. These differences must be accounted for when interpreting glucose tolerance results in geriatric patients. The American Diabetes Association criteria for diabetes have factored these age-related changes into the standards used to make a diagnosis of diabetes.52 Therefore, a diagnosis of diabetes is made when the fasting plasma glucose is greater than or equal to 126mg/dl. Alternatively, if the patient has classic diabetes symptoms, random hyperglycemia (random glucose concentration >200mg/dl), or a 2-hour plasma glucose level greater than 200mg/dl after a 75g glucose load, a diagnosis of diabetes is also possible. Impaired fasting glucose is diagnosed when patients have a fasting plasma glucose of 110–125 mg/dl. Extensive studies have been performed to determine the mechanism of altered glucose homeostasis with age.51 As mentioned previously, insulin response does not seem to be impaired. Insulin action beyond the level of the insulin receptor appears to be where the problem lies with glucose metabolism and aging. There is not much evidence that glucagon changes with age or in any way mediates the change in glucose metabolism seen with age. Since GH may decline with age, its action could not explain the agerelated rise in plasma glucose with a challenge. Also, although plasma cortisol may increase subtly with age, this rise does not seem to be sufficient to account for the observed glucose differences in young and old after glucose challenge. As alluded to earlier in the discussion of blood pressure (Table 18.2), plasma norepinephrine (noradrenaline) levels and norepinephrine release increase with aging. Although it does not appear that these increased resting levels have much effect on basal glucose levels, with catecholamine infusion (epinephrine/adrenaline), greater hyperglycemia is seen among older subjects than for the young when simultaneous glucose administration occurs. The clinical importance of the above-mentioned issues for the oncologist is multifaceted. First, diabetes is a common comorbidity among geriatric oncologic patients, and must be factored into treatment strategies. Second, geriatric patients without a history of diabetes may have hyperglycemia induced more easily than young subjects as a result of stress, the use of glucose infusion during intravenous therapy or total parenteral nutrition, or the administration of drugs (e.g. glucocorticoids) in the course of treatment of a malignancy. Changes in body composition described previously (i.e. loss of lean

Comprehensive Geriatric Oncology

388

mass and accumulation of adipose) and sedentary lifestyle may also predispose older persons to the development of diabetes. To conclude this section on endocrine function and introduce the discussion of renal function, there should be some mention of salt and water metabolism with aging. Arginine vasopressin (AVP) is a peptide hormone produced in the hypothalamus and released from the posterior pituitary. AVP levels have been reported to decline, remain steady, or increase in the resting state with advancing age.53 When AVP is stimulated using osmotic (saline infusion) or pharmacologic stimuli (e.g. metoclopramide injection), older subjects appear to have less inhibition of AVP release and loss of alcoholsuppressive effect compared with young subjects.53 Curiously, when AVP release is stimulated by blood volume/blood pressure using overnight dehydration and the stress of acute upright positioning, the response is not exaggerated, as just noted for osmotic/pharmacologic stimuli. Therefore, while the AVP response to osmotic stimuli with aging is exaggerated, the response to volume/pressure stimuli is blunted. The blunting may be the result of diminished baroreceptor sensitivity (Table 18.2) noted with aging. Although there is an increase in AVP response to osmotic stimuli, there appears to be relative resistance to the effect of AVP at the level of the kidney in late life.54 Reference values for serum electrolytes do not appear to be affected by aging. However, the hormonal systems governing sodium balance and blood pressure do appear to change. Plasma renin values are consistently lower when measured in older subjects and compared with the young.54 Not surprisingly, plasma and urinary concentrations of aldosterone are similarly depressed. Furthermore, it has been reported that atrial natriuretic factor (ANF) levels are higher for older subjects than younger ones.54 The net effect of these changes is that older patients may have greater difficulty retaining sodium/salt than their younger counterparts. There is evidence that with sodium restriction, healthy older patients with intact renal function are less able to effectively conserve sodium.54 There are a number of clinical implications of these physiologic changes in water/salt metabolism. The geriatric oncology patient who is placed on a sodium-restricted intake, who is given hypotonic fluid or agents that provoke AVP (e.g. narcotics or metoclopramide), or who is stressed (e.g. fearful, in pain, or postoperative) is at risk for the development of hyponatremia due to problems with faulty sodium retention and exaggerated AVP response, despite peripheral AVP resistance. Another scenario is that of the geriatric oncology patient who is salt/water-deprived (e.g. nil-by-mouth for diagnostic studies or anorectic) and more rapidly becomes dehydrated due to a lesser ability to conserve salt and water through the renin/angiotensin/aldosterone system as well as a less effective renal sodium-concentrating mechanism. Further compounding this situation is what appears to be a physiologic decline of thirst with aging that may make correction of water loss more difficult for the aged patient.55 Finally, with the depressed renin aldosterone response plus the decline in glomerular filtration rate with aging (see below), the oncologist must be on guard against the subtle development of hyperkalemia in aged patients associated with the use of non-steroidal anti-inflammatory agents, potassium-sparing agents, beta-blockers, or angiotensin-converting enzyme (ACE) inhibitors.

Physiology of aging: Relevance to symptoms, perceptions

389

Renal function There is little in the bedside examination that alerts clinicians to the important changes that occur in renal function with age. Even laboratory measurements of electrolytes, blood urea nitrogen, serum creatinine, or urinalysis do not readily convey age-related changes in renal physiology.

Figure 18.7 Cross-sectional difference in standard creatinine clearance with age. The numbers of subjects in each age group are indicated above the horozontal axis. Values plotted are mean ±SEM From Rowe JW, Andres R, Tobin JD et al. The effect of age on creatinine clearance in men: a crosssectional and longitudinal study. J Gerontol 1976; 31:155–63. Lindeman56 has summarized anatomic changes in the kidneys over the lifespan. Renal mass declines by 1% per year. This loss of mass is primarily from the renal cortex. The number of glomerular tufts per unit area as well as the numbers of glomerular and tubular cells decrease. Large renal arteries undergo sclerotic changes in their walls. Sclerotic

Comprehensive Geriatric Oncology

390

glomeruli increase with advancing age, so that at age 40 less than 5% of the total glomeruli are sclerotic, while 10–30% of the total are sclerotic by the eighth decade. The mesangium of the glomerulus takes up a greater percentage of glomerular volume, and the glomerular basement membrane thickens in older subjects. The glomerular filtration rate (GFR) has been shown to decline as a function of age, whether estimated by inulin or creatinine clearance54 (Figure 18.7). This decline is important to the clinician, who must take it into account when dosing patients with drugs that are affected by renal excretion (e.g. methotrexate or aminoglycosides). Unfortunately, the serum creatinine concentration does not reflect the drop in creatinine clearance with the expected rise in creatinine level. This is due to the fact that, with age, there is a loss of lean body mass and therefore a decline in creatinine production. Figure 18.8 makes the point that on longitudinal follow-up, one–third of healthy geriatric subjects have no decrease in creatinine clearance. This suggests that the

Figure 18.8 Individual plots of serial creatinine clearances versus age in years for representative subjects.5

Physiology of aging: Relevance to symptoms, perceptions

391

age-related decline in GFR demonstrated in cross-sectional studies may not be an inevitable consequence of age, but rather may reflect subclinical non-detectable renal disease.5 Estimates of creatinine clearance need to recognize this variation, so that appropriate clinical monitoring and serum drug levels are also used as guides to therapy of the geriatric patient. Other changes in renal function with age include a decrease in renal plasma flow, a decrease in tubular maximum transport for p-aminohippuric acid (PAH) and glucose, a decrease in concentrating ability probably due to a decline in medullary hypertonicity, a decline in maximum diluting ability due to nephron loss, and a reduced ability to excrete an acid load.54 Under basal conditions pH, pCO2, and bicarbonate are similar in old and young subjects. However, in the face of an acid load, older patients take longer to correct the acidosis and do not buffer/excrete acid as effectively as the younger person. Since urinary incontinence is seen commonly among geriatric patients, it is important to consider the physiology of micturition in late life. Table 18.7 lists some of the changes seen in the lower genitourinary tract with age that can affect micturition and the clinical assessment of bladder function.57 Owing to a smaller-capacity bladder, some older persons may need to void more frequently. When checking geriatric patients for residual volume after voiding, as much as 75 ml of urine may be obtained without there being any significant pathology. Involuntary bladder contractions can be documented on cystometrographic studies, and their significance is not always clear because of poor correlation of these contractions with clinical symptoms. Estrogen levels, injury and anatomic realignment of the urethra from childbirth, and deconditioning may all contribute to a reduction of resistance to urine flow in the elderly woman. As alluded to earlier, prostate growth may be the result of changing estrogento-testosterone ratio with advancing age in men. Although these changes may predispose to the development of urinary incontinence in elderly patients, the occurrence of incontinence should be viewed as a disease process and investigated for an underlying etiology. The oncologist must be aware that agents that affect

Table 18.7 Age-related changes in micturition Parameter

Age-related change

Bladder capacity

Decreased

Post-void residual volume

Increased

Involuntary bladder contraction

Common

Bladder outlet/urethral resistance

Decreased in women

Prostate size

Increased in men

autonomic function (e.g. anticholinergics or alpha-blockers) can affect bladder/urethral function (e.g. urinary retention or laxity of the internal urethral sphincter). Also, the use of agents such as diuretics may precipitate incontinence in patients with small bladder capacities or weakened urinary outlet, or who have difficulty in ambulating to the toilet.

Comprehensive Geriatric Oncology

392

Musculoskeletal function As the examination proceeds, the limbs and joints are next considered. Sarcopenia is the term that has been used to describe the loss of muscle mass. With advancing age, muscle mass has been shown to decline.58 This loss of mass is due to muscle fiber loss, particularly of type II (fast-twitch) muscle fibers, and a reduction in the size of muscle fibers. Clinical evaluation does not always readily show this loss, because of replacement of muscle with fat and connective tissue. Although not known for sure, it is speculated that this loss of muscle is related to a slowly progressive neurogenic process (i.e. loss of motor neurons in the spinal cord). When muscle strength is measured as a function of age, data suggest that strength peaks between the second and third decade, plateaus until age 45–50 and then declines by 12–15% per decade until the eighth decade.59 Some muscle groups tested have included the quadriceps, plantar/dorsal foot flexors, upper extremity muscle groups, and handgrips. Although these changes in strength are significant and well documented, the clinician must be aware that these measurements of strength are carefully recorded using sophisticated instruments that give precise values for force. The finding of clinically detectable weakness or atrophy should be evaluated so that myopathy or neuropathy is excluded. Attributing clinically significant weakness or atrophy to age without prior evaluation will likely result in missed diagnoses. Although sedentary lifestyle and inactivity accelerate and accentuate loss of muscle mass and strength, there does still appear to be an aging effect to account for these losses that is independent of disease. Additionally, since muscle mass is an important determinant of basal oxygen consumption, it is not surprising that basal metabolic rate declines with advancing age.60 There is also speculation that with loss of muscle mass, there is less ability to generate heat through shivering and less body insulation from the cold, which may predispose older persons to hypothermia.61 Osteoarthritis is the number one chronic illness occurring in late life. Geriatric patients will often have evidence on physical examination of this condition, particularly in the hips, knees, feet, hands, and spine. With normal aging, articular cartilage undergoes changes, with a decline in chondrocyte cell density once maturity has been reached, a decline in chondrocyte ability to synthesize proteoglycans, decreases in cartilage stiffness, fatigue resistance, and strength, a decline in water content, and changes in proteoglycan composition and the amount of keratin/chondroitin sulfate.7 Together, these cellular and biochemical changes may alter the stability and mechanical properties of the cartilage matrix and interfere with matrix turnover to replace degraded molecules. The relationship between age-related changes in cartilage and the occurrence of osteoarthritis is not completely understood and is the subject of active investigation. Another major component of evaluation of extremities is the bone. Unfortunately, bone does not readily lend itself to clinical examination, and plain radiographs are insensitive to many changes that occur in bone. Loss of bone mass is felt to be an inevitable consequence of aging.62 In women, this loss is accelerated by the menopause. Bone mass in late life is related to the complex interaction of factors such as genetics, race, exercise, nutrition (calcium intake), and habits (smoking, alcohol use, and caffeine intake). Although deficits in calcium intake, changes in vitamin D metabolism, and decline in estrogen in women and possibly androgen in men have traditionally been

Physiology of aging: Relevance to symptoms, perceptions

393

thought to mediate this bone loss, more recent studies have also implicated local factors in bone and cytokines as playing a role. Some considerations have included an agerelated stimulation of pluripotential stem cells to form osteoclasts through colonyforming units for the granulocyte-macrophage series (CFU-GM), increases in interleukin1 (IL-1) and tumor necrosis factor α (TNF-α) in later life mediating bone resorption, and prostaglandin secretion by bone cells in later life stimulating osteoclastic bone resorption.62 From the clinical standpoint, the treating oncologist must be aware that chemotherapy regimens that cause gonadal failure may accelerate physiologic bone loss. Agents such as steroids can also aggravate the age-related decline in bone loss. Immobility associated with poor performance status has a similar impact of augmenting physiologic loss of bone. Measures should be employed so that hormonal replacement is given to patients if appropriate, nutrition is optimized to promote adequate intake of vitamin D and calcium, and a program of exercise is encouraged. Bisphosphonate therapy should be considered when prolonged corticosteroid use is required. The nervous system It has been stated that postmitotic tissues (e.g. neural, muscular, and myocardial) are impacted the greatest by the effects of aging. The area of the neurobiology of aging and neural change associated with aging is large, and has been reviewed by Katzman.63 Some highlights of age-related changes in the central nervous system are listed in

Table 18.8 Age-related changes in neuroanatomy and neurochemistry Variable

Age-related change

Brain weight

Decrease

Ventricular volume

Increase

Neuronal number, especially superior temporal neocortex, locus ceruleus, and Decrease substantia nigra Neurofibrillary changes, especially parahippocampus and anterior olfactory nucleus

Increase

Synapse number, especially frontal cortex

Decrease

Biochemical markers: Choline acetyl transferase, especially in hippocampus and temporal neocortex Decrease Dopamine, especially in caudate

Decrease

Table 18.8. These changes result in the occurrence of atrophy on imaging studies such as computed tomography (CT) and magnetic resonance imaging (MRI) in geriatric patients.

Comprehensive Geriatric Oncology

394

From the physiologic perspective, higher cortical function remains intact into late life. Mental status should be assessed in all geriatric patients, and those with abnormalities should be investigated. Verbal ability seems to be maintained well throughout life. Timed tasks requiring speed in processing information or measuring reaction time do appear to be affected by aging, with delayed performance. Short-term memory and recall do not appear to be maintained as well in late life as compared with earlier years. On assessment of cranial nerve function in older patients, there are important changes in eyesight and hearing that must be considered. ‘Presbyopia’ results from changes in the lens with age so that accommodation is impaired and reading becomes more difficult. Other changes in the eye include a shrinking of the pupillary orifice and a diminished ability to dilate the pupil, yellowing of the lens, and a decrease in visual evoked response with decreased amplitude and increased latency.63 In addition to having problems with near vision, geriatric patients may have difficulty functioning in low light, may have problems functioning due to glare from light, may exhibit subtle changes in seeing bluegreen objects, and may have some difficulty with depth perception. ‘Presbycusis’ is the term used to describe hearing loss in elderly people. In countries such as the USA, there appears to be a loss of the ability to hear high-frequency sounds in late life. Additionally, speech understanding may be impaired through more central changes. Auditory evoked responses have been described as changing with age, and show a decrease in amplitude and increased latency.63 Motor assessment has been outlined above in the musculoskeletal section. Sensation should remain intact with aging, although the threshold for sensation (particularly vibration) has been described as declining with age.63 Gait and balance are reported to change with age. Healthy older persons have a shorter step length, lift their feet less, and are more flexed at the hips, knees, and elbows.64 On measures of balance, the elderly subject appears to sway more and appears to be less stable when balance is perturbed. Falls are a major problem for elderly patients, and although neural aging may serve as a risk factor, the physician should sort out environmental factors or diseases that might be causing a fall rather than ascribing the fall to aging. Conclusions With the passage of time, changes in anatomy and function occur in patients. These physiologic changes should be factored into the assessment of the geriatric patient with cancer. Changes in body composition and renal function will influence pharmacotherapy. Loss of reserve in some systems (e.g. cardiac, respiratory, endocrine, and musculoskeletal) may make patients more vulnerable to the adverse consequences of treatment. The impressive reserve in most physiologic systems, however, does allow for reasonable organ system function into senescence, particularly in the resting or unstressed state. Physiologic dysfunction at baseline assessment will frequently be the result of disease, either oncologic or some comorbidity.

Physiology of aging: Relevance to symptoms, perceptions

395

Acknowledgements This work was supported in part by the VAMC-Milwau-kee and its Research Service. The author withes to acknowledge Ms Karen Hartzell and June Hopkins for their invaluable assistance in preparing this chapter. References 1. Shock NW. Energy metabolism, caloric intake and physical activity of the aging. In: Nutrition In Old Age. X Capital Symposium Swedish Nutrition Foundation (Larson LA, ed). Uppsala: Almquist and Wiksell, 1972. 2. Brandfonbrener M, Landowne M, Shock NW. Changes in cardiac output with age. Circulation 1955; 12:557–66. 3. Port S, Cobb R, Coleman RE, Jones RH. Effect of age on the response of the left ventricular ejection fraction to exercise. N Engl J Med 1980; 301:1113–17. 4. Rodeheffer RS, Gerstenblith G, Becker LC et al. Exercise cardiac output is maintained with advancing age in healthy human subjects: cardiac dilatation and increased stroke volume compensate for a diminished heart rate. Circulation.1984; 69:203–13. 5. Lindeman RD, Tobin JD, Shock NW. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 1985; 33: 278–85. 6. Lipsitz LA, Goldberger AL. Loss of complexity and aging. Potential applications of fractals and chaos theory to senescence. JAMA 1992; 267:1806–9. 7. Buckwalter JA, Woo SL-Y, Goldberg VM et al. Soft-tissue aging and musculoskeletal function. J Bone Joint Surg 1993; 75A: 1533–48. 8. Sorkin JD, Muller DC, Andres R. Longitudinal change in height of men and women: implications for interpretation of the body mass index: the Baltimore Longitudinal Study of Aging. Am J Epidemiol 1999; 450:969–77. 9. Novak LP. Aging, total body potassium, fat-free mass, and cell mass in males and females between ages 18 and 85 years. J Gerontol 1972; 27:438–43. 10. Bruce A, Andersson M, Arvidsson B, Isaksson B. Body composition. Prediction of normal body potassium, body water and body fat in adults on the basis of body height, body weight and age. Scand J Clin Lab Invest 1980; 40:461–73. 11. Borkan GA, Hults DE, Gerzof SG et al. Age changes in body composition revealed by computed tomography. J Gerontol 1983; 38:673–7. 12. Fiatarone MA, Marks EC, Ryan ND et al. High-intensity strength training in nonagenarians. Effects on skeletal muscle. JAMA 1990; 263:3029–34. 13. Rudman D, Feller AG, Nagraj HS et al. Effects of human growth hormone in men over age 60 years old. N Engl J Med 1990; 323: 1–6. 14. Davies MJ. Pathology of the conduction system. In: Cardiology in Old Age (Caird F, Dall JLC, Kennedy RD, eds). New York: Plenum Press, 1976:57–80. 15. Lakatta EG. Cardiovascular aging in health. Clin Geriatr Med 2000; 16:419–44. 16. Fleg JL, O’Connor F, Gerstenblith G et al. Impact of age on the cardiovascular response to dynamic upright exercise in healthy men and women. J Appl Physiol 1995; 78:890–900. 17. Lakatta EG. Deficient neuroendocrine regulation of the cardiovascular system with advancing age in healthy humans. Circulation 1993; 87:631–6. 18. Williams L, Lowenthal DT. Hypertension in the elderly. Cardiovasc Clin 1992; 22:49–61.

Comprehensive Geriatric Oncology

396

19. Messerli FH, Ventura HO. Osler’s maneuver and pseudohypertension. N Engl J Med 1985; 312:1548–51. 20. Smith JJ, Porth CJM. Age and response to orthostatic stress. In: Circulatory Response to Upright Posture (Smith JJ, ed). Boca Raton FL: CRC Press, 1990:121–39. 21. Keilson L, Lambert D, Fabian D et al. Screening for hypothermia in the ambulatory elderly: the Maine experience. JAMA 1985; 254: 1781–4. 22. Collins KJ, Exton-Smith AN. Thermal homeostasis in old age. J Am Geriatr Soc 1983; 31:519– 24. 23. Fedullo AJ, Swineburne AJ. Relationship of patient age to clinical features and outcome for inhospital treatment of pneumonia. J Gerontol 1985; 40:29–33. 24. Kronenberg RS, Drage CW. Attenuation of the ventilatory and heart rate response to hypoxia and hypercapnia with aging in normal men. J Clin Invest 1973; 52:1812–19. 25. Yaar M, Gilchrest BA. Skin aging. Clin Geriatr Med 2001; 17:617–30. 26. Janssens JP, Pache JC, Nicod LP. Physiological changes in respiratory function associated with aging. Eur Respir J 1999; 13:197–205. 27. Enright PL, Kronmak RA, Higgins M et al. Spirometry reference values for women and men 65 to 85 years of age. Am Rev Respir Dis 1993; 147:125–33. 28. Kitzman DW, Scholz DG, Hagen PT et al. Age related changes in normal human hearts during the first 10 decades of life. Part II (maturity): a quantitative anatomic study of 765 specimens from subjects 20 to 99 years old. Mayo Clin Proc 1988; 63:137–46. 29. Kohn RR. Heart and cardiovascular system. In: Handbook of the Biology of Aging (Finch CE, Hayflick L, eds). New York: Van Nostrand Reinhold, 1977:281–317. 30. Shay K. Dental and oral disorders. In: Practice of Geriatrics, 3rd edn (Duthie E, Katz P, eds). Philadelphia: WB Saunders, 1998:481–93. 31. Baum BJ, Booner L. Aging and motor function; evidence for altered performance among old persons. J Dent Res 1983; 2:2–6. 32. Wolff A, Fox PC, Ship JA et al. Oral mucosa status and major salivary gland function. Oral Surg Oral Med Oral Pathol 1990; 70:49–54. 33. Ship JA. The influence of aging on oral health and consequences for taste and smell. Physiol Behav 1999; 66:209–15. 34. Shaker R, Staff D. Esophageal disorders in the elderly. Gastroenterol Clin North Am 2001; 30:335–61. 35. Ren J, Shaker R, Kusano M et al. Effect of aging on the secondary esophageal peristalsis: presbyesophagus revisited. Am J Physiol 1995; 268:G772–9. 36. Holt PR. The gastrointestinal tract. In: Handbook of Physiology. Section 11: Aging (Masoro EJ, ed). Oxford: Oxford University Press, 1995:505–54. 37. Russell RM. Changes in gastrointestinal function attributed to aging. Am J Clin Nutr 1992; 55:1203S–7S. 38. Bannister JJ, Abovzekry L, Read NW. Effect of aging on anorectal function. Gut 1987; 28:353– 7. 39. Nelson JF. The potential role of selected endocrine systems in aging processes. In: Handbook of Physiology. Section 11: Aging (Masoro EJ, ed). Oxford: Oxford University Press, 1995:377–94. 40. Odell WO. The menopause and hormonal replacement. In: Endocrinology, Vol 3, 3rd edn (DeGroot LJ et al, eds). Philadelphia: WB Saunders, 1995:2128–39. 41. Matthews KA, Cauley J. Menopause and mid-life health changes. In: Prindples of Geriatric Medicine and Gerontology, 4th edn (Hazzard WR, Blass JP, Ettinger WH et al, eds.). New York: McGraw-Hill, 1999:179–89. 42. Merry BJ, Holehan AM. Aging of the male reproductive system. In: Physiological Basis of Aging and Geriatrics, 2nd edn (Timiras PS, ed). Boca Raton, FL: CRC Press, 1994:171–8. 43. Harman SM, Metter EJ, Tobin JD et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrin Metab 2001; 86:724–31.

Physiology of aging: Relevance to symptoms, perceptions

397

44. Chapman IM. Hypothalamic growth hormone—IGF-1 axis. In: Endocrinology of Aging (Morley JE, Van den Berg L, eds). Totowa, NJ: Humana Press, 2000:23–40. 45. Corpas E, Harman SM, Blackman MR. Human growth hormone and aging. Endocrin Rev 1993; 14:20–39. 46. Shetty KR, Duthie EH. Anterior pituitary function and growth hormone use in the elderly. Endocrinol Metab Clin North Am 1995; 24:213–31. 47. Gruenewald DA, Matsumoto AM. Aging of the endocrine system. In: Principles of Geriatric Medicine and Gerontology, 4th edn (Hazzard WR, Blass JP, Ettinger WH et al, eds.). New York: McGraw-Hill, 1999:949–65. 48. Blackman MR, Elahi D, Harmann SM. Endocrinology and aging. In: Endocrinology, Vol 3, 3rd edn (De Groot et al, eds). Philadelphia: WB Saunders Harcourt Brace Johanovich, 1995:2702– 30. 49. Chapuy MC, Durr F, Chapuy P. Age-related changes in parathyroid hormone and 25 hydroxycholecalciferol levels. J Gerontol 1983; 38: 19–22. 50. Timiras PS. The endocrine pancreas and carbohydrate metabolism. In: Physiological Basis of Aging and Geriatrics, 2nd edn (Timiras PS, ed). Boca Raton, FL: CRC Press, 1995:191–9. 51. Halter J. Carbohydrate metabolism. In: Handbook of Physiology. Section 11: Aging (Masoro EJ, ed). Oxford: Oxford University Press, 1995; 119–46. 52. American Diabetes Association. Clinical practice recommendation 1998. Diabetes Care 1998; 21(Suppl):S1–98. 53. Miller, M. Water balance In older persons. In: Endocrinology of Aging (Morley JE, Van den Berg L, eds). Totowa, NJ: Humana Press, 2000: 73–92. 54. Lindeman RD. Renal and urinary tract function. In: Handbook of Physiology. Section 11: Aging (Masoro EJ, ed). Oxford: Oxford University Press, 1995:485–503. 55. Philips PA, Rolls BJ, Ledingham JJG et al. Reduced thirst after water deprivation in healthy elderly men. N Engl J Med 1984; 311:753–9. 56. Lindeman RD. Renal physiology and pathophysiology of aging. Contrib Nephrol 1992; 105:1– 12. 57. Ouslander, JG. Global symposium on aging: management of geriatric lower urinary tract disorders. Am J Med Sci 1997; 314:213–72. 58. Lexell J. Human aging, muscle mass, and fiber type composition. J Gerontol 1995; 50A:11–16. 59. Hurley B. Age, gender, and muscular strength. J Gerontol 1995; 50A: 41–4. 60. Tzankoff SP, Norris AH. Longitudinal changes In basal metabolism in man. J Appl Physiol 1978; 45:536–9. 61. Kenney WL, Buskirk ER. Functional consequences of sarcopenia; effects on thermoregulation. J Gerontol 1995; 50A:78–85. 62. Kalu DN. Bone. In: Handbook of Physiology. Section 11: Aging (Masoro EJ, ed). Oxford: Oxford University Press, 1995:395–412. 63. Katzman R. Human nervous system. In: Handbook of Physiology. Section 11: Aging (Masoro EJ, ed). Oxford: Oxford University Press, 1995:325–344. 64. Murray MP, Kory RC, Clarkson BH. Walking patterns in healthy old men. J Gerontol 1969; 24:169–78.

19 Assessment of the older patient with cancer Lodovico Balducci, Martine Extermann Introduction The management of cancer is determined by the disease and the patient. While most practitioners would be loath to administer adjuvant chemotherapy to a 95-year-old woman with stage I breast cancer, they would recommend some form of chemotherapy to the same woman for stage III or IV aggressive lymphoma.1 In the first case, the threat from cancer to the woman’s survival and welfare is negligible; in the second, it is substantial and worthy of the therapeutic risks. In more nuanced situations, the assessment of benefits and risks may be problematic, owing to the diversity of the older population in terms of life-expectancy, functional reserve, comorbidity, social support, and emotional and cognitive integrity. In this chapter, we review forms of geriatric assessment that may assist the practitioner in the management of elderly cancer patients. The management of the older cancer patient hinges on three questions: • Is the patient going to die of cancer or with cancer? • Is the patient able to tolerate the complications of the treatment? • Are the patient’s function and quality of life threatened by the cancer? Owing to the diversity of the older population, chronological age is of limited assistance. Nevertheless, it is reasonable to adopt two chronological milestones: ages 70 and 85. The rapid increase in age-related changes between 70 and 75 indicates age 70 as the lower limit of senescence.2 By age 85, the majority of persons have developed some form of functional dependence, as well as disturbances of memory, vision, and hearing, so that age 85 represents for most (albeit not all) persons the beginning of frailty.3–4 In this chapter, we review methods of geriatric assessment after an overview of aging and its consequences. The meaning of age The focus of this book is the influence of aging on cancer outcome and the influence of cancer on the outcome of aging. For this purpose, aging may be defined as a reduced ability to cope with stress.5 A decline in the functional reserve of multiple organ systems lessens the tolerance of physical stress, which includes cancer as well as its treatment.6

Assessment of the older patient with cancer

399

This decline may be compounded by comorbid conditions, whose prevalence increases with age as well.7–13 At the same time, cognitive limitations may compromise the adaptation to novel situations, including admission to hospital or to an assisted living facility, understanding of complex treatment plans, and timely reaction to medical emergency. These difficulties may be aggravated by economic restrictions, social isolation, restricted mobility, falls, malnutrition, and polypharmacy. A couple of examples illustrate very well the influence of age on cancer treatment. Case 1 An 84-year-old woman, living alone, was treated with the CHOP regimen for advancedstage large cell lymphoma. She tolerated the treatment well, but, because of nausea, neglected food and fluid intake for about one day. Getting up from bed to go to the bathroom, she experienced a fall that led to hip fracture, prolonged hospitalization, and treatment delay. Although able to tolerate the chemotherapy, this woman could not cope with fluid restriction; that led to orthostatism and fall, which in the presence of osteoporosis led to a fracture, which led to the complication of hospitalization and treatment delay, which may have jeopardized the whole outcome. Provision of home care during the treatment or temporary admission to an assisted living facility might have broken at the very beginning a vicious cycle of events that could have caused by itself death or permanent disability, and that compromised the chances of curing the lymphoma. Case 2 A 72-year-old man with mantle cell lymphoma was treated with lomustine, cyclophosphamide, procarbazine, and prednisone, and developed a neutropenic infection with fever during the night. On his way to the phone, to call for help, he tripped on a carpet, fell and lost consciousness, and lay 36 hours close to a radiator, experiencing second-degree burns. He required 16 days of intensive care unit treatment and several weeks of intermediate care and rehabilitation prior to full recovery. The sequence of events is typical of a situation in which the problems of aging had not been fully addressed. The infection had seemingly been associated with delirium, a common event in the aged,14 which in turn hampered the patient’s ability to reach help and caused a fall that might have had fatal consequences. The problem had been compounded by the presence of a carpet between the living room and the bedroom, which in older individuals with compromised cognition and eyesight is by itself a risk factor for falls. The complications experienced by these two patients were only indirectly related to chemotherapy, and might have been prevented by proper precautions, including a caregiver, a rearrangement of the home furniture, and an alarm for emergency. These examples are given to highlight the multidimensional nature of age and how non-medical conditions may affect the medical outcome.

Table 19.1 Geriatric glossarium15–16,18 • Functional impairment: a loss of structure (e.g. muscle fiber) or function (e.g. eyesight or hearing) at the organ level that may limit an individual’s activity • Functional limitation: difficulty in performing a certain gesture (e.g. bending or crouching)

Comprehensive Geriatric Oncology

400

• Disability: inability to carry on basic or instrumental activities of daily living (dressing, feeding, shopping, etc.) owing to the cumulative effect of internal factors (disease, cognition, or functional limitation) and external factors (lack of transportation or finances, environmental conditions, cancer treatment, etc) • Handicap: disadvantage due to interaction of disability and external factors (e.g. architectural barriers) that prevents a person from performing his/her usual role • Frailty: complete exhaustion of functional reserve; the frail person may be overcome by even minimal stress • Vulnerability: a condition of critically reduced functional reserve that makes an individual more susceptible to disability, disease, and death; unlike frailty, vulnerability may be reversible

These cases imply that the construct of a disease may be different in younger and older individuals (Figure 19.1). The management of the disease in the elderly involves the care of multiple concomitant conditions that may affect the ultimate outcome.

Figure 19.1 Difference in disease presentation in older and younger patients. In older patients, a complex

Assessment of the older patient with cancer

401

of social, emotional, and medical factors may complicate both diagnosis and treatment. Table 19.1 defines terms used to describe the functional limitations of aging that should be familiar to any practitioner dealing with older individuals.15–19 We wish to highlight how disability and handicap involve a combination of medical, non-medical, and environmental conditions. These constructs reflect the multidimensional nature of aging and also indicate a possible amelioration by creating a more favorable environment for the aged. Other concepts germane to our treatise include frailty and vulnerability.17–19 The frail person has negligible functional reserve and is unable to tolerate minimal stress. The frail person is generally eligible only for palliative cancer care; frailty is not susceptible to rehabilitation. Vulnerability implies increased susceptibility to stress; the functional reserve of the vulnerable person may be restored to some extent, and the vulnerable person may receive life-saving or life-prolonging treatment as long as special provisions are taken to prevent therapeutic complications. A clinical description of frailty and vulnerability is provided in the next section. Clinical evaluation of aging As aging is multidimensional, the most informative evaluation of the older person is a Comprehensive Geriatric Assessment (CGA). A number of performance tests and laboratory evaluations have also been proposed, and will be described here. The Comprehensive Geriatric Assessment The essential elements of the CGA are described in Table 19.2. The assessment of Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) is complementary to the assessment of performance status.20 ADL are the activities necessary to maintain life, and include feeding, transferring, use of the bathroom, dressing, grooming, and continence. Full dependence in one or more of the ADL is generally considered a sign of frailty.17 IADL are necessary to maintain independent living, and include use of transportation, use of the telephone, money management, ability to take medications, ability to go shopping, and ability to provide one’s own meals, laundering, and housekeeping. Dependence in one or more IADL may herald vulnerability. Dependence in one or more IADL has been associated with a twofold (and in one or more ADL with a threefold) increased 2-year mortality.21–25 In addition, dependence in one or more IADL is associated with a 55% risk of dementia in 2 years26 and an increased risk of neutropenic infection in patients receiving chemotherapy for lymphomas.27

Comprehensive Geriatric Oncology

402

Table 19.2 Essential elements of the Comprehensive Geriatric Assessment (CGA) Parameter assessed

Elements of the assessment

Function

• Performance status • Activities of Daily Living (ADL) • Instrumental Activities of Daily Living (IADL)

Comorbidity

• Number of comorbid conditions • Severity of comorbid conditions (comorbidity index)

Socioeconomic conditions

• Living conditions • Presence and adequacy of a caregiver

Cognition

• Folstein Mini Mental State • Other tests

Emotional conditions

Geriatric Depression Scale (GDS)

Pharmacy

• Number of medications • Appropriateness of medications • Risk of drug interactions

Nutrition

Mini Nutritional Assessment (MNA)

Geriatric syndromes

• Dementia • Delirium • Depression • Falls • Neglect and abuse • Spontaneous bone fractures

Comorbidity is associated with increased risk of mortality7,8 and reduced tolerance of combination chemotherapy.28 Despite broad consensus on its role, disagreement lingers over the assessment of comorbidity. The questions involved in the problem include: • Which comorbid conditions are meaningful? • How should the severity of each condition be assessed? In studying the interactions of comorbidity and breast cancer, Satariano and Ragland7 selected 17 conditions associated with increased mortality and counted the number of conditions present in different patients. They found that the risk of breast cancerunrelated mortality increased with the number of comorbid conditions. Using a similar

Assessment of the older patient with cancer

403

system, Piccirillo and Feinstein8 established that comorbidity is associated with increased mortality in patients with head and neck cancer and proposed that comorbidity be included as an independent factor in the staging system of this cancer. Another approach, represented by comorbidity scales, consist in rating according to severity each condition that may have an impact on survival and function. The Charlson Index and the Cumulative Illness Rating Scale-Geriatrics (CIRS-G) are those in more common use. The Charlson Index is more user-friendly and has been employed in the analysis of large databases;29 the CIRS-G utilizes a scoring system comparable to the NCI-CTC scoring system for the severity of chemotherapy-induced toxicity, but is more cumbersome and time-consuming.30 The two scales have been compared in 200 cancer patients aged 70 or more; the Charlson Index identified significant comorbidity in 60% of them and the CIRS-G in almost 90%.12 At present, it is not possible to establish which scale is a better predictor of outcome in cancer patients. Among the comorbid conditions, anemia deserves special mention: in older individuals, anemia has been associated with increased mortality,31,32 increased risk of chemotherapy-related myelosuppression,33 increased incidence of fatigue and functional dependence,34–35 and increased risk of delirium.36 The incidence of dementia increases with age; among persons aged 85 and older, the prevalence of dementia is 50% and higher.3,21 Decline in cognition has been associated with shortened survival.37–40 In addition, dementia (even mild dementia) may compromise the understanding of treatment plans and blunt the perception of a medical emergency. Even minor cognitive impairment indicates the need for a caregiver during antineoplastic treatment. It should be stressed that cognitive deficit may be aggravated by cytotoxic chemotherapy41,42 and some forms of hormonal cancer treatment.43 Dementia may predispose to delirium in the presence of infection.14 A common way to screen for dementia is assessment of the Folstein Mini Mental State.44 Depression, even subclinical depression,45–50 is associated with increased mortality. Depression may reduce the motivation to receive life-saving treatment and may jeopardize compliance with the treatment program. For this reason, it is recommended that older individuals be screened for depression in the course of a CGA.50 Important elements of socioeconomic conditions include income, living conditions (whether in a home or in assisted living), whether the patient lives at home alone, with family, or with friends, access to transportation, and closeness to the treatment center. Perhaps the pivotal aspect of the social assessment is the presence of an adequate caregiver51–52 (and see Chapter 63 of this volume53). The minimal requirements for the caregiver include: • around-the-clock availability on short notice, including the ability to provide transportation; • ability to understand and to respond timely to medical emergency. In addition, the ideal caregiver should act as spokeperson for the family and be able to mitigate family conflicts—which are likely when the sick person is an older parent with several children living in disparate parts of the country. The caregiver may become the best ally of the practitioner in the management of the older patient, facilitating the enactment of treatment plans and preventing multiple and discordant calls to the office. Hence, it behooves the practitioner to select, enable, and support the caregiver. In

Comprehensive Geriatric Oncology

404

addition to a realistic assessment of the patient’s condition, the caregiver should be appraised of the time commitment he or she is expected to make, should be instructed in communication techniques and conflict management, and should be provided with directions and counseling for stress management. In the majority of cases, the caregiver is an elderly spouse with health problems of his or her own, or a married child with family and professional commitment. The risk of protein malnutrition increases with age,54 owing to decreased access to food, decreased appetite,55 decreased production of sexual hormones, growth hormone, and insulin-like growth factor I,56–57 and the influence of catabolic cytokines whose concentration in the circulation increases with age.58–59 Protein-calorie malnutrition is associated with higher risk of complications from surgery, radiation therapy, and cytotoxic chemotherapy, which in turn may aggravate protein-calorie malnutrition.60 Nutritional replenishment is slower in older than younger individuals;61 hence, prevention of malnutrition is highly desirable, especially for persons scheduled to undergo intensive antineoplastic treatment. The Mini Nutritional Assessment (MNA) is a very complete and simple form of screening for malnutrition and risk of malnutrition, and enables the practitioner to address this risk proactively.62 The prevalence of polypharmacy, involving the intake of more than three medications a day, increases with age (see Chapter 41 of this volume63); in some cases, multiple medications are justified;64 however, in others, they are redundant and are associated with increased risk of drug interaction.65 This problem is compounded by the absence of a primary care provider responsible to coordinate the care of older individuals, in at least 30% of patients over 70.66 The CGA includes the evaluation of the so-called ‘geriatric syndromes’—health conditions that are typical of age, are diagnostic of frailty,16 and imply a decreased survival. In addition to dementia and severe depression, delirium due to infection, intake of anticholinergic medications, or other medical conditions unrelated to the central nervous system (e.g. myocardial ischemia) is a typical geriatric syndrome.14,67–68 The incidence of falls increases with age, and is associated with reduced survival.69–70 Falls compromise in more than one way the mobility of the older person. Fear of falling may lead to intentional avoidance of physical activity;69 falls may be associated with fractures and other traumatic events that may lead to deconditioning.70–73 The risk of falling may be predicted by a score based on assessment of different parameters, including cognition, living condition, and balance. To some extent, falls may be prevented or limited.74 Spontaneous fractures are a sign of advanced osteoporosis, generally associated with severe protein-calorie malnutrition, and predict reduced survival.75 Failure to thrive is a poorly understood but very real manifestation of age characterized by weight loss or lack of weight gain despite adequate nutritional intake.54,55,58,76 Seemingly, failure to thrive has multiple causes, from severe depression and limited activity, to critical circulating levels of catabolic cytokines.59 Neglect and abuse77–78 are also poorly defined but very real manifestations of aging, characterized by poor self-care, disheveling, and possibly signs of physical and emotional abuse, and are associated with reduced survival.79–80

Assessment of the older patient with cancer

405

The CGA has had an important influence in geriatrics, including reductions in the rates of hospitalization81–87 and of admission to an assisted living facility,81–85 prevention of falls72 and of in-hospital delirium,67 improvement of surgical outcome,88 and reduced cognitive decline.82 According to some studies, the CGA has also resulted in improved survival.82,89 The CGA is the basis of management of older individuals in adult living facilities, where the collection of a minimal data set (MDS) represents the standard evaluation both of individual needs and of rehabilitative potential. A taxonomy of aging has been attempted, based on the CGA (Table 21.3).90 Each group has a different life-expectancy, rehabilitative potential, and ability to tolerate stress.91 Two different but not mutually exclusive definitions of frailty have been provided. The classical definition16 allows immediate recognition of frailty and is highly specific, but is not comprehensive enough to embrace all frail individuals. The alternate definition is more laborious but more sensitive, and should be used to screen intermediate individuals for frailty.18 Frailty is a chronic condition: acutely ill patients are not frail if they were fully independent prior to the development of the acute illness. This distinction is extremely important when it comes to decisions related to cancer treatment that may be framed by this classification. This taxonomy may be complemented by the clinical definition of vulnerability (Table 19.4),13 developed from the results of a 13-item questionnaire involving some elements of the CGA. The investigators who established the definition followed almost 5000 patients aged 65 and older for approximately 2 years, and found that during this period of time the vulnerability score was correlated with the risk of death or functional decline. Vulnerability may help to classify more accurately the intermediate group of aged individuals, which is both the most common and the most heterogeneous. The applications of the CGA in geriatric oncology include the following:92 • estimation of life-expectancy, based on function, comorbidity, cognition, etc.;

Table 19.3 Taxonomy of agea Type

Description

Rehabilitative needs

Primary

• Fully independent

Health and function maintenance

• Negligible comorbidity Intermediate

• May be dependent in one or more IADL • Less than three comorbid conditions; intermediate comorbidity scores

Secondary or frailty

• Classical definition: one or more of the following:

May be rehabilitated to some extent

Prevention of further functional deterioration

– ADL dependence – one or more geriatric syndrome – three or more comorbid conditions • Alternate definition: at least three of the following:

Comprehensive Geriatric Oncology

406

– unintentional weight loss of 10% or more of the original body weight over 1 year; – self-reported exhaustion – decreased grip strength – slow movements – difficulty in initiating movements Near death

• Life-expectancy of 3 months or less; no treatment available

No rehabilitation

a

Modified from Hamerman et al.59

Table 19.4 Vulnerability (a) Vulnerability scale Element of assessment

Score

Age •

75–84

1

•

85+

3

•

Good or excellent

0

•

Fair or poor

1

•

Shopping

1

•

Money management

1

•

Light housework

1

•

Transferring

1

•

Bathing

1

•

Stooping, crouching, or kneeling

1

•

Lifting or carrying 10 Ib (5 kg)

1

•

Writing or handling small objects

1

•

Reaching or extending arm above shoulder

1

•

Walking ~1/4 mile (~1/2 km)

1

•

Heavy housework

1

Self-reported health:

ADL/IADL—needs help in:

Activities—needs help in:

(b) Vulnerability scores, functional decline, and survival

Assessment of the older patient with cancer

407

Score

Risk of functional decline or death (%)

1–2

11.8

3+

49.8

1–3

14.8

4+

54.9

• estimation of functional reserve and of tolerance of cancer treatment—in particular, cytotoxic chemo-therapy; • discovery and management of conditions that are reversible and may influence cancer outcome—these include malnutrition, previously unrecognized comorbidity, and depression; • prevention and management of unfavorable socioeconomic situations, including the absence of a caregiver, an inadequate caregiver, inadequate access to food and transportation, etc; • adoption of a common language in the evaluation of older cancer patients; this common language is necessary for several purposes, including study of the prognostic value of different aspects of the CGA, stratification of patients with similar clinical characteristics in prospective clinical trials, retrospective assessment of outcome of treatment, and quality control.

Comprehensive Geriatric Oncology

408

Figure 19.2 Algorithm for the management of the older cancer patient according to the results of the geriatric assessment. The occurrence of age-related changes is a common event among older patients. In the Senior Adult Oncology Program (SAOP) of the H Lee Moffitt Cancer Center in Tampa, Florida, all patients aged 70 or more undergo a CGA during the first clinic visit. Approximately 70% of patients were dependent in at least one IADL, 70% had significant comorbidity, 20% had either unsuspected dementia or depression or both, and 20% had malnutrition.12 Similar findings were reported from two cancer centers in Italy.93

Assessment of the older patient with cancer

409

Based on these findings and considerations, the National Cancer Center Network (NCCN) recommended that all cancer patients aged 70 or more undergo some forms of geriatric assessment prior to treatment.92 An algorithm that may be used as frame of reference for the application of CGA in cancer management is shown in Figure 19.2. It should be stressed here that palliative treatment for frail patients nowadays may include cytotoxic chemotherapy. Capecitabine, vino-relbine, gemcitabine, taxanes in low doses, and mitox-antrone may be tried, even in the frail, as palliation.12 Special precautions for the vulnerable patient include provision of a caregiver and reduction in the first dose of treatment. The CGA is a complex endeavor that may overtax an already time-stripped busy practice. Compelling questions include whether the assessment should be performed in all older individuals, whether the full assessment may be substituted by a small number of functional and laboratory tests, and whether a screening instrument may distinguish those patients who do and do not need a CGA. Other important concerns include the cost of the assessment and the risk of redundancy. The CGA involves a substantial time investment, however: the Mini Mental State examination requires approximately 15 minutes, when administered by a professional; the rest of the information is obtainable from questionnaires filled in by the patient. Of special interest is a report by Ingram et al.94 Of 266 male veterans, 67% were able to complete and report a 10-domain geriatric assessment mailed to them prior to the clinic visit. Still, the interpretation is time-consuming, and those persons who do not return the questionnaire require personal instructions and assistance. A reduction in the time burden of geriatric assessment has been pursued in two, non-mutually exclusive, directions. One includes the use of time-saving screening instruments that are able to weed out patients who do not need a full assessment (Table 19.5). Lachs et al,95 Maly et al,96 and Moore et al97 have devised such instruments, which have proved satisfactory in a busy practice. The Moore test includes a number of physical and functional assessments, and for this reason it may take 8–12 minutes—which is more time than the majority of practicing oncologists are ready to invest. The NCCN guideline meeting judged the Lachs instrument to be the most workable and comprehensive in an oncology practice.95 The second line of research was aimed at establishing whether a few selected tests may replace the whole assessment. After finding only a moderate level of correlation among functional status, measured as Eastern Cooperative Oncology Group (ECOG) Performance Status, ability to perform ADL and IADL, and comorbidity, assessed according to the Charlson Index and CIRS-G, in cancer patients aged 70 and older, Extermann et al12 concluded that each parameter supplied complementary information and that the geriatric assessment needed to include a separate assessment of each domain. A third, so-called commonsense, approach is often advocated in discussions of the issue. This approach holds that a detailed assessment is not necessary for those patients who are clearly frail at clinical examination (patients who are bedridden, who are unable to transfer on their own from wheelchair to examining table, who present clear signs of dementia, etc). In our opinion, this approach is short-sighted. Whereas a cursory clinical evaluation may be sufficient to exclude some patients from cytotoxic chemotherapy, a geriatric assessment may still be needed to assure that these patients receive optimal care for other conditions and enjoy the best obtainable quality of life. Given the benefits of a CGA, it is reasonable to recommend, with the NCCN, that all persons aged 70 and older

Comprehensive Geriatric Oncology

410

receive some form of geriatric assessment and that any practitioner dealing with older individuals be able to perform and to interpret such assessment.92 Ideally, older individuals should have a primary care provider who performs a geriatric assessment on a regular basis and communicates the results to other specialists as part of the coordination of the patient’s care. Unfortunately, coordination of care is most lacking for older individuals.66 Fragmentation of care for the elderly was a common occurrence in three countries—the USA, Canada, and Israel—and had multiple causes. A common trend in the three countries included more emphasis of the remuneration system on acute and specialist care than on chronic and primary care. In these circumstances, it cannot be expected that all older individuals will come to the oncologist with a CGA already performed, and the oncologist must be ready to perform and interpret this evaluation. In the meantime, a consistent flow of information with and from the primary care provider is highly desirable—when a primary care provider is available. With regard to cost, it is logical to assume that the management of the older person is more costly than that of the younger person, given the greater prevalence of comorbidity and functional dependence. Thus, the cost of the geriatric assessment should be examined in the light of two questions: Does the geriatric assessment improve the safety of cancer treatment in older persons? Does the geriatric assessment reduce the cost of managing older cancer patients by avoiding costly complications? Based on the demonstrated value of the geriatric assessment in other areas of geriatrics81–89 and on the unveiling of unsuspected comorbidities, functional dependences, and social inadequacies in older cancer patients,12 it is reasonable to conclude that the geriatric assessment may improve the safety and the cost of managing older cancer patients. In our opinion, future studies should focus on improving the effectiveness and reducing the cost, rather than trying to establish the benefits of geriatric assessment. Physical performance assessment of age A growing body of literature indicates a correlation between the ability to perform certain activities and risk of functional decline, disability, and death (Table 19.6). As one may easily infer from the table, these assessments involve different degrees of clinical sophistication, and are generally used to predict specific outcomes rather than providing a general patient assessment.

Table 19.5 Proposed screening tests Realm

Screening

Confirmatory test

Mental status

Serial three: tell patient: 1 am going to name three objects (pencil, truck, book), and I am going to ask you to repeat them now and a few minutes from now’

Folstein Mini Mental State: if score <24, then institute work-up for dementia

Emotional status/ depression

Ask patient: ‘Do you often feel depressed or sad?’

Geriatric Depression Scale (GDS): If positive (score >10), then work up for depression

ADL

•

Formal Katz ADL scale

Can you dress yourself?

Assessment of the older patient with cancer

IADL

Home environment

Social support

•

Do you need help to go to the bathroom?

•

Do you wet yourself?

•

Can you eat without help?

•

Can you move from one place to another without help?

•

Do you need help for taking a bath or a shower?

•

Do you drive? Are you able to use public transportation?

•

Do you prepare your own meals?

•

Do you go shopping?

•

Do you do your own checking?

•

Can you call somebody with the telephone?

•

Do you remember to take your medications?

•

Do you have trouble with stairs inside and outside the house?

•

Do you often trip on rugs?

Who would be able to help you in case of emergency

411

Formal IADL scale

• If there is no caregiver, then try to arrange for one. • If the caregiver is a spouse, a sibling, or a friend of the same age as the patient, then assess the independence of the caregiver

Comorbidity

Evaluate the presence of following conditions from Confirm the presence of the ROS: congestive heart failure; coronary artery condition and grade its disease; valvular heart disease; chronic lung disease level of severity (obstructive or restrictive); cerebrovascular disease; peripheral neuropathy; chronic renal insufficiency; hypertension; diabetes; coexisting malignancies; collagen vascular diseases; incapacitating arthritis

Nutrition

•

Weigh patient

•

Measure height

•

Inquire about weight loss

Polypharmacy

Review number and type of medications

Mini Nutritional Assessment (MNA)

If there are more than three medications, then look for duplications, interactions, and compliance

Comprehensive Geriatric Oncology

412

Additional problems include: • ability to understand instructions, which may be impaired by dementia and sensory deprivation, especially in the oldest old; • lack of standardization of different tests and of crosstest comparison. Despite these limitations, physical performance tests are promising, especially for screening individuals at risk of disabilities98 and falls99 and in need of rehabilitation. A hypothesis worth testing is whether abnormalities in physical performance may predict the risk of short- and long-term complications of antineoplastic treatment. Another important study may involve sequential physical performance tests to establish how cancer and cancer treatment influence the disabling process.

Table 19.6 Example of functional assessment of older individuals Activity

Description

Clinical implications

Get up and go

Ask the patient to rise from an armchair, • Increased performance time is observe walking 8 m, turn around, come associated with abnormalities in back, and sit. Calculate the total time this CGA takes, and observe any difficulties in • Shuffling gate and/or abnormal walking and balance balance are associated with risk of falls and other geriatric syndromes, and functional dependence

Grip strength

Handheld dynamometer

A decrease is associated with a risk of disability

Based on four activities:

• Correlates with weekly activity, which in turn may correlate with risk of disability

1.

Time employed to get up from an armchair five times

• Correlates with the presence of depression

2.

Time employed to walk 4 m

3.

Standing balance

4.

Distance covered in 6 minutes’ walking

Lower-extremity performance: • Summary Performance Score (SPS)

• Strength of lower extremities

Ergonomic measurement of dorsiflexion and plantarflexion of the ankle, and flexion and extension of the hip and the knee

Self-reported functional measurements

Correlates with the risk of falls

Assessment of the older patient with cancer

413

Two additional considerations are in order, related to physical performance tests: • Studies have shown that self-reports of difficulties in physical performance tests are reliable.100,101 Self-report as surrogate of actual test performance may involve noticeable savings in time and money. • Several authorities recommend that the ‘get up and go’ test may be used to screen patients in need of a more thorough geriatric assessment. This strategy may also be of interest in a busy practice. Laboratory assessment of aging A number of laboratory parameters change with age (Table 19.7). Some are non-specific and unhelpful in establishing the degree of aging. Others may reveal advanced aging and increased risk of mortality. The association between low serum cholesterol and mortality is complex.102–103 While a number of studies have identified low cholesterol levels as a predictor of mortality in the oldest old, Corti et al104 found that this association disappeared once other health indicators were accounted for in the Established Population for Epidemiologic Studies in the Elderly (EPESE). At the same time, pharmacologic lowering of serum cholesterol does not lead to increased mortality, and may even be beneficial in persons aged 65 and over.105 This discrepancy was clarified in a new study of the EPESE by Volpato et al.102 Among persons with low serum cholesterol levels, these authors identified three prognostic subgroups, when the albumin and high-density lipoprotein (HDL) levels were also accounted for. Low serum albumin is an independent risk for disability and mortality in older individuals.106 Among persons with low serum cholesterol, those with low albumin levels had increased mortality risk, those with normal serum albumin and low HDL an intermediate risk, and those with normal albumin and high HDL levels, low risk. These simple laboratory measurements may thus be extremely helpful in predicting independent mortality in older cancer patients. The ratio between circulating cysteine and thiolic groups (S/d) increases with age,107 and may reflect functional impairment to some degree. This ratio is reflective of oxidative damage, and may also be increased in cancer and malnutrition, irrespective of aging. Although these are not routine laboratory measurements, they are simple to obtain and may become of general use should it be found that the S/d is related to mortality, functional status, and risk of therapeutic complications. Special attention has been paid to the concentration of catabolic cytokines,18,108 coagulation markers (especially D-dimer),109–110 and acute-phase reactants111,112 in the circulation of older individuals. Underlying the interest in these markers is a construct of aging as an accumulation of inflammatory damage.18,108 A clear association was seen

Table 19.7 Laboratory determination of age Test

Change with aging

Clinical implications

Creatinine clearance

Decreases

Non-specific: a number of kidney diseases may alter creatinine clearance; even in the absence of

Comprehensive Geriatric Oncology

414

kidney disease, the rate of change varies from person to person Serum osmolality

Decreases

Non-specific; highly variable

Serum cholesterol

Lower

Associated with increased mortality, but nonspecific

Serum albumin Combination of Decreases tests: serum albumin, serum cholesterol, and high-density lipoprotein (HDL)

Non-specific, associated with increased mortality Very helpful for predicting mortality and prognosis, but not for staging age. In the presence of low cholesterol, three prognostic groups may be distinguishable:102 1. Low albumin: poor prognosis; 2. High albumin, low HDL: intermediate prognosis 3. High albumin, high HDL: good prognosis

S/d (cysteine/thiolic groups)

Increases

May also increase in the presence of cancer and malnutrition; may be used to measure muscular mass

lnterleukin-6

Increases

Although non-specific, an increase in IL-6 in the circulation may reflect some degree of vulnerability

Tumor necrosis factor

Increases

Non-specific; uncertain significance

D-dimer

Increases

Non-specific; associated with any form of intravascular coagulation

Combination of tests

—

May be helpful; for example a combined increase in IL-6 and D-dimer is highly suggestive of frailty

between increased levels of interleukin-6 (IL-6) and disability113,114 and death.111,113 In addition, high levels of cytokines are associated with sarcopenia59 and failure to thrive.115 Of special interest, improvement of malnutrition with megestrol acetate is associated with a decline in circulating cytokine levels. The clinical significance of these markers is unclear. A report from the McArthur Study (a subset of 880 highly functional persons from the EPESE)112 showed that IL-6 and C-reactive protein (CRP) levels predict mortality but not decline in physical performance over 7 years in this highly functional population. Also, there was a lack of significant cross-sectional correlation between these markers and physical performance tests. It should be noted, however, that this study failed to consider other outcomes that might have been more meaningful, such as functional dependence and development of geriatric syndromes. Cohen et al116 found a strong correlation between frailty and concentration of IL-6 and D-dimer in the circulation. Based on present evidence, it is reasonable to conclude the following: • High levels of IL-6 in the circulation do predict death and disability. • Frailty is associated with increased concentrations of IL-6 and D-dimer in the circulation, and these determinations may be used to confirm the diagnosis of frailty. It is reasonable to study how the concentrations of cytokines in the circulation correlate

Assessment of the older patient with cancer

415

with the outcome of cancer—in particular, mortality, treatment tolerance, and the development of functional dependence. Prior to concluding this section on laboratory assessment of aging, we should mention a construct that is gaining momentum, namely somatopause.56,57 This is a catabolic condition due to the combined increase in the concentrations of circulating cytokines and loss of production of growth hormone and insulin-like growth factor I (IGF-I). Somatopause may become a biologic landmark of aging once it has been established whether it is a predictable occurrence—not unlike the way in which menopause is a predictable end to the reproductive life of a woman. Also, it is important to establish the relationship between somatopause and frailty. Assessment of aging in an oncology practice The assessment of aging is evolving. Current information is sufficient for planning an uniform assessment of the older person both in clinical practice and in the research setting. In clinical practice, it appears reasonable: • To inquire about primary care provider and caregiver in all persons aged 70 and older. In the absence of a primary care provider, it behooves the oncologist to highlight the need for coordination of care, to make the proper referral for management of comorbidity and social, nutritional and pharmacy issues, and to institute some form of case management. Likewise, the oncologist should make an effort to assess the need for a caregiver as well as the adequacy of the current caregiver, and to explore the potential caregiver pool to establish which person may be most suitable for the present and anticipated needs of the patient. • To assess the cholesterol and albumin levels and the presence of anemia, and to investigate the causes of anemia, even if mild. • To screen the patient for the need for an ‘in-depth’ CGA, and to remedy the reversible situations that may emerge from the CGA. In clinical research in older cancer patients, we feel that a complete assessment is important, to apply a uniform taxonomy of age. As a frame of reference, the taxonomy proposed by Hamerman et al59 (Table 19.3) might be used. Older individuals may be subclassified as independent, intermediate non-vulnerable, intermediate vulnerable, and frail. In this way, older individuals may be subdivided into more homogeneous groups, and the influences of function, comorbidity, and social support on treatment outcome may be studied. In addition, special research treatment protocols for the management of frail patients may be instituted. Important topics of future research may include: • evaluation of physical performance tests for screening patients in need of CGA; • the prognostic value of physical performance; • physical performance and prediction of treatment tolerance; • prognostic values of circulating cytokines; • circulating cytokines and treatment tolerance;

Comprehensive Geriatric Oncology

416

• application of decision analysis to the management of the older cancer patient. An example of these was provided by Extermann et al,1 who established a threshold for the risk of recurrence of breast cancer below which the use of adjuvant chemotherapy may be contraindicated, Future research may include the use of physical functional and laboratory assessment to predict individual life-expectancy, and application of the decision model to other neoplasms. References 1. Extermann M, Balducci L, Lyman GH. What threshold for adjuvant therapy in older breast cancer patients? J Clin Oncol 2000; 18: 1709–17. 2. Sehl ME, Yates E. Kinetics of human aging. Rates of senescence between ages 30 and 70 in healthy people. J Gerontol Biol Sci 2001; 56A, B198–208. 3. Hogan DB, Ebly EM, Fung TS. Disease, disability, and age in cognitively intact seniors: results from the Canadian Study of Health and Aging. J Gerontol 1999; 54A, M77–82. 4. Femia EE, Zarit SH, Johansoon B. The disablement process in very late life: a study of the oldest-old in Sweden. J Gerontol Psychol Sci 2001; 56B, P12–23. 5. Yashin AI, Ukraintseva SV, De Benedictis G et al. Have the oldest old adults ever been frail in the past? A hypothesis that explains modern trends in survival. J Gerontol Biol Sci 2001; 56A, B432–42. 6. Balducci L, Extermann M. A practical approach to the older patient with cancer. Curr Probl Cancer 2001; 25:6–76. 7. Satariano WA, Ragland DR. The effect of comorbidity on 3-year survival of women with primary breast cancer. Ann Intern Med 1994; 120:104–10. 8. Piccirillo JF, Feinstein AR. Clinical symptoms and comorbidity: significance for the prognostic classification of cancer. Cancer 1996; 77:834–42. 9. Coebergh JWW, Janssen-Heijnen MLG, Razenberg PPA. Prevalence of co-morbidity in newly diagnosed patients with cancer: a population-based study. Crit Rev Oncol Hematol 1998; 27:97– 100. 10. Extermann M. Measurement and impact of comorbidity in older cancer patients. Crit Rev Oncol Hematol 2000; 35:181–200. 11. Extermann M. Measuring comorbidity in older cancer patients. Eur J Cancer 2000; 36:453– 471. 12. Extermann M, Overcash J, Lyman GH et al. Comorbidity and functional status are independent in older cancer patients. J Clin Oncol 1998; 16:1582–7. 13. Yancik R, Ganz PA, Varricchio CG et al. Perspectives on comorbidity and cancer in the older patient: approach to expand the knowledge base. J Clin Oncol 2001; 19:1147–51. 14. Bucht G, Gustafson Y, Sandberg O. Epidemiology of delirium. Dement Geriatr Cogn Disord 1999; 10:315–18. 15. Cho CY, Alessi CA, Cho M et al. The association between chronic illness and functional impairment among participant in a comprehensive geriatric assessment program. J Am Geriatr Soc 1998; 46: 677–82. 16. Balducci L, Stanta G. Cancer in the frail patient: a coming epidemic. Hematol Oncol Clin North Am 2000; 14:235–50. 17. Balducci L, Extermann M. Management of the frail cancer patient. Crit Rev Hematol Oncol 2000; 33:143–8. 18. Fried LP, Tangen CM, Walston J et al. Frailty in older adults: evidence for a phenotype. J Gerontol Med Sci 2001; 56A, M146–56.

Assessment of the older patient with cancer

417

19. Saliba D, Elliott M, Rubenstein LZ et al. The Vulnerable Elders Survey: a tool for identifying vulnerable older people in the community. J Am Geriatr Soc 2001; 49:1691–9. 20. Extermann M, Overcash J, Lyman GH et al. Comorbidity and functional status are independent in older cancer patients. J Clin Oncol 1998; 16:1582–7. 21. Manton K. A longitudinal study of functional change and mortality in the United States. J Gerontol 1988; 43:S153–61. 22. Reuben DB, Rubenstein LV, Hirsch SH et al. Value of functional status as predictor of mortality. Am J Med 1992; 93:663–9. 23. Inouye SK, Peduzzi PN, Robison JT et al. Importance of functional measures in predicting mortality among older hospitalized patients. JAMA 1998; 279:1187–93. 24. Siu AL, Moshita L, Blaustein J. Comprehensive Geriatric Assessment in a day hospital. J Am Geriatr Soc 1994; 42:1094–9. 25. Ramos LR, Simoes EJ, Albert MS. Dependence in activities of daily living and cognitive impairment strongly predicted mortality in older urban residents in Brazil. J Am Geriatr Soc 2001; 49:1168–75. 26. Barbeger Gateau P, Fabrigoule C, Helmer C et al. Functional impairment in Instrumental Activities of Daily Living: an early clinical sign of dementia? J Am Geriatr Soc, 1999; 47:456– 62. 27. Monfardini S, Ferrucci L, Fratino L et al. Validation of a multidimensional evaluation scale for use in elderly cancer patients. Cancer 1996; 77:395–401. 28. Extermann M, Chen A, Cantor AB et al. Predictors of toxicity from chemotherapy in older patients. Proc Am Soc Clin Oncol 2000; 19:617a. 29. Charlson M, Szatrowski TP, Peterson J et al. Validation of a combined comorbidity index. J Clin Epidemiol 1994; 47:1245–51. 30. Parmelee PA, Thuras PD, Katz IR, Lawton MP. Validation of the cumulative illness rating scale in a geriatric residential population. J Am Geriatr Soc 1995; 43:130–137. 31. Chaves PH, Volpato S, Fried L. Challenging the World Health Organization criteria for anemia in the older woman. J Am Geriatr Soc 2001; 49:S3, A10. 32. Izaks GJ, Westendorp RGJ, Knook DL. The definition of anemia in the older person. JAMA 1999; 281:1714–17. 33. Balducci L, Hardy CL, Lyman GH. Hemopoietic growth factors in the older cancer patient. Curr Opin Hematol 2001; 8:170–87. 34. Cleeland CS, Demetri GD, Glaspy J et al. Identifying hemoglobin levels for optimal quality of life. Results of an incremental analysis. Proc Am Soc Clin Oncol 1999; 16: Abst 2215. 35. Gabrilove JL, Einhorn LH, Livingston RB et al. Once weekly dosing of epoietin alfa is similar to three-times weekly dosing in increasing hemoglobin and quality of life. Proc Am Soc Clin Oncol 1999; 18:574A. 36. Marcantonio ER, Goldman L, Orav EJ et al. The association of intraoperative factors with the development of postoperative delirium. Am J Med 1998; 105:380–4. 37. Stump TE, Callahan CM, Hendrie HC. Cognitive impairment and mortality in older primary care patients. J Am Geriatr Soc 2001; 49: 934–40. 38. Nakanishi N, Tatara K, Ikeda K et al. Relation between intellectual dysfunction and mortality in community-residing older people. J Am Geriatr Soc 1998; 46:583–9. 39. Eagles JM, Beattie JAG, Restall DB et al. Relationship between cognitive impairment and early death in the elderly. BMJ 1990; 300:239–40. 40. Bruce ML, Hoff RA, Jacobs SC et al. The effect of cognitive impairment on 9-year mortality in a community sample. J Gerontol 1995; 50B, P289–96. 41. Crossen JR, Garwood D, Glatstein E et al. Neurobehavioral sequelae of cranial irradiation in adults: a review of radiation induced encephalopathy. J Clin Oncol 1994; 12:627–42. 42. Schagen SB, Van Dam FSAM, Muller MJ et al. Cognitive deficit after postoperative adjuvant chemotherapy for breast carcinoma. Cancer 1999; 85:640–50.

Comprehensive Geriatric Oncology

418

43. Chlebowski RT, Ernst T, Chang L et al. Tamoxifen and estrogen effect on brain chemistry determined by MRI spectroscopy. Proc Am Soc Clin Oncol 2001; 20:28a (Abst 108). 44. Folstein ME, Folstein SE, McHugh PR. A Mini Mental State: a practical method for grading the cognitive status of patients for the clinician. J Psychiatr Res 1975; 12:189–98. 45. Kivela S-L, Pahkala K. Depressive disorder as predictor of physical disability in old age. J Am Geriatr Soc 2001; 49:290–6. 46. Blazer DG, Hybels CF, Pieper CF. The association of depression and mortality in elderly persons: a case for multiple independent pathways. J Gerontol Med Sci 2001; 56A, M505–9. 47. Covinsky KE, Kahana E, Chin MH et al. Depressive symptoms and three-year mortality in older hospitalized medical patients. Ann Intern Med 1999; 130:563–9. 48. Bruce ML, Leaf PJ, Rozal GP et al. Psychiatric status and nine year mortality data in the New Haven Epidemiologic Catchment Area study. Am J Psychiatr 1994; 151:716–21. 49. Lyness JM, Ling DA, Cox C et al. The importance of subsyndromal depression in older primary care patients. Prevalence and associated functional disability. J Am Geriatr Soc 1999; 47:647– 52. 50. Lyness JM, Noel TK, Cox C et al. Screening for depression in elderly primary care patients: a comparison of the Center for Epidemiologic Studies Depression Scale and the Geriatric Depression Scale. Arch Intern Med 1997; 157:449–54. 51. Weitzner MA, Haley WE, Chen H. The family caregiver of the older cancer patient. Hematol Oncol Clin North Am 2000; 14:269–82. 52. Hoffman SB, Balmes JA. Assessing needs and providing comfort to geriatric cancer patients and their families In: Comprehensive Geriatric Oncology, 1st edn (Balducci L, Lyman GH, Ershler WB, eds). Amsterdam: Harwood Academic Publishers, 1998:793–804. 53. Haley WE, Burton AM, LaMonde LA, Schonwetter RS. Family caregiving issues in geriatric oncology. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:843–52. 54. Melton LJ, Khosla S, Crowson CS et al. Epidemiology of sarcopenia. J Am Geriatr Soc 2000; 48:625–30. 55. Roberts SB, Fuss P, Heyman MB et al. Control of food intake in older men. JAMA 1994; 272:1601–6. 56. Rosen CJ. Growth hormone and aging. Endocrine 2000; 12:197–201. 57. Martin F. Frailty and the somatopause. Growth Hormone IGF Res 1999; 9:3. 58. Yeh S-S, Wu S-Y, Levine DM et al. The correlation of cytokine levels with body weight after megestrol acetate treatment in geriatric patients. J Gerontol Med Sci 2001; 56A, M48–54. 59. Hamerman D, Berman JV, Albers GW et al. Emerging evidence of inflammation in conditions frequently affecting older adults: reports of a symposium. J Am Geriatr Soc 1999; 47:1016–25. 60. Astani A, Smith RC, Allen BJ. The predictive value of body proteins for chemotherapy induced toxicity. Cancer 2000; 88:796–903. 61. Balducci L, Hardy CL. Cancer and malnutrition: a clinical interaction. A review. Am J Hematol 1985; 18:91–103. 62. Guigoz Y, Vellas B, Garry PJ. Mini Nutritional assessment: a practical assessment tool for grading the nutritional state of elderly patients. In: Facts, Research, and Interventions in Geriatrics 1997. New York: Serdi Publishing, 1997:15–60. 63. Corcoran ME. Polypharmacy in the senior adult patient. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M eds). London: Martin Dunitz, 2004:502–9. 64. Flaherty JH, Perry HM, Lynchard GS, Morley JE. Polypharmacy and hospitalization among older home care patients. J Gerontol Med Sci 2000; 55:M554–9. 65. Willcox SM, Himmelstein DU, Woolhandler S. Inappropriate drug prescribing for communitydwelling elderly. JAMA 1994; 272:292–6.

Assessment of the older patient with cancer

419

66. Clarfield AM, Bergman H, Kane R. Fragmentation of care for frail older people—an international problem. Experience from three countries: Israel, Canada, and the United States. J Am Geriatr Soc 2001; 49:1714–21. 67. Inouye SK, Bogardus ST, Charpentier PA et al. A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med 1999; 340:669–74. 68. Marcantonio ER, Flacker JM, Michaels M et al. Delirium is independently associated with poor functional recovery after hip fracture. J Am Geriatr Soc 2000; 48:618–24. 69. Kressig RW, Wolf SL, Sattin RW et al. Association of demographic, functional and behavioral characteristics with activity-related fear of falling among older adults transitioning to frailty. J Am Geriatr Soc 2001; 49:1456–62. 70. American Geriatrics Society, British Geriatric Society, and American Academy of Orthopedic Surgeons Panel on Falls Prevention: guidelines for the prevention of falls in older persons. J Am Geriatr Soc 2001; 49:664–72. 71. Tinetti ME, Williams CS. The effects of falls and fall injuries in functioning in community dwelling older persons. J Gerontol 1998; 53A M112–19. 72. Tinetti ME, McAvay G, Claus G et al. A multifactorial intervention to reduce the risk of falling among elderly people living in the community. N Engl J Med 1994; 331:821–7. 73. Johnson MF, Kramer AM, Lin MK et al. Outcomes of older persons receiving rehabilitation for medical and surgical conditions compared with hip fractures and stroke. J Am Geriatr Soc 2000; 48: 1389–97. 74. Tinetti ME, Williams TF, Mayewski R. Fall risk index in elderly persons based on number of chronic disabilities. Am J Med 1986; 80: 429–34. 75. Rizzoli R, Ammann P, Chevalley T et al. Protein intake and bone disorders in the elderly. Joint Bone Spine 2001; 68:383–92, 76. Verdery RB. Failure to thrive in old age: follow-up on a workshop. J Gerontol Biol Sci Med 1997; 52:M333–6, 77. Pavlik VN, Hyman DJ, Festa NA. Quantifying the problem of abuse and neglect in adults: analysis of a Statewide database. J Am Geriatr Soc 2001; 49:45–8, 78. Lachs MS, Williams C, O’Brien S et al. Risk factors for reported elder abuse and neglect: a nine-year observational cohort study. Gerontologist, 1997; 37:469–74. 79. Dyer CB, Pavlick VN, Murphy KP et al. The high prevalence of depression and dementia in elder abuse or neglect. J Am Geriatr Soc 2000; 48:205–8. 80. Lachs MA, Williams CS, O’Brien S et al. Mortality of elder mistreatment. JAMA 1998; 280:428–32. 81. Boult C, Boult LB, Morishit L et al. A randomized clinical trial of outpatient geriatric evaluation and management. J Am Geriatr Soc 2001; 49:351–9. 82. Stuck AE, Siu AL, Wieland GD et al. Comprehensive Geriatric Assessment: meta-analysis of controlled trials. Lancet 1993; 342:1032–6. 83. Reuben DB, Franck J, Hirsch S et al. A randomized clinical trial of outpatient geriatric assessment (CGA), coupled with an intervention, to increase adherence to recommendations. J Am Geriatr Soc 1999; 47:269–76. 84. Bula CJ, Berod AC, Stuck AE et al. Effectiveness of preventive in-home geriatric assessment in well functioning, community dwelling older people: secondary analysis of a randomized trial. J Am Geriatr Soc 1999; 47:389–95. 85. Tulloch AJ, Moore V. A randomized controlled trial of geriatric screening and surveillance in general practice. J R Coll Gen Pract 1979; 29:733–42. 86. Landi F, Onder G, Russo A et al. A new model for integrated home care in the elderly: impact on hospital use. J Clin Epidemiol 2001; 54:968–70. 87. Bernabei R, Venturiero V, Tarsitani P et al. The Comprehensive Geriatric Assessment: when, where, how. Crit Rev Hematol Oncol 2000; 33:45–56. 88. McCorkle R, Strumpf NE, Nuamah IF et al. A specialized home care intervention improves survival among old post-surgical cancer patients. J Am Geriatr Soc 2000; 48:1707–13.

Comprehensive Geriatric Oncology

420

89. Burns R, Nichols LO, Martindale-Adams J et al. Interdisciplinary geriatric primary care evaluation and management. Two year outcomes. J Am Geriatr Soc 2000; 48:8–13. 90. Hamerman D. Toward an understanding of frailty. Ann Intern Med 1999; 130:945–50. 91. Rockwood K, Stadnyk K, Macknigt C et al. A brief instrument to classify frailty in elderly people. Lancet 1999; 353:205–6. 92. Balducci L, Yates G. General guidelines for the management of older patients with cancer. Oncology (Huntingt) 2000; 14:221–7. 93. Repetto L, Fratino L, Audisio RA et al. Comprehensive Geriatric Assessment adds information to the Eastern Cooperative Group Performance Status in elderly cancer patients. An Italian Group for Geriatric Oncology study. J Clin Oncol 2002; 20:494–502. 94. Ingram SS, Seo PH, Martell RE et al. Comprehensive assessment of the elderly cancer patient: the feasibility of self-report methodology. J Clin Oncol 2002; 20:770–5. 95. Lachs MS, Feinstein AR, Coonley LM et al. A simple procedure for general screening for functional disability in elderly. Ann Intern Med 1990; 112:699–706. 96. Maly RC, Hirsch SH, Reuben DB. The performance of simple instruments in detecting geriatric conditions and selecting community-dwelling older people for geriatric assessment. Age Ageing 1997; 26:223–31. 97. Moore AA, Siu LL. Screening for common problems in ambulatory elderly: clinical confirmation of a screening instrument. Am J Med 1996; 100:448–53. 98. McDermott M, Greenland P, Ferrrucci L et al. Lower extremity performance is associated with daily life physical activity in individuals with and without peripheral arterial disease. J Am Geriatr Soc 2002; 50:247–55. 99. Pavol MJ, Owings TM, Foley KT et al. Influence of lower extremities strength of healthy older adults on the outcome of induced trip. J Am Geriatr Soc 2001; 50:256–62. 100. Daltroy LH, Larson MG, Eaton HM et al. Discrepancies between self-reported and observed physical function in the elderly: the influence of response shift and other factors. Soc Sci Med 1999; 48:1549–61. 101. Merrill SS, Seeman TE, Kasl SV et al. Gender differences in the comparison of self-reported disability performance measures. J Gerontol Biol Sci Med Sci 1997; 52:19–26. 102. Volpato S, Leveille SG, Corti MC et al. The value of serum albumin and high density lipoprotein cholesterol in defining mortality risk in older persons with low serum cholesterol. J Am Geriatr Soc 2001; 49:1142–7. 103. Weverling-Rijnsburger AWE, Blow GJ, Lagaaj AM et al. Total cholesterol and the risk of mortality in the oldest old. Lancet 1997; 350:1119–23. 104. Corti MC, Guralnik JM, Salive ME. Clarifying the direct relation between total cholesterol levels and death from coronary artery disease in older persons. Ann Intern Med 1997; 126:753– 60. 105. Bucher HC, Griffith LE, Guyatt CH. Systematic review of the risk and benefits of different cholesterol-lowering interventions. Arteriosd Thromb Vasc Biol 1999;19:187–95. 106. Goldwasser P, Feldman J. Association of serum albumin and mortality risk. J Clin Epidemiol 1997; 50:693–703. 107. Hack V, Breitkreutz R, Kinscherf R et al. The redox status as a correlate of senescence and wasting and as a target for therapeutic intervention. Blood 1998; 54:59–67. 108. Cohen HJ. In search of the underlying mechanisms of frailty. J Gerontol Med Sci 2001; 55a, 706–8. 109. Currie MS, Rao KMK, Blazer DG et al. Age and functional correlation of markers of inflammation and coagulation in the elderly: functional implications of elevated cross-linked fibrin degradation products (D-dimers). J Am Geriatr Soc 1994; 42:738–42. 110. Pieper CF, Rao KMK, Currie MS et al. Age, functional status, and racial differences in plasma D-dimer levels in community dwelling elders. J Gerontol Med Sci 1999; 55A, M649–57. 111. Harris TB, Ferrucci L, Tracy RP et al. Associations of elevated interleukin 6 and C-reactive protein levels and with mortality in the elderly. Am J Med 1999; 106:506–12.

Assessment of the older patient with cancer

421

112. Taaffe DR. Harris TB, Ferrucci L et al. Cross-sectional and prospective relationships of interleukin 6 and C-reactive protein with physical performance in elderly persons: MacArthur study of successful aging. J Gerontol Med Sci 2000; 55A, M709–15. 113. Ershler WB, Keller ETR. Age-associated increased interleukin-6 gene expression, late life disease and frailty. Annu Rev Med 2000; 51:245–70. 114. Ferrucci L, Harris TB, Guralnik JM et al. Serum IL6 level and the development of disability in older persons. J Am Geriatr Soc 1999; 47:639–46. 115. Thompson MP, Morris LK. Unexplained weight loss in ambulatory elderly. J Am Geriatr Soc 1991; 39:497–500. 116. Cohen HJ, Pieper CF, Harris T. Markers of inflammation and coagulation predict decline in function and mortality in community-dwelling elderly. J Am Geriatr Soc 2001; 49:S1 (A3).

20 Frailty, cancer cachexia, and near death David Hamerman Introduction The present author has previously described frailty in terms of the health provider’s perception of the patient rather than the expression of a defined clinical state.1 Frailty is a condition of multifactorial origin, particularly influenced by and associated with advanced age, without necessarily having an evident underlying etiologic basis. For example, such non-specific findings as leg and arm weakness, reduced vision or hearing, and anxiety were associated with frailty in a cohort of older persons living in the community.2 With respect to this chapter in a text on geriatric oncology, the term frailty may be less appropriate as a clinical perception of the patient under consideration than the term cachexia. ‘A physician’s first experience with a cachectic patient may be memorable, if indescribable’.3 Cachexia is a debilitating state of involuntary weight loss where the underlying etiology is almost always cancer, and in palliative care centers may be a more common problem than pain.4 A more generalized discussion of cachexia without a defining underlying basis has been presented by Kotler;3 other associations with the concept of cachexia have been described, such as the term ‘geriatric cachexia’.5 Yet there is a unique aspect to the cancer-host interactions ‘where the metabolic changes are the cause of the cachexia rather than the consequence’6 that gives this association a degree of specificity. Cachexia is characterized to a variable extent by early satiety, anorexia, changes in taste perception, and weakness; its cardinal feature of weight loss gives the individual the appearance of emaciation, and this is certainly evident to the patient. This appearance may reflect malnutrition, but clearly differs from it. In malnutrition, adaptations are made to reduce energy expenditure, and nutritional supplements may be restorative—aspects that seem to fail in cancer cachexia.7,8 Moreover, in starvation, the resting energy expenditure (REE) declines,9 and sources of energy are derived mainly from fat; in cancer cachexia, the REE is highly variable, but may be increased as energy sources are derived inefficiently not only from fat but particularly from muscle breakdown.6,10–14 If serious illness is a metaphor for despair, then cachexia is the evident and profound basis for the desolation and isolation that cancer in late stages may represent to the patient and the caregivers. On this theme, Sontag15 wrote that ‘cancer is a metaphor for what is most ferociously energetic; and these energies constitute the ultimate insult to natural order’. These words seem to be reflected, in a philosophical sense, even among those who appear to have survived cancer, by the perception of the ‘body as a hostile object which has gone seriously wrong, and could do so again’,16 or by a ‘liminal’

Frailty, cancer cachexia, and near death

423

individual ‘wasting away’,17 not expected to recover but not yet deceased. Sontag’s words even reverberate at the cellular level, where a general hypermetabolic state exists, involving enhanced glycolysis, lactate production, increased protein turnover with muscle wasting, high lipid mobilization from fat, and enhanced synthesis of phase reactant proteins—all associated with cancer cachexia.10,18 The ominous sense of cachexia is inherent in its derivation—the Greek kayos meaning ‘bad’, and hexes, meaning ‘condition’.8,11,19,20 Cachexia is seen mostly with advanced cancer of the stomach, pancreas, lung, and colon, but is rarely associated with breast cancer or hematological malignancies12,21 The other metaphor for illness that Sontag cites is AIDS, and cachexia has been described in that condition as well. The term ‘wasting syndromes’ has been used for a state of non-volutional/uncontrolled weight loss that generally occurs in the setting of an underlying illness, where AIDS in particular is cited.22–24 Before the antibiotic era, chronic suppurative conditions (lung abscess and osteomyelitis) might have resulted in the appearance and metabolic state of cachexia. Table 20.1 presents an overview of some wasting conditions. These are viewed in a sense as a transition from those conditions that may be remediable (starvation, frailty, and non-specific cachexia), to those that are essentially irreversible (cancer and AIDS). In a geriatric continuum, where frailty has been placed in a mid-position between independence and taking to bed with severe decline,1 cachexia in the cancer patient reflects a position of a more terminal nature, with implications of near death. A history of weight loss is a powerful predictor for shortened survival—with a decreased

Table 20.1 Overview of wasting conditionsa Starvation

Frailty

Cachexia

Voluntary

Geriatric

Non-specific/cancer/ AIDS

Involuntary

Decline Failure to thrive

Anorexia nervosa

Taking to bed

Low resting energy expenditure

Near death High resting energy expenditure and severe muscle breakdown

Energy sources from fat Supplemental nutrition improves

Fails to improve

a

Represents transitions from potentially remediable clinical states (starvation or frailty) to conditions approaching near death (cancer or AIDS), with associated metabolic aspects and responses to nutritional supplements.

chemotherapy response rate and lower performance status.4,18,24 Quality of life is also profoundly affected, since much of the cultural pleasure associated with eating and social interactions18,25 is denied to the person with cachexia, who has an aversion to food; the refusal to eat in the face of persistent loss of weight invokes personal despair and helplessness, caregiver anger and frustration,4 and the physician’s awareness of the hopelessness of treatment.26 Moreover, as Heber18 pointed out, ‘despite the development

Comprehensive Geriatric Oncology

424

of advanced technology and costly delivery systems for total parenteral nutrition and continuous enteral nutrition, nutrition therapy alone has had little impact on this problem’ of progressive weight loss—a point also made in a number of reviews.4,6 In this chapter, the approach in considering cancer cachexia will include an overview of nutritional status in normative aging and cancer, current understanding of the biologic basis for cancer cachexia, and therapies that are in use and those that are emerging to counter this dreaded condition. This chapter is presented more in the form of an essay on the subject with literature citations to recent review articles rather than to individual references describing experimental studies. Nutritional status in aging and cancer cachexia Striking changes in body composition occur normally with advancing decades of life (Table 20.2). Among the promi

Table 20.2 Body composition changes with normative aging10,27–32,35–38 • Weight gain until older age (75 years) • Decreased lean body mass • Decreased water • Decreased body fat: Redistributes to visceral fat Cardiovascular morbidity and mortality • Malnutrition—in the case of food deprivation • Sarcopenia—decreased physical activity • Osteopenia—fracture potential

nent changes are a decrease in lean body mass and body water, and an increase in fat mass.10,27,28 Fat mass redistributes from the periphery to the trunk and viscera,29–32 with the development of insulin resistance, type 2 diabetes, and implications for cardiovascular morbidity and mortality as well,33,34 especially in middle-aged men.27,35 Rosenberg and Miller36 noted that the decline in lean body mass impacted on muscle strength, respiratory function, and ambulatory capacity. Elderly frail people were least able to maintain muscle mass. Involuntary loss of muscle (sarcopenia)37 is compounded by reduced strength due also to lack of physical training38 and to low intake of dietary magnesium and vitamin D. With aging, there are decreases in total body nitrogen, calcium, and water; bone mineral content also declines with age (ostopenia).29 Older persons have distinct metabolic characteristics that alter their requirements for specific nutrients and their responses to deliberate overfeeding or underfeeding, i.e. they seem less able to adapt.39

Frailty, cancer cachexia, and near death

425

The actual state of body composition with advancing age, especially relating to the amount and distribution of body fat and even to bone mineral content,40 is an excellent marker for adverse health risks and for disease.27 Quantitative methods for body composition measurements include anthropometry, densitometry, bioelectrical impedence, isotope dilution, total body potassium, neutron activation, and dual-energy Xray absorptiometry.22,41 Many of these tests are not generally available in office practice, are used for research purposes, or are unsuitable for frail elderly persons.28 Reservations have been expressed about the use of body mass index (BMI) as a measure of nutritional status,22,35 particularly with regard to its failure to distinguish contributions to body weight from fat versus muscle, bone, and water,22 or to convey information concerning regional fat distribution.42 Nevertheless, BMI derived from office measures of weight in kilograms divided by the square of the height in meters provides a close relationship with the incidence of several chronic conditions caused by excess fat, such as type 2 diabetes, hypertension, and coronary artery disease.43 A nomogram can be consulted in Figure 2 of the paper by Bray and Ryan.44 The World Health Organization (WHO) recommends desirable mean measures of BMI for men as 22 kg/m2 and for women 20.8 kg/m2 between the ages of 18 and 34.35 There are, of course, extremes reflected by emaciation at one end of a continuum to gross obesity at the other end,32 but in the USA the trend for persons over 35 is for weight gain and a BMI of 21–27 kg/m2. The apparent optimal BMI for those over 65 seems to be increasing from 20–25 kg/m2 to 24–29 kg/m2.35 Overweight is a BMI of 27–30 kg/m2 and obesity is a BMI greater than 30 kg/m2. In the period 1960–94, the prevalence of obesity increased by 8 percentage points from 14% to 22% in the US population aged 20–74.45 More than one-third of North Americans are obese,35,44,46—a veritable ‘epidemic’47—with associated metabolic modifications that account for increased cardiovascular morbidity and mortality.48 Stigmatization of obese persons49,50 is widely prevalent, but social attitudes seem to have little effect on deterrence. The trend towards obesity in the population is likely to be due to environmental and social aspects rather than genetic modifications, although the major factors involved—energy requirements, nutrient partitioning with dietary intake, and physical activity—interact to contribute to obesity, and each factor is influenced by genotype.43,51–54 The number of obese persons aged over 70 is likely to be small because of associated mortality and decreasing fatness with advanced age.35 The obese state is characterized by a small decline in resting metabolic balance, a decrease in physical activity,55 and a higher energy cost for a given activity.28 An interesting nutritional condition imposed on certain animal species in the laboratory bears on the borderland between caloric replenishment and restriction in the aging process. Caloric restriction is the only intervention that increases both average and maximal lifespan in laboratory rodents,27 and appears to attenuate metabolic stress responses arising from the generation of oxidants and the effects of glycemia and insulinemia.56 The outcome of caloric restriction is under study in primates.57 The dramatic change in body composition with caloric restriction is expressed mainly as a decreased fat mass. A decline in the incidence of autoimmune diseases and neoplasms in dietary restricted animals,58 and conversely the possible induction of tumors with fat feeding, are relevant to the genetic and environmental factors that are associated with cancer development in humans.59,60

Comprehensive Geriatric Oncology

426

Average body weight seems to remain relatively stable until persons reach the age of 75.46,55 The trend in advanced age is for weight loss.35 The extreme expression of weight loss—malnutrition—is a common problem in very elderly persons, manifest in up to 30% of those who live in the community, and at much higher rates (up to 75%) among those who reside in nursing homes.10,61,62 Caloric intake decreases by an average of 12.4 kcal/day for each year of age increase. Loss of more than 10% of body weight in an elderly person in a 6-month period is a signal to search for potential causes,24,55 such as depression, Parkinson’s disease, adverse interaction of medications, and chronic pulmonary or cardiac disease.32 In the absence of a discernible cause, this workup often seeks to detect an underlying malignancy.1 Malnutrition in aged persons is of course associated with loss of weight, and, unlike normative aging (where fat mass is gained), in malnutrition and especially acute starvation, energy sources derived from glucose and protein diminish while fat mass is selectively depleted, perhaps in an effort to spare muscle.4,11,22 Malnutrition in a geriatric population appears to be independently associated with morbidity and mortality,10 with low serum albumin being an identifiable predictor for healthcare costs and mortality.63,64 Yet, unlike the case in cancer cachexia, nutritional supplementation may reverse or slow this downward trend of weight loss in elderly frail individuals,10 as noted. Besides the different causality in cancer cachexia, marginal nutrient intake may be the underlying problem in advancing age, a physiologic ‘anorexia of aging’,65,66 arising from a variety of social, economic, and physical conditions: isolation, depression, poverty, poor dental hygiene, loss of taste and smell impairing appetite, limited physical activity, the failure to increase food intake after deprivation (e.g. hospitalization), neuromuscular diseases, and visual limitations.28 The period of time at which cancer cachexia becomes manifest in an older person depends on the premorbid nutritional status, the type and location of the cancer, and the success or failure of therapeutic interventions. Thus, whether the individual has been obese, of normal weight, or malnourished may account for reports of great variability— ranging from 3% to more than 80%—in the appearance of cachexia at the time of clinical presentation.6 Indeed, Simons et al67 described the presentation of initially obese patients who have sustained a 21% loss of weight with still normal weight, or those presenting with very low pre-illness weight who remained weight-stable at the time of study. Early phases of tumor-host relationship and cachexia development are of great interest in terms of pathogenetic mechanisms. A patient may present with tissue wasting as a manifestation of cachexia in the early stages of tumor growth, prior to the onset of other symptoms, i.e. with a low tumor burden.7 Cachexia manifestations are not necessarily related to tumor size, but are clearly caused by the tumor: in animal studies, tumor ablation reversed all symptoms unless a critical end stage of weight loss was reached.7 Death from starvation in human subjects can be extrapolated to 66% of ideal body weight, suggesting that it is the degree of wasting rather than its specific cause that leads to death.23 Thus, the metabolic basis for cachexia is in itself life-threatening. In the development of cancer cachexia, all the evidence points to a unique nutritional state taking over in a dominant way (Table 20.3). A number of reviews have

Table 20.3 Metabolic state in cancer cachexia4,6,8,10–13,18,20

Frailty, cancer cachexia, and near death

427

Glucose •

Enhanced glycolysis

•

Anerobic lactate production

•

Gluconeogenesis via the Cori cycle

•

Hyperglycemia

•

Insulin resistance

Proteins •

Muscle proteolysis

•

Loss of lean body mass

Lipids •

Fat-store depletion

•

Increased triglycerides

•

Decreased lipoprotein lipase

documented in detail the metabolic changes in carbohydrate, protein, and lipid metabolism,4,6,8,10–13,18,20 and the concepts emerging suggest an overwhelming catabolic state of wasteful nutrient use and energy expenditure, and impaired anabolism in terms of glucose, lipids, and, in particular, protein stores in muscle. With respect to glucose metabolism, there is enhanced glycolysis, anaerobic lactate production (cycling through the Cori cycle to regenerate glucose via gluconeogenesis), and reduced glucose utilization because of insulin resistance. In muscle, there is increased protein turnover, with breakdown and depletion of lean tissue mass to generate calories—perhaps the major cause of muscle wasting. A molecular basis for muscle wasting and failure of repair associated with cancer cachexia has been attributed to tumor necrosis factor α (TNF-α) and interferon-γ (IFN-γ) suppressing myogenesis by activating the transcription factor NF-κB in muscle cells.68,69 It is of interest that in bone, a receptor activator of NF-κB termed RANK ligand (RANKL) is present on osteoblasts and binds to RANK on the osteoclast with stimulation of bone resorption.70 Upregulation of NF-κB by a variety of cytokines appears to be an important event in a number of aging-related diseases, such as atherosclerosis, cancer, osteoporosis, and Alzheimer’s disease.71 In terms of lipids, increased lipolysis depletes fat stores with hypertriglyceridemia; decreased activity of lipoprotein lipase, the enzyme responsible for hydrolysis of lipoprotein-associated triglycerides, limits fatty acid uptake into hepatic adipocytes for triglyceride synthesis. With respect to the general failure of cachectic cancer patients to gain weight despite adequate caloric intake under metabolic ward conditions,18 the progestational steroid megestrol acetate, perhaps by reversing the abnormalities in lipid metabolism, may be effective in providing weight gain in some patients,21 as will be discussed later. Hyperlipidemia may contribute to a state of immunosuppression in the cachectic patient.20

Comprehensive Geriatric Oncology

428

Biologic basis for the metabolic disorders in cancer cachexia Overview There are at least four interactive areas based on tumor-host responses that contribute to the biologic underpinnings of cancer cachexia: the immunologic responses of the host to the tumor, with cytokine activation and ‘dysregulation’,72 part of the ‘stress responses’73 that activate the hypothalamic-pituitary-adrenal (HPA) axis and drive the metabolic manifestations by way of widespread peripheral and central hormonal effects. Included in the metabolic effectors is leptin, the cytokinelike peptide around which there has been a virtual ‘explosion’19,74 of information with respect to its origin in fat cells, its blood level, and its entry into the central nervous system to act as a satiety signal—although leptin has other far-reaching effects.75 The inception and progression of cachexia in the affected individual arise primarily from the neoplasm, but the complex host responses noted above drive the process. As discussed, great individual variations can be observed in the patient’s condition at the time of presentation based on the type and site of the tumor, the premorbid nutritional status, age, genetic makeup (affecting particularly the immune system and its response), and the subsequent outcome depending on the results of therapeutic interventions to shrink or ablate the tumor. A similar ‘reckoning’ prevails with that other widely recognized cause of cachexia—AIDS—where the human immunodeficiency virus (HIV) is the etiologic agent, and defining roles are also played by virus-host interactions, acquired infections, and therapy. The discussion of the biologic basis of cancer cachexia that follows is an attempt to present these interactive, complex associations so that a coherent picture emerges of anorexia and the cachectic state. While cytokine actions tend to dominate the literature on cachexia, the aim here is also to raise for consideration the biology of leptin and the HPA axis as part of broad endocrine and metabolic responses that, in experimental studies, have not specifically been focused on mechanisms of cancer cachexia, but seem highly relevant to it. Since these systems are so interactive, there will be overlap in the discussion below. Cytokines Cytokines have spurred widespread interest as part of the immune responses of the host to many types of challenges and the potential adverse effects of circulating cytokines on the host. Distinct patterns of cytokine secretion that have been described in other conditions, such as rheumatoid arthritis and systemic lupus erythematosus,76 seem not to have received the same attention in relation to cancer cachexia. This may be due, in part, to the intense search for pathogenetic mechanisms underlying those autoimmune diseases. In cachexia development, tumor antigens may be an initial challenge, processed within the cells and presented as short peptide fragments bound in the groove of the tumor major histocompatibility complex (MHC) class I molecules to which the host’s CD8+ cytotoxic lymphocytes respond;77,78 the persistence of the cancer maintains the immune challenge—manifested by cytokine activation and release.72,79 Chemotherapy or radiation may also provide host conditioning for cytokine secretion. Injury to the gastrointestinal mucosal surface may release endotoxin, with eventual further activation of macrophages to release cytokines.80 The association of cachexia with cytokine

Frailty, cancer cachexia, and near death

429

mediators received support from studies on rabbits responding to infection with trypanosomiasis, where profound hyperlipidemia and a wasting diathesis occurred—the original observations of Cerami, Beutler, and their colleagues.20,23,81 The apparent humoral mediator, called cachectin, isolated from activated macrophages, was subsequently noted to be identical with TNF-α: ‘two sides of the same biological coin’.82 The inhibition of lipoprotein lipase by this cytokine in vitro is the observation that links the earlier work with the present. Lipoprotein lipase supplies the adipocytes with free fatty acids for intracellular esterification by hydrolyzing triglyceride-rich proteins in the circulation.83,84 The cytokine TNF-α also contributes to the insulin resistance observed in obese states, in type 2 diabetes, and in cancer, and it is interesting that in obese mice with homozygous null mutation of TNF-α, insulin sensitivity improves and lower lipid levels occur.85 The argument for the role of cytokines as mediators in catabolic states is most convincing in terms of their additive and interactive effects,23,86 since each one individually produces variable metabolic manifestations in animal tumor models: decrease in lipoprotein lipase, increase in hepatic synthesis of fatty acids, muscle protein breakdown, weight loss, food avoidance, and catabolism of adipose tissue. The conditions relating to the cancer’s ability to drive the cachexia are probably related in large part to cytokine dysregulation, and this is a dominant yet poorly understood aspect.72 While the hypermetabolic state of cancer cachexia may suggest a rather unique association, many of the known organ responses to cytokines are non-specific. One of the most clear-cut manifestations of non-specific responses to cytokines is the augmentation of acute-phase reactant protein synthesis by the liver, related especially to TNF-α, interleukin-1 (IL-1), and IL-6.87 One such hepatic protein most widely measured is Creactive protein (CRP). Elevations in CRP occur in aging-related conditions, such as osteoarthritis,88 and with low-grade inflammation in atheromatous plaques, even without symptomatic coronary artery disease.89,90 What Barber et al12 refer to as a ‘reprioritization’ of liver protein synthesis of acute-phase proteins in states of trauma, inflammation, and infection is also observed in patients with cancer cachexia, and the levels of the acute-phase proteins may reflect disease persistence. Diminished serum albumin observed in cancer cachexia91 is a marker for mortality in older persons,63,64 as noted. Perhaps if nutritional intake is insufficient to supply the required amino acids for acute-phase protein synthesis, the exaggerated muscle breakdown may continue to supply a source.12 IL-6 is widely appreciated as a ‘cytokine for gerontologists’,92 and has been referred to as the most ‘endocrine of all cytokines’ because it is hormonally regulated.93 The wider family of cytokines related to IL-6 includes IL-11, leukemia inhibitory factor (LIF), oncostatin M (OSM), and ciliary neurotropic factor (CNTF), which share a common signal transducer, glycoprotein 130 (gp130),94,95 and leptin—to be discussed below. IL-6 is produced in immune cells and other cell types, and, with TNF-α, also arises from adipose tissue; indeed, fat mass accumulation may increase IL-6 levels in aging.96 IL-6 production is suppressed by glucocorticoids and estrogens, and stimulated by catecholamines and the β-adrenergic pathway of the sympathetic nervous system.93,96,97 IL-6, and even more so its soluble receptor sIL-6R, promote osteoclastogenesis and osteopenia in human subjects,98 an effect reversed by estrogens.99 IL-6 also decreases lipoprotein lipase and increases hepatic triglyceride synthesis.96,100 IL-6 stimulates the

Comprehensive Geriatric Oncology

430

HPA axis during inflammatory stress, promoting release of corticotropin-releasing hormone (CRH) from the hypothalamus, which elevates systemic levels of corticosteroids.101 Increased levels of IL-6 are well documented in aging,92 and are observed in older community dwellers who appear frail,102 or depressed,103 or at risk for cardiovascular disease related to polymorphisms in IL-6 that induce lipid abnormalities.100 Indeed, higher circulating levels of IL-6 and CRP are associated with mortality in healthy older persons100,104 and those with low serum albumin.63 Markers for cytokine activation were found to be associated with immune changes in healthy older persons105 and in frail nursing home residents (mean age 86) without defined disease,106 and may have predictive power for mortality.63 Higher levels of cytokines have been observed in the final stages of debilitating diseases in frail older persons.1 Thus, with or without associated diseases, there is already a ‘background’ in advanced age of genetic polymorphism and metabolic and antigenic responses that activate and elevate cytokines, and these subsequently contribute to the development and progression of cachexia associated with cancer. One consideration that may raise questions about cytokine causality in the metabolic manifestations of cachexia is failure to detect elevated levels of circulating TNF-α in clinical studies of cachectic patients.87,107,108 However, cytokines are not easily measured in the circu-lation, and some workers have concentrated on downstream markers of cytokine activity, such as plasma levels of the soluble products of immune activation, including neopterin for IFN-γ, and sTNF-R11 for TNF-α activity. These markers reflect immune activation in frail aged persons;106 patients with advanced gastrointestinal cancer had significantly raised serum levels of neopterin.109 There is a second limitation with respect to the apparent role of cytokines in promoting cancer cachexia: in animal studies, soluble receptor antibodies directed against TNF-α or IL-1 did not reduce symptoms.72,87 In a clinical study, pentoxifylline, a potent inhibitor of TNF-α secretion, failed to reduce anorexia and cachexia, but of course other cytokines may not have been inhibited.4,13 This subject needs more study in view of the effectiveness of cytokine blockade in reducing symptoms in other conditions, such as rheumatoid arthritis,110 or the risk of rejection after renal transplantation.111 Leptin The literature on leptin, a hormone-like peptide arising (principally) from adipose tissue, is concerned primarily with obesity. Leptin was discovered by cloning and characterizing the ob gene in obese/obese (ob/ob) mice, where the ob transcript is a mutant leptin without function.112 Leptin normally acts as an afferent signal that is part of a feedback loop involving the leptin receptor-binding sites in the arcuate nucleus of the hypothalamus: there, neuropeptide Y (NPY) is activated to stimulate appetite when leptin levels are low, or inhibited with diminution of appetite when leptin levels are high.112 In humans, there is a correlation between total fat mass, especially subcutaneous fat,113–118 and circulating leptin. The greater the amount of adipose tissue, the higher the level of leptin.119 Blood leptin levels are also quickly responsive to a high-fat diet, with a sustained increase in circulating leptin,120 which normally diminishes hypothalamic NPY output and suppresses appetite, as noted; leptin resistance may be a factor in continued eating in obese states.121,122

Frailty, cancer cachexia, and near death

431

Thus, leptin is considered an ‘obesity signal’ by virtue of its secretion in proportion to body fat, its access to appropriate areas of the nervous system, and its influence on food intake and body weight. (Insulin is an obesity signal as well, arising from the pancreatic β cells in response to ambient glucose, but in proportion to body fat.113) Should a discussion of obesity signals be part of a chapter on cancer cachexia? The justification lies in consideration of appetite control, and its loss in the anorexia of cancer. Again we observe a contrast between starvation and the anorexia of cancer cachexia. Starvation induces a rapid fall in leptin levels before adipose mass shrinks,123,124 and the adaptive responses, such as lower thyroid hormone levels and the enhanced NPY output, stimulate food intake and conserve energy for survival.125 Caloric restriction in normal animals also reduces leptin secretion and activates NPY in the hypothalamus to enhance food intake.126,127 In cancer cachexia, an a priori consideration would be that leptin levels are high, NPY is suppressed, and appetite is diminished. However, in one study, this did not prove to be the case: leptin levels were not detectable in subjects with lung cancer who had lost more weight and had a lower BMI than subjects with detectable leptin levels whose weight loss was less and BMI higher.67 That is, leptin homeostasis seemed to be normal, since non-detectable levels in subjects with low BMI (presumed low fat mass) should enhance food intake via activation of NPY, yet anorexia and cachexia were observed. Tumor-bearing rats were found to ‘underexpress’ the leptin gene in adipose tissue, while the circulating concentration of leptin decreased with higher tumor burden.13 Thus, if ‘leptin’s main physiological role is to signal nutritional status during periods of food deprivation’,112 then undetectable levels are ‘appropriate’ in cachectic patients with cancer and also reflect absence of fat mass. Similarly, patients with anorexia nervosa have extremely low leptin levels.112 Thus, it seems that in both states of severe weight loss, low or absent levels of leptin do not appear to activate the NPY appetite-enhancing mechanism, suggesting that other factors may affect leptin secretion and hypothalamic responses in disease states. In experimental animals, the cytokines TNF-α and IL-1 increase leptin expression in adipose tissue and plasma, but in humans, inflammatory disease activity seems not to be correlated with leptin levels.123 The state of the sympathetic nervous system (SNS) poses an interesting question with respect to leptin and food intake. Bray and York,128 in a paper with the title The Mona Lisa hypothesis…’ (Most obesities known are Low in sympathetic activity) indicate that obesity is associated with low SNS activity. If leptin is high in obese persons (in connection with a high fat mass), it also appears that there may be leptin resistance, and hence NPY is not suppressed and its activation continues to promote hyperphagia. In cancer cachexia, where presumably there is activation of the HPA axis and the SNS (see below), the high SNS tone has been thought to reduce leptin synthesis.129 The status of NPY in this situation seems unclear, since, ordinarily, low leptin levels would activate NPY, as noted, yet hypophagia is the rule.130 There are likely to be many other factors influencing the leptin-hypothalamus system in cancer cachexia. If indeed there are low leptin levels in cancer cachexia, an important question is why hypothalamic NPY is not stimulated to increase appetite. The NPY receptor mechanism may be impaired in tumor-bearing animals. Hypothalamic NPY production was lower in cachectic sarcoma-bearing rats than in non-tumor-bearing controls whose food intake was restricted to the same degree,

Comprehensive Geriatric Oncology

432

Figure 20.1 Summary of adiposity and satiety signals that regulate appetite through central nervous system effectors. In a state of increasing adiposity, higher levels of insulin (secreted from the endocrine pancreas in proportion to fat mass) and leptin (from adipocytes) constitute adiposity signals that turn on the catabolic effector systems, reduce appetite, increase energy expenditure, and turn off the anabolic systems. The converse occurs in a state of diminishing adiposity: the levels of the signals fall, the anabolic pathways are turned on,

Frailty, cancer cachexia, and near death

433

appetite increases, energy expenditure diminishes, and the catabolic systems are turned off. The hypothalamus is the major site for these systems. Satiety signals arise from food in the gastrointestinal tract by way of CCK and GLP, which convey messages to the nucleus of the solitary tract. Abbreviations: AgRP, agouti-related protein; CART, cocaine-and amphetamine-regulated transcript; CCK, cholecystokinin; GLP, glucagon-like peptide; MC, melanocortin; MCH, melanin concentrating hormone; α-MSH, αmelanocyte-stimulating hormone; NPY, neuropeptide Y; ORX, orexin; POMC, proopiomelanocortin-derived peptide. Adapted from Woods and Seeley.113 consistent with inappropriate NPY suppression.131 In models of tumor-bearing animals, cytokines such as IL-1 and CNTF may mimic leptin action by inhibiting and producing a dysregulation of NPY.19,132,133 NPY may also be inhibited by chronic CRH stimulation134 due to activation of chronic stress pathways124 (see below), and thus food intake may be suppressed and weight loss progress. Yet this is not necessarily in accord with mice, where NPY production is genetically inactivated. Although the relevance to humans of animal models of ‘life without NPY’135 may not be valid, these mice with deletion of the genes for NPY are remarkably normal with respect to appetite and weight; lack of appetite is not observed, although their NPY deficiency does partially ameliorate the hyperphagia and obesity of leptin deficiency.135 Leptin and insulin acting as obesity signals also affect pathways other than NPY in the hypothalamus that influence appetite and energy homeostasis, as shown in Figure 20.1.113,136 Neuropeptides inhibited by leptin are called orexigenic (appetite-enhancing), and include, besides NPY, orexin (ORX), agouti-related protein (AgRP), and melaninconcentrating hormone (MCH). Neuropeptides stimulated by leptin that are anorexigenic are the melanocortins, such as α-melanocyte-stimulating hormone (α-MSH) arising from cleavage of pro-opiomelanocortin-derived peptide (POMC), cocaine- and amphetamineregulated transcript (CART), and CRH. To paraphrase Flier and Maratos-Flier,125 one can envision a loop in which rising leptin (with obesity) drives increased POMC expression, which then projects α-MSH signals to melanocortin receptors (MC-3 and MC-4), inducing decreased food intake. Is this circuit overexpressed for some reasons in cancer

Comprehensive Geriatric Oncology

434

cachexia? The answer is not yet known. It is of interest that many of the conditions that seem to occur in patients with cancer cachexia are observed in mice with a targeted deletion of the MCH gene; these mice have an inappropriately increased metabolic rate; despite reduced leptin levels, NPY is not elevated, and they are hypophagic and lean.137 Thus MCH may be necessary for the hyperphagic response to leptin deficiency; perhaps MCH modification is the result of one or more cytokines overexpressed in cancer cachexia. There are many excellent recent reviews and diagrams of the complex ‘circuitry’ regulating appetite and energy homeostasis to produce a stable state of body weight or the extremes of obesity or emaciation.19,47,112,113,124,125,134,138–143 A greater understanding of the biologic basis of appetite control has been forthcoming in connection with obesity research; perhaps there will also emerge a greater understanding of the hypothalamic neuropeptides and their control by leptin and insulin relevant to the anorexia of cancer cachexia. Equally important, from such insight, new therapeutic approaches may result in clinical applications (see below). There are other implications with respect to apparently undetectable leptin levels in cachectic patients with cancer. In the obese (ob/ob) mouse, a functionally impaired leptin is associated with endotoxin-induced liver injury and lethality,144 perhaps due to endotoxin leaking out of the affected gastrointestinal mucosa. Endotoxin is a highly specific stimulus to hypothalamic-hypophyseal activity, and enhances neuronal cytokine production in the brain with a rise in peripheral levels of IL-6 and TNF-α.145 Leptin insufficiency in starvation, in cancer cachexia, or in the ob/ob mouse impairs CD4+ helper T cells75,146 and macrophage phagocyte functions.123,144,146 In the leptin-deficient ob/ob mouse, wound healing is severely impaired, and is improved by leptin administration.147 Thus, immunodeficiency and immunosuppression in the cachectic state, apparently associated with high serum lipids and low or absent leptin levels, could have profound implications by virtue of impaired host resistance to infection, diminished capacity for tumor suppression, limited wound healing, and poor responses to antineoplastic therapies. The leptin signal involving appetite control is said to be ‘tonic’ because it translates the extent of adipose tissue mass periodically via a humoral route to the hypothalamus. Another mediator of appetite is serotonin (5-hydroxytryptamine), which seems more responsive to factors such as cholecystokinin (CCK) and glucagon-like peptide (GLP), associated with the process of eating itself and gastric distention. These factors transmit satiety signals via neuronal pathways to the nucleus of the solitary tract in the central nervous system113,124,134 (Figure 20.1). NPY and serotonin within the hypothalamus appear to have an antagonistic relationship, with high levels of one inhibiting the other. In this sense, administration of a serontonin antagonist (cyproheptadine)148 with activation of NPY synthesis might have a place in cachexia therapy to stimulate appetite, since there is evidence that cytokines such as IL-1 increase serotonin in the hypothalamus.149 Hypothalamic-pituitary-adrenal axis The HPA axis and the SNS consist, respectively, of the CRH and arginine-vasopressin (AVP) neurons of the paraventricular nuclei of the hypothalamus, and the noradrenergic neurons of the locus ceruleus/norepinephrine nuclei of the brain stem. Diagrams of these connections in the central nervous system are displayed in references 150–152.

Frailty, cancer cachexia, and near death

435

Figure 20.2 attempts to portray the complex interactions contributing to cancer cachexia. Stress and cytokine activation of CRH release145,153 leads in turn to stimulation

Figure 20.2 Complex responses of the host to the tumor contributing to anorexia, weight loss, and cachexia. This figure presents a composite of the overall host-tumor interactions that contribute to cancer cachexia. Some factors that influence the host’s response at the outset to the tumor’s presence are shown at the top left, and include the host’s age, genetics, immune state, BMI, and site and type of tumor. The immune and inflammatory responses of the host to the cancer activate cytokines, which set in motion a catabolic metabolic state—with losses of fat, muscle (sarcopenia), and bone (osteopenia), and the appearance of wasting. Stress responses—especially cytokines— activate the HPA axis, reflected in high CRH, acting in synergy with AVP on

Comprehensive Geriatric Oncology

436

the pituitary to stimulate ACTH release and high adrenal glucocorticoid output. Glucocorticoids enhance bone and muscle loss, and are immunosuppressive. Elevated CRH inhibits NPY and promotes melanocortins from POMC, all contributing to anorexia despite apparent low leptin levels. There are several areas where apparent dysregulation leads to impairment of expected feedback functions: for example, glucocorticoids should enhance leptin, inhibit CRH and melanocortin, suppress cytokines, and stimulate NPY; loss of fat stores with low leptin and low serotonin should activate NPY and reduce POMC expression, thereby enhancing food intake. Abbreviations: ACTH, adrenocorticotropic hormone; APP, acute-phase proteins; AVP, arginine vasopressin; BMI, body mass index; CRH, corticotropin-releasing hormone; HPA, hypothalamic-pituitary-adrenal; IFN-γ, interferon-γ; IL, interleukin; NPY, neuropeptide Y; POMC, proopiomelanocortin; SNS, sympathetic nervous system; TNF-α, tumor necrosis factor α; ↑, high; ↓, low. of the pituitary and the adrenal, thus elevating circulating glucocorticoids. Low levels of leptin may also be a factor in high glucocorticoid output.154 AVP acts synergistically with CRH to promote the release of pituitary adrenocorticotropic hormone (ACTH) and hypothalamic POMC-derived peptide.152 POMC is a precursor of the melanocortins, which exert a marked anorexigenic effect, as noted.154 Endocrine associations of stress activation are dominated by tipping the balance to catabolic and proinflammatory events, including pituitary-derived prolactin, which stimulates cytokine expression, T-cell proliferation, reactive oxygen species, prostaglandins, and nitric oxide.151 Yet there are also counter, suppressive immune and inflammatory components released from

Frailty, cancer cachexia, and near death

437

inflammatory sites (e.g. in the tumor), including IL-1 receptor antagonist, other antiinflammatory cytokines (e.g. IL-4 and IL-10),13 somatostatin, and α-MSH, which normally inhibits the release of hypothalamic CRH or downregulates proinflammatory cytokines such as IFN-γ.151 With the progression of the cachexia, it is reasonable to surmise that the proinflammatory forces overwhelm the anti-inflammatory ones. There may be a ‘double-edged’ sword here in relation to glucocorticoid actions in cancer cachexia. On one side, many of the steroidal effects that would promote more beneficial homeostasis seem to be impaired—effects such as appetite enhancement by virtue of stimulating NPY and inhibiting CRH and melanocortins. Instead, NPY seems to be inhibited150 and CRH and SNS stimulated,128 resulting in anorexia. Impaired affinity of glucocorticoid receptors in the CRH neurons limiting feedback inhibition152 may occur in cancer cachexia. Additional presumed beneficial effects of elevated glucocorticoids would be suppression of inflammatory mediators,155 including cytokines—especially TNF-a and IL-1 (more than IL-6156)—and NF-κB.71 Yet, on the other side of the doubleedged sword, the deleterious effects of elevated glucocorticoids in cancer cachexia appear to enhance the activity of proinflammatory cytokines, impair immunity,156 promote hyperglycemia and insulin resistance, depress a number of hormonal systems— including growth hormone, IGF, and the reproductive system84,154,157—and induce bone mineral loss and osteopenia.99 These dual aspects (beneficial and deleterious) of enhanced glucocorticoid levels and HPA axis activation in response to stress and cytokines (Figure 20.2) go to the heart of the catabolic expressions in cancer cachexia: failure of NPY response that normally should stimulate appetite, increased SNS activity, heightened thermogenesis, enhanced lipolysis, and elevated blood glucose all seem to perpetuate anorexia and weight loss.158 The basis for these apparently aberrant hypothalamic responses to the wasting state in cancer cachexia remains the central issue for experimental clarification. Until then, therapy to counter this condition must rest on a poorly defined foundation. Therapeutic approaches to cancer cachexia Overview Clues to devising therapy for cancer cachexia may arise from observing events on the ‘road back’ towards premorbid nutritional status when the cancer is therapeutically suppressed or apparently eradicated. As Barber et al12 have stated, ‘the best way to treat cancer cachexia is to cure the cancer’. It would be of interest to observe this process of improvement in terms of changes over time in BMI, hormonal and hypothalamic factors, serum levels of cytokines, etc., to determine in what way the conditions discussed above appeared to reverse. The cachectic state is related to cancer inception and the underlying factors in the host responses, as noted in Figure 20.2. Perhaps the most encouraging signs of improvement would be hyperphagia and weight gain—hallmarks of remission. Means to enhance appetite and food intake in anorectic cancer patients are limited, yet inducing temporary weight gain may result in ‘improvement in the quality of life, thus positively affecting psychological status…’ to better withstand the ‘detrimental effects of aggressive antineoplastic regimens’.149 The problem, however, is that patients manifesting cachexia

Comprehensive Geriatric Oncology

438

may already be in an essentially non-reversible state. If this is so, then current therapies that have been tried to limit or reverse cachexia may be largely palliative and supportive, and it is not yet clear whether expectations can be otherwise. In this respect, it is of interest that an article by Michael Specter in the February 5, 2001 issue of The New Yorker entitled The outlaw doctor’ presents what might be called an ‘unorthodox’ approach used by Nicholas Gonzales, MD. He prescribes massive enzyme-dietary supplements and other means to bring about what he describes as ‘many—not all by any means—of my patients are alive when they should be dead’. This group of patients includes particularly those with advanced pancreatic cancer. While these results await further controlled study, the issue for oncologists is whether there are new ways to address cancer cachexia therapeutically based on emerging knowledge presented in this chapter, and the literature, especially affecting the metabolic-humoral pathways. Even though the cancer would not be eradicated, quality time may be secured, and new insights gained into pathogenesis. Current therapies A list of therapies for treating the general state of cachexia, as described by Kotler,3 includes all those that have also been tried for cancer cachexia.148,159 Some approaches and their presumed therapeutic purposes are noted below and in Table 20.4. However, this list is intended only as a

Table 20.4 A partial list of approaches to treatment of cancer cachexia Category

Refs

Example

Appetite stimulants

4, 11, 21

Progestational agents

148, 161

Anti-serotonergic agents Marijuana derivatives β2-adrenoceptor agonists Metoclopramide

Enteral/parenteral nutrition

10, 12, 68,

Amino acids

91, 149,

Polyunsaturated fatty acids

163, 165

Formulas Branched-chain amino acids

Cytokine inhibitors

13, 87, 107, 148

Pentoxifylline Thalidomide Melatonin Antibodies

Anabolic steroids*

a

a

a

a

29, 38, 166, 176, 178

a

Dehydroepiandrosterone

Frailty, cancer cachexia, and near death

439

Testosterone Androstenedione Oxandrolone Growth factors

12, 38,a 179a

Growth hormone Insulin-like growth factor I

a

These references are for non-neoplastic but wasting-related conditions.

summary, and an appraisal of effectiveness is beyond the scope of this chapter.159,160 1. Enhancing appetite and use of dietary supplements—for which the progestational compounds megestrol acetate (also used in a clinical trial in ‘geriatric cachexia’161) and medroxyprogesterone acetate seem to be the most widely accepted; also included are marijuana derivatives (e.g. dronabinol), the α2-adrenoceptor agonist Clenbuterol, which theoretically might inhibit leptin, and cyproheptadine (Periactin), which is antiserotonergic—both of which might elevate NPY, metoclopramide to diminish delayed gastric emptying associated with circulating cytokines,162 eicosapentaenoic acid (a polyunsaturated fatty acid) to limit muscle breakdown68,163 and enhance immunity,164 and branched-chain amino acids to lower tryptophan and thus serotonin.149 2. Nutritional supplementation—by enteral or parenteral means.91,165 3. Presumed cytokine inhibitors—such as thalidomide, pentoxifylline, and melatonin.13,107 4. Non-steroidal anti-inflammatory drugs (NSAIDs). 5. Androgenic and anti-inflammatory steroids—such as dehydroepiandrosterone (DHEA),165 androstenedione, and testosterone, also used in the sarcopenia of aging,29,38 and to improve insulin sensitivity and bone mineral density.166 6. Corticosteroids. 7. Growth factors—such as growth hormone and insulin-like growth factor I (IGF-I). The actions attributed to the various agents listed above and shown in Table 20.4 are obviously much more complex when these agents are administered in pharmacologic doses to a patient with cancer cachexia. Since none of these agents has cancer-eradicating properties, their broader effects may be on replenishing low levels of anabolic hormones (e.g. with growth hormone or IGF-I), modulating the immune and cytokine balances (e.g. with DHEA in particular, which can repress the IL-6 gene promoter via inhibition of NFκB),76 or using progestational agents, which may inhibit cortisol levels4 (but may increase proinflammatory cytokines98). Testosterone167,168 and adrenergic agents129 decrease leptin levels and may stimulate NPY, as may the antiserotonergic agents. Prospects for new therapies However, uncertainty about the apparent low leptin levels and the state of responsiveness of NPY in patients with cancer cachexia, discussed above, means that therapeutic approaches that might affect this system need more study. Indeed, in these older individuals, there is said to already exist a state of leptin resistance169 that in turn may

Comprehensive Geriatric Oncology

440

lead to deleterious metabolic consequences. These include a shift in unoxidized longchain fatty acids from adipose tissue to other critical cellular sites, with resulting organ dysfunctions. The affected tissues include the β cells of the pancreas, with insulin resistance and hyperglycemia, and myocytes in skeletal and cardiac muscle, with sarcopenia and cardiac failure, respectively.169 A possible new therapeutic option in these patients might be the use of agents with antilipogenic, antidiabetogenic properties, i.e. the thiazolidinediones. These drugs counter the above-noted metabolic trends and inhibit the hormone resistin, arising from adipocytes, which impairs glucose tolerance and insulin action.170 With the remarkable advances in our understanding of the neuroendocrine controls of appetite, as discussed above, pharmacologic or genetic therapies may put appetite stimulation in a sort of overdrive for patients with cancer cachexia. The incentive to improve appetite is a goal linked to enhancing quality of life as well, as noted above; while megestrol may improve appetite to some extent, it seems to have little effect on quality of life.171 Newer approaches might be to enhance orexigenic agents125 (e.g. NPY or AgRP) or conversely to inhibit melanocortin-derived anorexigenic agents, for example with the use of antagonists to α-MSH or inhibition of the melanocortin receptors MC-3 or MC-4 by a peptide fragment of AgRP.124 (Human models in this regard are severely obese subjects with hyperphagia who have a mutation in the gene encoding the MC-4 receptors.172) Perhaps these approaches to therapy would also diminish the stressactivated release of CRH, reducing anorexia, as well as slowing the tempo of catabolic processes. β-adrenergic blockade of selective β1 adrenoreceptors (atenolol) and non-specific β1 and β2 blockade (with propranolol), have been tried in weight-losing patients with cancer in an effort to reduce cardiovascular work, peripheral tissue lipolysis, and resting energy expenditure, which was found to be elevated in these patients.173 Again, this is the converse of anti-obesity therapies, where the goal is to increase energy dissipation—in cancer cachexia, the goal is to decrease energy expenditure to improve ‘adaptive thermogenesis’, or the regulated production of heat.9 A β3-receptor antagonist might act on adipocytes and muscle cells to inhibit mitochondrial uncoupling proteins that enhance thermogenesis174 and thereby reduce energy expenditure and muscle wasting—the opposite of therapeutic goals in obesity treatment, where β3 agonists appear to increase thermogenesis by activating uncoupling proteins.9,47,175 A final consideration relates to what may be called adjunctive treatment for cancer cachexia—not medications, but crucial social and psychological supports, and exercise regimens. The prototype for this kind of exercise is progressive resistance training to stabilize or strengthen muscle mass. In fact, in patients with AIDS-related wasting, this exercise regimen increased lean body mass and muscle area independent of testosterone administration, and had a cardioprotective effect as well. However, the patients in that study had lost weight but were not cachectic or malnourished.176 The capability and motivation for patients with cancer cachexia to enter into an exercise program need to explored by the health provider and family; reluctance to do so is much more understandable than the inactive state of the majority of overweight adult men and women in the USA where the need for exercise has become a public health priority.177

Frailty, cancer cachexia, and near death

441

Acknowledgements The author is grateful to Stephen C Woods, Department of Psychiatry, University of Cincinnati Medical Center, Ohio for advice concerning Figure 20.1, and to Dawn BowenJenkins for expert assistance in the preparation of the manuscript. A brief version of this chapter, describing molecular-based therapeutic approaches to cancer cachexia, appeared in J Gerontol: Med Sci 2002; 57A:M511–18. References 1. Hamerman D. Toward an understanding of frailty. Ann Intern Med 1999; 130:945–50. 2. Wagner EH. Preventing decline in function: evidence from randomized trails around the world. West J Med 1997; 167:295–8. 3. Kotler DP. Cachexia. Ann Intern Med 2000; 133:622–34. 4. Goldberg RM, Loprinzi CL. Cancer anorexia/cachexia. In: Palliative Care and Rehabilitation of Cancer Patients (von Gunten CF, ed). Boston: Kluwer, 1999:31–41. 5. Yeh SS, Schuster MW. Geriatric cachexia: the role of cytokines. Am J Clin Nutr 1999; 70:183– 97. 6. De Blauuw I, Deutz NEP, Von Meyenfeldt MF. Metabolic changes in cancer cachexia. Clin Nutr 1997; 16:169–76, 223–8. 7. Langstein HN, Norton JA. Mechanisms of cancer cachexia. Hematol Oncol Clin North Am 1991; 5:103–23. 8. Tisdale MJ. Biology of cachexia. J Natl Cancerlnst 1997; 89:1763–73. 9. Lowell BB, Spiegelman BM. Towards a molecular understanding of adaptive thermogenesis. Nature 2000; 404:652. 10. Pironi L, Ruggeri E, Mecchia F. Nutrition and elderly cancer patients. In: Handbook of Nutrition in the Aged, 3rd edn. Boca Raton, FL: CRC Press, 2001:49–66. 11. Puccio M, Nathanson L. The cancer cachexia syndrome. Semin Oncol 1997; 24:277–87. 12. Barber MD, Ross JA, Voss AC et al. The effect of an oral nutritional supplement enriched with fish oil in weight-loss in patients with pancreatic cancer. Br J Cancer 1999; 81:80–6. 13. Argiles JM, López-Soriano FJ. The role of cytokines in cancer cachexia. Med Res Rev 1999; 19:223–48. 14. Nelson KA, Walsh D, Sheehan FA. The cancer anorexia-cachexia syndrome. J Clin Oncol 1994; 12:213–25. 15. Sontag S. Illness as a Metaphor and AIDS and its Metaphors. New York: Doubleday, 1989:68. 16. Little M, Sayers EJ, Paul K et al. On surviving cancer. J R Soc Med 2000; 93:501–3. 17. McClement SE, Woodgate RL. Care of the terminally ill cachectic cancer patient: interface between nursing and psychological anthropology. Eur J Cancer Care 1997; 6:295–303. 18. Heber D. Cancer and malnutrition. In: Geriatric Nutrition (Morley JE, Glick Z, Rubenstein LZ, eds). New York: Raven, 1990:307–13. 19. Inui A. Cancer anorexia-cachexia syndrome: Are neuropeptides the key? Cancer Res 1999; 59:4493–501. 20. Kern KA, Norton JA. Cancer cachexia. J Parent Ent Nutr 1998; 12: 286–98. 21. Vadell C, Segui MA, Giménez-Arnau JM et al. Anticachectic efficacy of megestrol acetate at different doses and versus placebo in patients with neoplastic cachexia. Am J Clin Oncol 1998; 21:347–51. 22. Koch J. The role of body composition measurements in wasting syndromes. Semin Oncol 1998; 25:12–19.

Comprehensive Geriatric Oncology

442

23. Grunfeld C, Feingold KR. Metabolic disturbances and wasting in the acquired immunodeficiency syndrome. N Engl J Med 1992; 327: 329–36. 24. Bunn PA Jr. Cancer and acquired immunodeficiency syndrome wasting syndromes: current and future therapies. Semin Oncol 1998; 25:1–3. 25. Seligman PA, Fink R, Massey-Seligman EJ. Approach to the seriously ill or terminal cancer patient who has a poor appetite. Semin Oncol 1998; 25:33–4. 26. Larkin M. Thwarting the dwindling progression of cachexia. Lancet 1998; 351:1336. 27. Colman RJ, Roecker EB, Ramsey JJ et al. The effect of dietary restriction on body composition in adult male and female rheusus macaques. Aging Clin Exp Res 1998; 10:83–92. 28. Gariballa SE, Sinclair AJ. Nutrition, ageing and ill health. Br J Nutr 1998; 80:7–23. 29. Bross R, Javanbakht M, Bhasin S. Anabolic interventions for aging-associated sarcopenia. J Clin Endocrinol Metab, 1999; 84:3420–30. 30. Ley CJ, Lees B, Stevenson JC. Sex- and menopause-associated changes in body-fat distribution. Am J Clin Nutr 1992; 55:950–4. 31. Bonora E. Relationship between regional fat distribution and insulin resistance. Int J Obesity, 2000; 24:S32–5. 32. Whitehead C, Finucane P. Malnutrition in elderly people. Aust NZ J Med 1997; 27:68–74. 33. Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest 2000; 106:473–81. 34. Grundy SM. Metabolic consequences of obesity. Endocrine 2000; 13: 153–65. 35. Dey DK, Steen B. Overweight and obesity in the aged. In: Handbook of Nutrition in the Aged, 3rd edn. Boca Raton, FL: CRC Press, 2001: 179–90. 36. Rosenberg IH, Miller JW. Nutritional factors in physical and cognitive functions of elderly people. Am J Clin Nutr 1992; 55:1237S-43S. 37. Melton LJ, III, Khosla S, Crowson CS et al. Epidemiology of sarcopenia. J Am Geriatr Soc 2000; 48:625–30. 38. Short KR, Nair KS. Mechanisms of sarcopenia of aging. J Endocrinol Invest 1999; 22:95–105. 39. Russell RM. The aging process as a modifier of metabolism. Atn J Clin Nutr 2000; 72:529S32S. 40. Kado DM, Browner WS, Blackwell T et al. Rate of bone loss is associated with mortality in older women: a prospective study. J Bone Miner Res 2000; 15:1974–80. 41. Chumlea WC, Guo SS. Assessment and prevalence of obesity. Application of new methods to a major problem. Endocrine 2000; 13:135–42. 42. Hubbard VS. Defming overweight and obesity: What are the issues? Am J Clin Nutr 2000; 72:1067–8. 43. Kopelman PG. Obesity as a medical problem. Nature 2000; 404:635. 44. Bray GA, Ryan DH. Clinical evaluation of the overweight patient. Endocrine, 2000; 13:167– 86. 45. Flegel KM, Carrol MD, Kuczmarski RJ et al. Overweight and obesity in the United States: prevalence and trends, 1960–1994. Int J Obes Rehab Metab Disord 1998; 22:39–47. 46. Li H, Matheny M, Nicolson M et al. Leptin gene expression increases with age independent of increasing adiposity in rats. Diabetes 1997; 46:2035–9. 47. Van der Ploeg LHT. Obesity: an epidemic in need of therapeutics. Curr Opin Chem Biol 2000; 4:452–60. 48. Erlinger TP, Pollack H, Appel LJ. Nutrition-related cardiovascular risk factors in older people: results from the Third National Health and Nutrition Examination Survey. J Am Geriatr Soc 2000; 48: 1486–9. 49. Friedman JM. Obesity in the new millennium. Nature 2000; 404: 632–4. 50. Bray GA, Tartaglia LA. Medicinal strategies in the treatment of obesity. Nature 2000; 404:672. 51. Weinsier RL, Hunter GR, Heini AF et al. The etiology of obesity: relative contribution of metabolic factors, diet, and physical activity. Am J Med 1998; 105:145–50. 52. Barsh GS, Farooqi IS, O’Rahilly S. Genetics of body-weight regulation. Nature 2000; 404:644.

Frailty, cancer cachexia, and near death

443

53. Bessesen DH, Faggioni R. Recently identified peptides involved in the regulation of body weight. Semin Oncol 1998; 25:28–32. 54. Motulsky AG. Nutrition and genetic susceptibility to common diseases. Am J Clin Nutr 1992; 55:1244S-5S. 55. Morley JE, Mooradian AD, Silver AJ. Nutrition in the elderly. Ann Intern Med 1988; 109:890– 904. 56. Lee CK, Klopp RG, Weindmch R et al. Gene expression profile of aging and its retardation by caloric restriction. Science 1999; 285: 1390–3. 57. Roth GS, Ingram DK, Lane MA. Caloric restriction in primates: Will it work and how will we know? J Am Geriatr Soc 1999; 47:896–903. 58. Weindruch R, Albanes D, Kritchevsky D. The role of calories and caloric restriction in carcinogenesis. Hematol Oncol Clin North Am 1991; 5:79–89. 59. Winick M. Calories and cancer. Hematol Oncol Clin North Am 1991; 5:1–6. 60. Lee MM, Lin SS. Dietary fat and breast cancer. Annu Rev Nutr 2000; 20:221–48. 61. Vellas BJ, Albarede J-L, Garry PJ. Diseases and aging: patterns of morbidity with age; relationship between aging and age-associated diseases. Am J Clin Nutr 1992; 55:1225S–30S. 62. Rubenstein LZ. An overview of aging-demographics, epidemiology, and health services. In: Geriatric Nutrition (Morley JE, Glick Z, Rubenstein LZ, eds). New York: Raven, 1990:1–10. 63. Reuben DB, Ferrucci L, Wallace R et al. The prognostic value of serum albumin in healthy older persons with low and high serum interleukin-6 (IL-6) levels. J Am Geriatr Soc 2000; 48:1404–7. 64. Callahan CM, Stump TE, Stoupe KT et al. Cost of health care for a community of older adults in an urban academic health care system. J Am Geriatr Soc 1998; 46:1371–7. 65. Maclntosh C, Morley JE, Chapman IM. The anorexia of aging. Nutrition 2000; 16:983–95. 66. Morley JE, Perry HM, III, Baumgartner RP et al. Commentary: Leptin, adipose tissue and aging—Is there a role for testosterone? J Gerontol Biol Sci 1999; 54A:B108–9. 67. Simons JPFHA, Schols AMWJ, Campfield LA et al. Plasma concentration of total leptin and human lung-cancer associated cachexia. Clin Sci 1997; 93:273–7. 68. Tisdale MJ. Protein loss in cancer cachexia. Science 2000; 289: 2293–4. 69. Guttridge DC, Mayo MW, Madrid LV et al. NF-K-B-induced loss of myoD messenger RNA: possible role in muscle decay and cachexia. Science 2000; 289:2363–5. 70. Hofbauer LC, Heufelder AE. The role of receptor activator of nuclear factor-κB ligand and osteoprotegerin in the pathogenesis and treatment of metabolic bone diseases. J Clin Endocrinol Metab 2000; 85:2355–63. 71. Baldwin AS Jr. The transcription factor NF-κB and human disease. J Clin Invest 2001; 107:3– 6. 72. Slifka MK, Whitton JL. Clinical implications of dysregulated cytokine production. J Mol Med 2000; 78:74–80. 73. Bjorntorp P, Rosmond R. Obesity and cortisol. Nutrition 2000; 16: 924–36. 74. Blum WF, Englaro P, Attanasio AM et al. Human and clinical perspectives on leptin. Proc Nutr Soc 1998; 57:477–85. 75. Harris RBS. Leptin—much more than a satiety signal. Annu Rev Nutr 2000; 20:45–75. 76. Cutolo M, Sulli A, Villaggio B et al. Relations between steroid hormones and cytokines in rheumatoid arthritis and systemic lupus erythematosus. Ann Rheum Dis 1998; 57:573–7. 77. Coulie PG, Van den Eynde BJ, van der Brugen, P. Antigens recognized by T-lymphocytes on human tumors. Biochem Soc Trans 1997; 25:544–8. 78. Young A, Kerr DJ. Genetic and immunological therapy for cancer. J R Soc Med 2000; 93:10– 14. 79. Noble A. Molecular signals and genetic reprogramming in peripheral T-cell differentiation. Immunology 2000; 101:289–99. 80. Krenger W, Hill GR, Ferrara JLM. Cytokine cascades in acute graft-versus-host disease. Transplantation 1997; 64:553–8.

Comprehensive Geriatric Oncology

444

81. Oliff A, Defeo-Jones D, Boyer M et al. Tumors secreting human TNF/cachectin induce cachexia in mice. Cell 1987; 50:555–63. 82. Beutler B, Cerami A. Cachectin and tumor necrosis factor as two sides of the same biological coin. Nature 1986; 320:584–8. 83. Zechner R, Strauss J, Frank S et al. The role of lipoprotein lipase in adipose tissue development and metabolism. Int J Obesity 2000; 24(Suppl 2): S53–6. 84. DePergola G. The adipose tissue metabolism: role of testosterone and dehydroepiandrosterone. Int J Obesity 2000; 24(Suppl 2): S59–63. 85. Hotamisligil GS. Molecular mechanisms of insulin resistance and the role of the adipocyte. Int J Obesity 2000; 24(Suppl 2): S23–7. 86. Akira S, Hirano T, Taga T et al. Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF). FASEB J 1990; 4:2860–7. 87. Moldawer LL, Copeland EM II. Proinflammatory cytokines, nutritional support, and the cachexia syndrome. Cancer 1997; 79: 1828–39. 88. Spector TD, Hart DJ, Nandra D et al. Low-level increases in serum C-reactive protein are present in early osteoarthritis of the knee and predict progressive disease. Arthritis Rheum 1997; 40:723–7. 89. Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation 1998; 97:2007–11. 90. Tracy RP, Lemaitre RN, Psaty BM et al. Relationship of C-reactive protein to risk of cardiovascular disease in the elderly. Arterioscler Thromb Vasc Biol 1997; 17:1121–7. 91. Chen MK, Souba WW, Copeland EM. Nutritional support of the surgical oncology patient. Hematol Oncol Clin North Am 1991; 5: 125–45. 92. Ershler WB. Interleukin-6: a cytokine for gerontologists. J Am Geriatr Soc 1993; 41:176–81. 93. Papanicolaou DA, Vgontzas AN. Editorial: Interleukin-6: the endocrine cytokine. J Clin Endocrinol Metab 2000; 85:1331–3. 94. Heymann D, Rousselle A-V. gp130 cytokine family and bone cells. Cytokine 2000; 12:1455– 68. 95. O’Brien CA, Lin S-C, Bellido T et al. Expression levels of gp130 in bone marrow stromal cells determine the magnitude of osteoclastogenic signals generated by IL-6-type cytokines. J Cell Biochem 2000; 79:532–41. 96. Straub RH, Hense HW, Andus T et al. Hormone replacement therapy and interrelation between serum interleukin-6 and body mass index in postmenopausal women: a population-based study. J Clin Endocrinol Metab 2000; 85:1340–4. 97. Chrousos GP, Gold PW. Editorial: A healthy body in a healthy mind—and vice versa—The damaging power of uncontrollable stress. J Clin Endocrinol Metab, 1998; 83:1842–5. 98. Abrahamsen B, Bonnevie-Nielsen V, Ebbesen EN et al. Cytokines and bone loss in a 5-year longitudinal study—Hormone replacement therapy suppresses serum soluble interleukin-6 receptor and increases interleukin-1-receptor antagonist: the Danish Osteoporosis Prevention Study. J Bone Miner Res, 2000; 15:1545–54. 99. Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 2000; 21:115–37. 100. Fernández-Real J-M, Broch M, Vendrell J et al. Interleukin-6 gene polymorphism and lipid abnormalities in healthy subjects. J Clin Endocrinol Metab 2000; 85:1334–9. 101. Ershler WB, Keller ET. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med 2000; 51: 245–70. 102. Cohen HJ, Pieper CF, Harris T et al. The association of plasma IL-6 levels with functional disability in community-dwelling elderly. J Gerontol Med Sci 1997; 52A:M201–8. 103. Dentino AN, Pieper CF, Rao KMK et al. Association of interleukin-6 and other biologic variables with depression in older people living in the community. J Am Geriatr Soc 1999; 47:6–11.

Frailty, cancer cachexia, and near death

445

104. Harris TB, Ferrucci L, Tracy RP et al. Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med 1999; 106:506–12. 105. Rink L, Cakman I, Kirchner H. Altered cytokine production in the elderly. Mech Aging Dev 1998; 102:199–209. 106. Fahey JL, Schnelle JF, Boscardin J et al. Distinct categories of immunologic changes in frail elderly. Mech Aging Dev 2000; 115: 1–20. 107. Eigler A, Sinha B, Hartmann G et al. Taming TNF: strategies to restrain this proinflammatory cytokine. Immunol Today 1997; 18: 487. 108. Noguchi Y, Yoshikawa T, Matsumoto A et al. Are cytokines possible mediators of cancer cachexia? Surg Today 1996; 26:467–75. 109. Iwagaki H, Hizuta A, Uomoto M et al. Cancer cachexia and depressive states: a neuroendocrine-immunological disease? Acta Med Okayama 1997; 51:233–6. 110. Fox DA. Cytokine blockade as a new strategy to treat rheumatoid arthritis. Inhibition of tumor necrosis factor. Arch Intern Med 2000; 160:437–44. 111. Vincenti F, Kirkman R, Light S et al. Interleukin-2-receptor block-age with daclizumab to prevent acute rejection in renal transplantation. N Engl J Med 1998; 338:161–5. 112. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998; 395:763–70. 113. Woods SC, Seeley RJ. Adiposity signals and the control of energy homeostasis. Nutrition 2000; 16:894–902. 114. Baile CA, Della-Fera MA. Regulation of metabolism and body fat mass by leptin. Annu Rev Nutr 2000; 20:105–27. 115. Ahren B, Larsson H, Wilhelmsson C et al. Regulation of circulating leptin in humans. Endocrine 1997; 7:1–8. 116. Ahima RS, Flier JS. Leptin. Annu Rev Physiol 2000; 62:413–37. 117. Armellini F, Zamboni M, Bosello O. Hormones and bone composition in humans: clinical studies. Int J Obesity 2000; 24:S18-S21. 118. Coppack SW, Pinkney JH, Mohamed-Ali V. Leptin production in human adipose tissue. Proc Nutr Soc 1998; 57:461–70. 119. Trayhurn P, Hoggard N, Mercer JG et al. Leptin: fundamental aspects. Int J Obesity 1999; 23:22–8. 120. Frederich RC, Hamann A, Anderson S et al. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med 1995; 1:1311–14. 121. Caro JF, Sinha MK, Kolaczynski JW et al. Leptin: the tale of an obesity gene. Diabetes 1996; 45:1455–62. 122. North MA. Advances in the molecular genetics of obesity. Curr Opin Genet Dev 1999; 9:283– 8. 123. Fantuzzi G, Faggioni R. Leptin in the regulation of immunity, inflammation, and hematopoiesis. J Leukoc Biol 2000; 68:437–46. 124. Schwartz MW, Woods SC, Porte D Jr et al. Central nervous system control of food intake. Nature 2000; 404:661–71. 125. Flier JS, Maratos-Flier E. Obesity and the hypothalamus: novel peptides for new pathways. Cell 1998; 92:437–40. 126. Flier JS. Discussion in ‘Weindruch R, Sohal RS. Caloric intake and aging’. N Engl J Med 1997; 337:993. 127. Barzilai N, Gupta G. Revisiting the role of fat mass in the life extension induced by caloric restriction. J Gerontol Biol Sci 1999; 54A: B89–96. 128. Bray GA, York DA. The Mona Lisa hypothesis in the time of leptin. Rec Prog Hormone Res 1998; 53:95–118. 129. Trayhurn P, Duncan JS, Hoggard N et al. Regulation of leptin production: a dominant role for the sympathetic nervous system? Proc Nutr Soc 1998; 57:413–19.

Comprehensive Geriatric Oncology

446

130. Chance WT, Balasubramaniam A, Fischer JE. Neuropeptide Y and the development of cancer anorexia. Ann Surg 1995; 221:579–89. 131. Dreyden S, Brown M, King P et al. Decreased plasma leptin levels in lean and obese Zucker rats after treatment with the serotonin reuptake inhibitor fluoxetine. Horm Metab Res 1999; 31:363–6. 132. Plata-Salamán CR. Central nervous system mechanisms contributing to the cachexia-anorexia syndrome. Nutrition 2000; 16: 1009–12. 133. Copeland, EM, III. Discussion in ‘Chance WT, Fischer JE.. Neuropeptide Y and the development of cancer cachexia’. Ann Surg 1995; 221:587. 134. Halford JCG, Blundell JE. Separate systems for serotonin and leptin in appetite control. Ann Med 2000; 32:222–32. 135. Palmiter RD, Erickson JC, Hollopeter G et al. Life without neuropeptide Y. Rec Prog Hormone Res 1998; 53:163–99. 136. Mystowski P, Schwartz MW. Gonadal steroids and energy homeostasis in the leptin era. Nutrition 2000; 16:937–46. 137. Shimada M, Tritos NA, Lowell BB et al. Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature 1998; 396:670–4. 138. Cone RD. Editorial: The ups and downs of leptin action. Endocrinology 1999; 140:4921–2. 139. Blum WF. Leptin: the voice of the adipose tissue. Horm Res 1997; 48:2–8. 140. Gura T. Tracing leptin’s partners in regulating body weight. Science 2000; 287:1738–41. 141. Mantzoros CS. The role of leptin in human obesity and disease: a review of current evidence. Ann Intern Med 1999; 130:671–80. 142. York A, Bouchard C. How obesity develops. Insights from the new biology. Endocrine 2000; 13:143–54. 143. Elmquist JK, Elias CF, Saper CB. From lesions to leptin: hypothalamic control of food intake and body weight. Neuron 1999; 22: 221–32. 144. Loffreda S, Yang SQ, Lin HZ et al. Leptin regulates proinflammatory immune responses. FASEB J 1998; 12:57–65. 145. Reichlin S. Neuroendocrinology of infection and the innate immune system. Rec Prog Horm Res 1999; 54:133. 146. Lord GM, Matarese G, Howard JK et al. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 1998; 394:897–900. 147. Frank S, Stallmeyer B, Kampfer H et al. Leptin enhances wound re-epithelialization and constitutes a direct function of leptin in skin repair. J Clin Invest 2000; 106:501–9. 148. Gagnon B, Bruera E. A review of the drug treatment of cachexia associated with cancer. Drugs 1998; 55:675–88. 149. Meguid MM, Fetissov SO, Varma M et al. Hypothalamic dopamine and serotonin in the regulation of food intake. Nutrition 2000; 16: 843–57. 150. Chrousos GP. The role of stress and the hypothalamicpituitary-adrenal axis in the pathogenesis of the metabolic syndrome: neuro-endocrine and target tissue-related causes. Int J Obesity 2000; 24:S50–5. 151. Chikanza IC, Grossman AB. Reciprocal interactions between the neuroendocrine and immune systems during inflammation. Rheum Dis Clin North Am 2000; 26:693–711. 152. O’Connor TM, O’Halloran DJ, Shanahan F. The stress response and the hypothalamicpituitary-adrenal axis: from molecule to melancholia. Q J Med 2000; 93:323–33. 153. Reichlin S. Editorial: What’s in a name or what does leukemia inhibitory factor have to do with the pituitary gland? Endocrinology 1998; 139:2199–200. 154. Cavagnini F, Croci M, Putignano P et al. Glucocorticoids and neuroendocrine function. Int J Obesity 2000; 24:S77–9. 155. Barnes PJ. Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clin Sci 1998; 94:557–72.

Frailty, cancer cachexia, and near death

447

156. Sternberg EM. Neural-immune interactions in health and disease. J Clin Invest 1997; 100:2641–7. 157. Orban Z, Bornstein SR, Chrousos GP. The interaction between leptin and the hypothalamicpituitary-thyroid axis. Horm Metab Res 1998; 30:231–5. 158. Schwartz MW, Dallman MF, Woods SC. Hypothalamic response to starvation: implications for the study of wasting disorders. Am J Physiol 1995; 269:R949–57. 159. Nelson KA. The cancer anorexia-cachexia syndrome. Semin Oncol 2000; 27:64–8. 160. MacDonald N. Cachexia-Anorexia Workshop: Introduction. Nutrition 2000; 16:1007–8. 161. Yeh SS, Wu SY, Lee TP et al. Improvement in quality-of-life measures and stimulation of weight gain after treatment with megestrol acetate oral suspension in geriatric cachexia: results of a double-blind, placebo-controlled study. J Am Geriatr Soc 2000; 48:485–92. 162. Plata-Salamán CR. Cytokines and feeding. News Physiol Sci 1998; 13:298–304. 163. Barber MD, Ross JA, Fearon KCH. Disordered metabolic response with cancer and its management. World J Surg 2000; 24:681–9. 164. Hwang D. Fatty acids and immune responses—A new perspective in searching for clues to mechanism. Annu Rev Nutr 2000; 20:431–56. 165. Heys SD, Walker LG, Smith I et al. Enteral nutritional supplementation with key nutrients in patients with critical illness and cancer. Ann Surg 1999; 229:467–77. 166. Casson PR, Carson SA, Buster JE. Replacement dehydroepiandrosterone in the elderly: rationale and prospects for the future. Endocrinologist 1998; 8:187–94. 167. Wabitsch M, Blum WF, Muche R et al. Contribution of androgens to the gender difference in leptin production in obese children and adolescents. J Clin Invest 1997; 100:808–13. 168. Jockenhovel F, Blum WF, Vogel E et al. Testosterone substitution normalized elevated serum leptin levels in hypogonadal men. J Clin Endocrinol Metab 1997; 82:2510–13. 169. Wang Z-W, Pan W-T, Lee Y et al. The role of leptin resistance in the lipid abnormalities of aging. FASEB J 2001; 15:108–14. 170. Steppan CM, Bailey ST, Bhat S et al. The hormone resistin links obesity to diabetes. Nature 2001; 409:307–12. 171. Jatoi A, Kumar S, Sloan JA et al. On appetite and its loss. J Clin Oncol 2000; 18:2930–32. 172. Farooqi IS, Yeo GSH, Keogh JM et al. Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J Clin Invest 2000; 106:271–9. 173. Hyltander A, Daneryd P, Sandstrom R et al. β-adrenoceptor activity and resting energy metabolism in weight losing cancer patients. Eur J Cancer 2000; 36:330–4. 174. Astrup A. Thermogenic drugs as a strategy for treatment of obesity. Endocrine 2000; 13:207– 12. 175. Harper ME, Kozak LP. Mitochondrial uncoupling proteins in energy expenditure. Annu Rev Nutr 2000; 20:339–63. 176. Grinspoon S, Corcoran C, Parlman K et al. Effects of testosterone and progressive resistance training in eugonadal men with AIDS wasting. Ann Intern Med 2000; 133:348–55. 177. Sherwood NE, Jeffrey RW. The behavioral determinants of exercise: implications for physical activity interventions. Annu Rev Nutr 2000; 20:21–44. 178. Demling R, De Santi L. Closure of the ‘non-healing wound’ corresponds with correction of weight loss using the anabolic agent oxandrolone. Ostomy Wound Mgmt 1998; 44:58–68. 179. Tritos NA, Mantzoros CS. Recombinant human growth hormone: old and novel uses. Am J Med 1998; 105:44–57.

21 Practical proposals for clinical protocols in elderly patients with cancer Martine Extermann, Lodovico Balducci Introduction The goal of this chapter is to review some principles and methods of clinical research in elderly patients with cancer. In the process, we shall examine the tools that may be used in this research. These tools may have widespread clinical applications in providing individualized treatment to the older cancer patient. Older cancer patients are different from those who are younger because they have shorter life-expectancy and higher prevalence of comorbid conditions, functional limitations, and emotional, cognitive, and socioeconomic restrictions. Clinical trials of older persons must take into account each of these factors in defining individual patient profiles that may affect both the goals of treatment and the type of intervention planned. Among the unique issues that pertain to studies in older patients is the fact that the sample of patients enrolled in traditional therapeutic trials represents a very selected group of patients: How can studies be designed so that results can be generalized to the older patient population? Can we find a valid stratification model based on the Comprehensive Geriatric Assessment (CGA)? Now that agents with a better safety profile are being developed, how do these agents compare with best supportive care for frail elderly patients? Who should be enrolled in adjuvant trials? How does community practice reflect the results of therapeutic trials, and are results comparable? In the following discussion, we shall explore the issues of external validity of clinical research in older individuals, choice of research endpoints, assessment of functional status, comorbidity, pharmacology, and quality of life in geriatric oncology protocols, and mathematical analysis of data from older individuals, including mathematical models. External validity Clinical studies in the elderly are particularly prone to selection bias. A major characteristic of the older population is diversity. Hence, there is a risk that clinical trials involve only a particularly healthy fringe of this population and that the results of these trials will not be generalizable to the older population at large. Patients referred to tertiary care centers are generally selected with regard to comorbidity and function. Patients with other diseases or poor performance status are most likely to be treated in a primary care center. Medications taken for other conditions may influence the course of cancer (e.g. aspirin and coumarinic anticoagulants). They may also influence the effectiveness of chemotherapy.1 Patients with comorbidities may be more sensitive to the complications of the tumor and of antineoplastic treatment. Financial bias is also becoming increasingly

Practical proposals for clinical protocols in elderly patients with cancer

449

important, especially in countries without universal insurance coverage. An increasing number of patients cannot afford care in a tertiary care center because of no or partial insurance coverage and limited income. Predictably, further selection will occur as an effect of managed care. Older persons are less likely than younger ones to receive aggressive cancer treatment, even after stratification for comorbidity.2–5 Elderly patients are also less likely than younger ones to be referred to specialized practitioners, such as medical oncologists.3 These biases are not always avoidable, and may themselves be the objects of future studies. A particular example of bias is represented by cooperative studies. For example, whereas 23% of breast cancers occur in patients aged 75 and older, only 3% of cooperative trial patients are in that age range.6 Despite active attention being paid to this, the accrual of older patients in cooperative trials is a persistent problem.7 One of the issues at stake is the requirement by most protocols to have patients in good condition to be able to ‘truly’ assess the effectiveness of a regimen. One creative approach would be to use mathematical adjustment methods, such as Bayesian estimates, in order to control for the influence of comorbidities and expand the accrual to less favored populations. It is particularly important to establish the roles of the physician and the patient in the decision to limit cancer care.3,4,8–10 Many cultural aspects may be involved. Exter-

Table 21.1 Willingness to undertake a hypothetical strong or moderate chemotherapy: results from elderly patients from geriatric and oncologic clinics in France and the USA.11 Strong chemotherapy

Moderate chemotherapy

USA

France

USA

France

Cancer patients

70.5%

77.8% (p = 0.43)

88.5%

100% (p = 0.11)

Non-cancer geriatric patients

73.8%

34% (p <0.0001)

95.2%

67.9% (p <0.001)

nal validity also implies transferability between countries or different populations. Certain views about cancer are held in the general population, whereas cancer patients can sometimes have dramatic alterations of these view.8,11 For example, in a case vignettes study, whereas a French geriatric population was less willing to undertake chemotherapy than an American one, older cancer patients in both countries had a similar eagerness for treatment11 (Table 21.1). Cultural aspects may also strongly influence things such as self-perceived health, depression, or decision-making processes.12 Another situation in which external validity has to be assessed is in cost-effectiveness studies. For example, the cost-effectiveness of pamidronate can be extremely different between two neighboring countries, such as the USA and Canada.13 These sampling issues should be carefully accounted for in analysis of results, when one wants to establish the applicability of these results to the general population of older cancer patients. Comorbidity, an independent predictor of survival in elderly patients,14–15 should be graded independently of performance status.16 In addition to overall mortality, disease-specific mortality should be reported. The general type of patients seen by the center should be described, as well as data allowing evaluation of the external validity of

Comprehensive Geriatric Oncology

450

the study. Such data may include the proportion of eligible patients included/excluded from the study, the proportion of eligible/non-eligible patients with the disease, and the level of dependence of the study population. A fundamental step in allowing a good evaluation of the external validity of a study is the use of common evaluation tools to analyze patient characteristics between studies, in both retrospective and prospective trials. Validated and reproducible geriatric assessment tools, or the design of a common ‘staging’ of aging, are key in allowing strict comparisons between studies, pooling of data for meta-analyses, or subgroup analyses. We shall review some of the available tools below. The elements allowing assessment of the external validity of a study are summarized in Table 21.2.

Table 21.2 Data that should be reported in clinical trials involving older individuals, to establish the external validity of the study. • External validity assessment • Profile of the study population: –Functional status/dependence –Comorbidity (qualitative and quantitative), measured with validated instruments –Nutrition –Depression, cognitive function –Others as appropriate • Overall mortality • Disease-specific mortality • Overall population of the institution(s) where the studies are conducted • Enrolled/non-enrolled patients • Eligible/ineligible patients

Choice of endpoints The treatment of elderly patients raises issues about study endpoints that are specific to their age group. Cure of the cancer may not increase survival, because of competing causes of death. Therefore, overall survival may not always represent the ‘gold standard’ of treatment effectiveness, and alternative endpoints should be examined (Table 21.3). One of these is the distinction between cancer-related and unrelated mortality, since the prevalence of comorbidity is high in older cancer patients.16 An endpoint with major impact on the patient’s quality of life and on the cost of patient care to the society is active life-expectancy. This term refers to the length of time during which the patient is capable of independent living.17,18

Practical proposals for clinical protocols in elderly patients with cancer

451

Certain tumors, more prevalent in the elderly, may not lead to measurable lesions, as is the case with metastatic prostate cancer or locally advanced pancreatic cancer. In such settings, assessment of symptom evolution, such as pain, can prove a highly sensitive and relevant endpoint.19–21 More generally, quality of life is an important endpoint that should be assessed whenever possible, although it may not be directly related to tumor response.

Table 2.13 Alternative study endpoints in the older cancer patient • Overall survival • Disease-free survival • Tumor response rates • Cancer-related survival • Cancer-unrelated survival • Active life-expectancy • Symptom reduction (e.g. of pain) • Quality of life

Comorbidities Comorbidities significantly influence life-expectancy in elderly persons. For persons in their 60s or 70s, these can increase the non-cancer mortality 10- or 20-fold.22 Even with tumors leading to poor survival, such as metastatic lung cancer, comorbidity can significantly influence the outcome of older patients.23 Comorbidity may influence not only the patient’s survival but also the pharmacokinetics of antineoplastic agents and the patient’s tolerance to treatment. Comorbidity levels should be graded independently of functional status. In elderly patients, comorbidity is an independent predictor of outcomes such as survival, functional dependence, and risk and duration of hospitalization.24 Scant information is presently available from prospective therapeutic trials in older cancer patients, since these studies have generally selected patients in good general condition. However, such information seems congruent with that from geriatric studies.23 Cohort studies (prospective and retrospective) and pooling of large prospective studies represent the most powerful way to explore the impact of comorbidity on the treatment and survival of older cancer patients. Cohort studies and epidemiologic studies offer the advantage of very large numbers, but rarely contain information on functional status, and control poorly for treatment variation. Pooling large prospective trials such as cooperative studies allows excellent control of treatment and outcomes. However, a coordinated data collection strategy needs to be established in order to allow future meta-analysis, since a minimum of 2000–3000 elderly patients will be needed for any analysis of how individual comorbidities interact with each other to influence outcomes. An average large chemotherapy cooperative trial at present includes some 100–200 patients aged 70 and above. Comorbidity is very sensitive to definition. For example, in our program, 36% of

Comprehensive Geriatric Oncology

452

the patients had a comorbidity when assessed with the Charlson Index, whereas 94% presented a comorbidity on the Cumulative Illness Rating Scale-Geriatrics (CIRS-G) (43% grade 3–4).16 The most frequent comorbidities, when assessed with the CIRS-G, were locomotive/tegumental problems (43%), vascular conditions (36%), genito-urinary diseases (31%), cardiac conditions (30%), and breast and endocrine diseases (29%). On the Charlson Index, the most frequent diseases were second tumors (10%) and diabetes. (7%). Therefore, it is essential to grade comorbidity according to objective scales, to have reproducible data that establish the impact of comorbidity on treatment and survival. As the list of possible comorbidities is practically unending, several approaches have been taken to select clinically significant conditions, to group these conditions into specific categories of disease, and to attribute a relative weight to each condition and to each category of disease. Some indices use a limited number of diseases, related, for example, to mortality. Other instruments allow extensive recording and grading of comorbidities. Some of the best-validated comorbidity instruments have been reviewed,

Table 21.4 Construction of some major comorbidity scalesa Scale

Type

Charlson Index Weighted

Items and rating

How constructed Interrater reliability

Test-retest reliability

19 diseases weighted 1–6 Total: 0–30

Internal medicine patients: 1 year mortality

0.86–0.92

Charlson/age

Composite Original Charlson Same as Charlson Index plus each Index decade above 50 as 1 point

Cumulative Illness Rating Scale (CIRS)

Weighted

Index of Coexistent Disease (ICED)

KaplanFeinstein

0.1 59– 0.945b

Comprehensive 0.76–0.91c listing of diseases weighted by clinician estimate or manual

0.95c

Composite Disease severity subindex: 14 diseases (0–4) Functional severity subindex: 12 conditions (0– 2) Total: 0–3

Breast cancer patients: anticipated outcome 2 years after hospitalization

0.57–0.71

0.93

Weighted

VA diabetics: diseases that might be expected to impair survival

0.82

Not available

13 or 14 organ system categories, rated 0 to 4 Total: 0–52 or 56

12 conditions (10 diseases, locomotive function, and alcoholism): 0–3

Practical proposals for clinical protocols in elderly patients with cancer

453

Total: 0–3 a

Adapted from reference 25 with permission. See this reference for further details. Lowest score from a study with technical limitations. c Total score. b

with their characteristics, their metrologic performance, and their correlation with various outcomes.24,25 (Table 21.4). Additional information on comorbidity can be found in Chapter 19 of this volume.26 The use of validated instruments Better than any other, the example of comorbidity above emphasizes the need for the use of validated instruments in oncogeriatric clinical trials. Other circumstances demonstrate the need for the use of validated instruments. One of them is functional status. Oncologists are familiar with the Eastern Cooperative Oncology Group (ECOG) or World Health Organization (WHO) Performance Status. In our program, about 80% of patients present an ECOG Performance Status of 0–1. However, when these patients are evaluated with a scale such as the Lawton Instrumental Activities of Daily Living (IADL), 56% of patients present some level of dependence, whereas about 20% of patients are dependent in basic (Katz) Activities of Daily Living (ADL).16,27,28 Therefore, the picture that one can get from the functional status of older patients is highly variable. At present, we still know little about the relative relevance of various levels of functional impairment in older cancer patients; therefore, studies integrating both types of assessments (oncologic and geriatric) are needed. This would also facilitate comparisons with the general geriatric population. For example, the patients seen in our program had twice the proportion of functional impairments as that of large cohorts of US communitydwelling elderly.16,29 Whereas for supportive and palliative care studies, both ADL and IADL should be integrated, in chemotherapy studies, using IADL only is probably legitimate, since very few of these patients would be dependent in basic ADL. Several direct tests of physical functioning can be used, such as the Physical Performance Test,30 or the Performance-Oriented Mobility Assessment (POMA).31 Shorter tests can be used for screening, such as the timed ‘get up and go’, or gait speed tests. Test combinations relevant to the population studied should be chosen. These tests may yield information different from functional questionnaires.32 For assessment of nutritional status, the Mini Nutritional Assessment (MNA)33 has been used in several geriatric and oncologic studies, and represents one practical tool available. It correlates well with other elements of nutritional status.34 For the assessment of cognitive functioning, Folstein’s Mini Mental State (MMS)35 is a convenient and widely used tool that has also demonstrated relevance in the field of oncology.36 Screening for depression can be done with several validated instruments.37 Many oncological trials use the Geriatric Depression Scale (GDS),38,39 in either its full 30question form or its short 15-question form. The definition of quality of life in the literature has been quite diverse.40–42 A reliable definition of quality of life is especially important for elderly patients undergoing a

Comprehensive Geriatric Oncology

454

Comprehensive Geriatric Assessment, since other dimensions such as performance status or functional status are analyzed on separate scales. Quality of life can be conveniently defined as a patient’s appraisal of and satisfaction with their current level of functioning as compared with what they perceive to be possible or ideal.43 More technically, quality of life may be defined as ‘a multidimensional construct encompassing perceptions of both positive and negative aspects of dimensions such as physical, emotional, social, and cognitive functions, as well as the negative aspects of somatic discomfort and other symptoms produced by the disease or its treatment’.44 Clearly, assessment of quality of life is patient-centered. Indeed, it has been shown that there is a low correlation between patient’s own estimate of quality of life and those provided by the physician or the caregiver.44–46 The physician or the caregiver tend to underestimate the quality of life of severely ill patients.46 Therefore, every effort should be made to have quality of life measures obtained directly from the patient. A plethora of quality of life scales have been created during the last two decades, and have been reviewed elsewhere.42,47–49 A list of scales frequently used in oncology includes FLIC,50 CARES,51 EORTC-QLQ-C30,52 FACT,53 SF-36,54 and LASA.55 Some scales also have complementary subscales specific to certain tumors (EORTC-30 and FACT). The Functional Assessment of Cancer Therapy-Geriatric (FACT) scale has been validated specifically in older cancer patients.56 With adjustment for ECOG Performance Status, the scores of older patients were similar to those of younger patients.53 SF-36 has norms specifically for older patients. Three studies have been conducted to establish population-based norms for EORTC-QLQ-C30, but none with adjustment for ECOG/WHO Performance Status.57 FACT-G and EORTC-QLQ-C30 have optional extension modules for specific cancer types. There is no absolute rule determining the choice of a particular quality of life scale. A scale adapted to the patient population and the type of question addressed in the study should be selected among the scales with which the investigators are familiar. Assessment of quality of life in older individuals is dealt with in detail in Chapter 24 of this volume.58 Patient-rated subjective status, such as depression, quality of life, and self-rated health, is sensitive to culture. For example, in a large geriatric cohort study (the Seven Countries study), 10–22% of Finnish men perceived themselves as healthy, versus 72–86% of Italians and 84% of Dutchmen.25,59 In multicultural studies, it is therefore desirable to look for markers of external validity within each culture, such as results in parallel relevant studies. One should be aware that the translation of tools such as quality of life scales requires nowadays a strict methodology. Fortunately, the major quality of life instruments, such as those mentioned above, exist in a large number of languages. Comprehensive Geriatric Assessment A multidimensional assessment of the older person, capable of evaluating several areas of potential interventions, has been utilized for several years in geriatric practice. The Comprehensive Geriatric Assessment (CGA) complemented by appropriate geriatric follow-up has proved helpful in prolonging the survival and improving the opportunity to live at home for older individuals.60 The CGA may be performed at home or in the hospital setting. The specific contribution of the CGA to the management of treatment of

Practical proposals for clinical protocols in elderly patients with cancer

455

elderly cancer patients is largely unexplored. Seemingly, the CGA may provide important leads for therapeutic choices—mostly in a palliative setting. The basic core of the CGA includes medical history and physical examination, and appropriate scales for the assessment of ADL, IADL, cognition, and depression, and a form of evaluation of social support. Classically, the CGA entails a multidisciplinary approach to the older patient. The assessment team should include at least a physician with geriatric orientation, a nurse or nurse practitioner, and a social worker. The team is most often complemented by a clinical pharmacist, a dietician, a physical therapist, a gerontopsychologist, and any other specialty that is needed.61–64 A practical approach to the use of the CGA in elderly cancer patients is discussed in Chapters 26 and 64 of this volume.65,66 In large multi-center trials, such an approach may not be feasible, and more limited strategies might be used. In our experience, 20 minutes of direct interview by a research nurse are usually sufficient to administer the IADL, GDS, MMS, FACT-G, and MNA, and 10 additional minutes of rating on chart allow for completion of the CIRS-G and Charlson Index.67 This evaluation is now introduced in the design of multicentrer studies, with a centralized rating of the CIRS-G. The relative relevance of tumor stage, CGA, and comorbidity for the prognosis and therapeutic strategy of an elderly cancer patient is an area of active research in our program and in other institutions.68 We recently conducted a study using the CGA and comprehensive follow-up assessments in patients with early breast cancer. These patients presented on average sk problems at the first examination (beside their cancer), and developed three new problems within the next 6 months.69 Many of these problems led to meaningful interventions, which included some interventions directly modifying cancer treatment. This suggests that, even in this ‘problem-free’ cancer population, a comprehensive geriatric approach may be relevant. Our general patient population is presenting twice the level of functional impairment as the community-dwelling elderly: 44% of dependence in IADL versus 19–22%, and therefore a multidisciplinary intervention has a clear potential for functional improvement.16,29,60 Pharmacological studies Older patients present a number of physiological or physiopathological changes that will affect the pharmacokinetics and pharmacodynamics of anticancer agents. These changes are discussed in detail in Chapter 39 of this volume.70 Unfortunately, owing to the general under-representation of elderly patients in clinical trials, the information on these patients is still sparse. Various approaches have been designed to try to palliate this problem. One approach is a stratified phase II trial where two or more age-defined cohorts of patients are enrolled.71 Another approach uses a stepwise phase I/II design, where patients above a certain age are treated one group of dose escalation behind the younger group. Another possible approach is to find means to individualize patient dosing. This can include metabolic tests (e.g. the urinary β-hydroxycortisol excretion for docetaxel72), formulas (e.g. the Calvert formula for carboplatin), and body composition studies. Things become more complicated when combination regimens are employed, and more general predictive indices valid for several regimens are desirable.

Comprehensive Geriatric Oncology

456

Mathematical studies Aging is highly individualized. Consequently, elderly cancer patients represent a very diverse population, whose assessment in terms of functional reserve, comorbidity, emotional and cognitive function, and socioeconomic conditions is problematic. Chronologic age is a poor predictor of individual age-related changes, and there are no reliable biological or physiological markers of extent of aging in individual situations. The diversity of aging is a major obstacle to the recruitment of a representative sample of older individuals into clinical trials and the major limit to the use of clinical studies in clinical practice. This diversity also represents a major therapeutic challenge, since it mandates individualized treatment plans, which cannot be tested in large clinical trials. Furthermore, the ability of the human mind to integrate complex prognostic data has limits.73 This complexity of data is particularly common in medical decisions involving older individuals. Meta-analysis of different clinical trials may allow firmer conclusions to be drawn regarding the value of prognostic factors and the effectiveness of therapeutic interventions in older persons with cancer. Decision analysis models may help in estimating individual benefits and risks of different courses of action and in calculating the cost-effectiveness of specific interventions. We should emphasize, however, that the reliability of mathematical methods is predicated upon the reliability of clinical data. Thus, a uniform and comprehensive evaluation of the older patient is essential to the applications of these methods. A recent example of mathematical methods applied to individual treatment planning is adjuvant therapy for breast cancer, as discussed below. Meta-analysis Meta-analysis has proved a powerful tool in the acquisition of knowledge from clinical studies.60,74–76 It is particularly usefiil in establishing trends from inconclusive studies, and for this reason may become an important way to obtain information about older patients. The use of meta-analysis in the elderly population encounters, however, certain hurdles. Of these, diversity represents probably the major challenge. One should therefore pay very careful attention to the way in which patients have been selected for studies. For example, the setting of the study may play a role, as demonstrated by Stuck et al,60 in the case of the CGA. Stratification of study populations in each trial, by comorbidity or functional level, could certainly increase the reliability of meta-analysis in the elderly. Decision analysis The term ‘decision analysis’ refers to an ensemble of mathematical methods trying to consider in a systematic way the elements that influence (medical) decision-making. These allow evaluation of the accuracy of diagnostic procedures, interpretation of the meaning of positive or negative results of a procedure in a specific patient, and modeling of complex patient problems in order to select the most appropriate approach. The management of elderly patients involves very complex clinical decisions, implying the consideration of multiple factors, cancer-related or not. Even when we limit

Practical proposals for clinical protocols in elderly patients with cancer

457

ourselves to cancer alone, a prognostic estimation is a difficult exercise. For example, estimates given for the 10-year survival rate of breast cancer patients by trained oncologists varied on a range of 20–50% for each of three hypothetical cases.73 Physicians were basing their judgment on a few variables, and the addition of more variables, such as tumor grade or proliferation markers, was only adding to the diversity of opinions. We can thus postulate that having to integrate information on comorbidities would lead to an even greater diversity of prognostic estimates and hence treatment options. Computer databases may prove useful in this respect. A recent example of applications of decision analysis as help tools for clinicians is in the adjuvant treatment of breast cancer. A Markov model applied to older patients with various levels of comorbidity did produce benefit graphs that can be of significant help in decision-making for these patients. It demonstrated that benefits on relapse and survival differ significantly as age advances, and that benefit on survival is highly sensitive to comorbidity.77 Some other models exist for the general breast cancer population, ranging from simple tables78 to computer software.79 They can also provide useful information for healthy or averagehealth elderly patients. Several tools are available for decision analysis projects, such as decision trees, Markov models, classification and regression trees (CARTs), and neural networks.80 An essential aspect of decision analysis is the estimate of the expected value of different interventions. The expected value generally integrates objective outcomes, such as prolongation of survival, cost, and relief of symptoms, with personal perceptions of those outcomes, such as the desirability to live longer at the price of loss of function or pleasure. Several methods have been proposed for estimating the expected value of clinical outcomes. Of these, the ‘trade-off’ and the ‘standard bargaining’ methods have become particularly popular. Trade-off methods are methods that propose an exchange between two options: for example, ‘Suppose that you can live 10 years in your present condition and that I could offer you a lesser number of years in perfect health. How many years of life in perfect health would you be willing to exchange for 10 years in the present condition?’ In the ‘standard bargaining techniques’, the patient is asked to state how many chances of the worst outcome (generally death) he or she is willing to take to reverse the present condition of misery. An example of a standard bargaining technique is the following: ‘Chemotherapy may relieve your cancer pain, but involves a risk of dying. How many chances of dying are you willing to accept, to relieve your current pain?’ These methods are widely used in decision analysis for including quality of life in models. They are also used for comparing different estimates of the same situation by different persons. These situations may include global estimates of quality of life, or willingness to receive treatment under specific conditions.8,9,45,48 These techniques may prove very valuable in estimating the expected value of certain outcomes by specific cohorts of elderly patients. An application of these methods is, for example, to studies of the willingness of older patients to undertake chemotherapy, where patients are asked to tell what minimal benefit they would want from chemotherapy before accepting to endure the potential side-effects. Several studies have addressed this issue, with different nuances.8–11,81

Comprehensive Geriatric Oncology

458

Cost-effectiveness As we are living in a cost-conscious environment, this domain will undergo intensive development in the coming years. Cost-effectiveness refers to the cost of the outcome of specific interventions. It may be expressed as cost per additional year of life, cost per life saved, or cost per quality-adjusted life-year (QALY) of survival. Cost-effectiveness may be examined from the point of view of a medical center (charges generated by the treatment), of the patient (charges of treatment and loss of gain), and of society (costs and productivity). Guidelines for the design of cost-effectiveness studies were drawn up a few years ago.82–84 Interestingly, a study on projected Medicare expenditures from 1990 to 2020 showed that only 3.2% of the increase in costs would be due to improved lifeexpectancy beyond 65 years, while 74.3% would be due to the larger size of the original cohort of persons and 22.5% to an increase in the proportion of that cohort expected to survive to age 65.85 However, Medicare covers only 5% of nursing home care, which represents 20% of total healthcare expenditure in the USA. Nursing home care spending increases with age.85 Therefore, a particularly interesting point will be to incorporate evaluations of the cost of cancer treatment into the more general issue of preventing institutionalization. In this perspective, some treatments may prove more cost-effective or even cost-saving in the elderly, when compared with younger patients. Survival evaluation should also include, when relevant, quality of life correction, especially if the intent of the treatment is palliative. One should also realize that, while cost-effectiveness concerns may play an important part in societal or insurance budget decisions, the care of the individual patient should always be aimed at the best reasonable care to improve survival and quality of life. At individual levels, cost-effectiveness studies should be aimed at choosing the most cost-effective method to achieve the same results. From a research point of view, cost-effectiveness studies could emphasize domains where there is a need to develop cheaper techniques or approaches. One should also keep in mind that charges are highly volatile data and that any analysis refers to a certain time and location. A somewhat extreme example is provided by two studies on the cost-effectiveness of pamidronate for metastatic breast cancer.86,87 Whereas the American study found a marginal cost-effectiveness of US$108200 with chemotherapy and US$305300 with hormonal therapy per QALY (which is usually considered as not cost-effective), the Canadian study found a marginal cost-effectiveness of Can$18700 (about US$12 700) per QALY gained over 1 year for chemotherapy-treated patients (which is considered as very cost-effective). The major differential factor was the cost of the pamidronate infusion—a very modifiable factor.13 A comprehensive consideration of all possible charges (such as time lost by the family) is also extremely difficult.88 Guidelines tend to exclude them. However, while this may be less important in younger patients, it can be a very significant element in older cancer patients. A recent study for example estimated the costs of informal care of actively treated seniors to be about US$1200 per patient per year, or an additional 3 hours per week—namely, 45% more time than patients without cancer or with inactive cancers (without counting the time used to accompany the patient to medical treatment).89 However, cost-effectiveness analyses may prove a very useful tool in identifying the major influences on the cost of a treatment (e.g. duration of

Practical proposals for clinical protocols in elderly patients with cancer

459

hospitalization, treatment of complications, cost of a specific procedure, and nursing home care), and in helping focus on them as study or cost-intervention goals. They could also help in discriminating the costs of treating cancer from the costs of aging itself. Conclusions Clinical research in older cancer patients requires clarification of research goals and comprehension of the diversity of the older population. Many older individuals may be compromised by alternative causes of death, and death may not represent the most reliable endpoint of clinical trials. Alternative endpoints of relevance include disease-free survival, cancer-related mortality, and preservation of independence and of quality of life. Multidimensional geriatric evaluation (including comorbidity) of older cancer patients in clinical trials and in clinical practice may allow meaningful comparisons of different studies and meta-analysis of these studies, as well as assessment of the validity of community practices. The use of validated assessment tools is critical for proper analysis of the internal and external validity of the study, as well as for their pooled assessment. Abundant tools are available that are fitted to afford the challenge of developing solid bases to treat elderly cancer patients with therapies best tailored to their personal conditions. As mentioned frequently elsewhere in this book, the elderly are the fastestgrowing segment of Occidental populations. They deserve an important and sustained high-quality research effort—in oncology as elsewhere. References 1. Relling MV, Pui CH, Sandlund JT et al. Adverse effect of anticonvulsivants on efficacy of chemotherapy for acute lymphoblastic leukemia. Lancet 2000; 356:285–90. 2. Obrist R, Honegger HP, Pichert G, Senn HJ. Physician’s attitudes in the treatment of elderly patients with aggressive NHL. Ann Oncol 1992; 3(Suppl 5):123. 3. Newcomb PA, Carbone PP. Cancer treatment and age: patient perspectives. J Natl Cancer Inst 1993; 85:1580–4. 4. Bergman L, Dekker G, van Kerkhoff EHM et al. Influence of age and comorbidity on treatment choice and survival in elderly patients with breast cancer. Breast Cancer Res Treat 1991; 18:189–198. 5. Greenfield S, Blanco D, Elashoff RM, Ganz P. Patterns of care related to age of breast cancer patients. JAMA 1987; 257:2766–70. 6. Trimble EL, Carter CL, Cain D et al. Representation of older patients in cancer treatment trials. Cancer 1994; 74:2208–14. 7. Hutchins LF, Unger JM, Crowley JJ et al. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 1999; 341:2061–7. 8. Slevin ML, Stubbs L, Plant HJ et al. Attitudes to chemotherapy: comparing views of patients with cancer with those of doctors, nurses, and general public. BMJ 1990; 300:1458–60. 9. Bremnes RM, Andersen K, Wist EA. Cancer patients, doctors and nurses vary in their willingness to undertake cancer chemotherapy. Eur J Cancer 1995; 31A:1955–9. 10. Coates A. Who shall decide? Eur J Cancer 1995; 31:1917–18. 11. Extermann M, Zanetta S, Chen H et al. Are older French patients as willing as older American patients to undertake chemotherapy? J Clin Oncol 2003; 21:3214–19.

Comprehensive Geriatric Oncology

460

12. Extermann M, Aapro M. International issues. In: Cancer in the Elderly (Hunter CP, Johnson KA, Muss HB, eds). New York: Marcel Dekker, 2000:459–76. 13. Extermann M. Pamidronate associated with high incremental costs per adverse event avoided in patients with metastatic breast cancer. Commentary. Evidence-Based Oncol 2000; 1:95–96. 14. Keller BK, Potter JF. Predictors of mortality in outpatient geriatric evaluation and management clinic patients. J Gerontol 1994; 49:M246–51. 15. Parmelee PA, Thuras PD, Katz IR, Lawton MP. Validation of the Cumulative Illness Rating Scale in a geriatric residential population. J Am Geriatr Soc 1995; 43:130–7. 16. Extermann M, Overcash J, Lyman GH et al. Comorbidity and functional status are independent in older cancer patients. J Clin Oncol 1998; 16:1582–7. 17. Rogers A, Rogers RG, Belanger A. Longer life but worse health? Measurement and dynamics. Gerontologist 1990; 30:640–9. 18. Liu X, Liang J, Muramatsu N, Sugisawa H. Transitions in functional status and active lifeexpectancy among older people in Japan. J Gerontol 1995; 50B:S383–94. 19. Reyno LM, Egorin MJ, Eisenberger MA et al. Development and validation of a pharmacokinetically based fixed dosing scheme for suramin. J Clin Oncol 1995; 13:2187–95. 20. Andersen JS, Burris HA, Casper E et al. Development of a new system for assessing clinical benefit for patients with advanced pancreatic cancer. Proc Am Soc Clin Oncol 1994; 13:A1600. 21. Rothenberg ML, Burris HA, Andersen JS et al. Gemcitabine: effective palliative therapy for pancreas cancer patients failing 5-FU. Proc Am Soc Clin Oncol 1995; 14:A470. 22. Satariano WA, Ragland DR. The effect of comorbidity on 3-year survival of women with primary breast cancer. Ann Intern Med 1994; 120:104–110. 23. Frasci G, Lorusso V, Panza N et al. Gemcitabine plus vinorelbine versus vinorelbine alone in elderly patients with advanced non-small-ceU lung cancer. J Clin Oncol 2000; 18:2529–36. 24. Extermann M. Measurement and impact of comorbidity in older cancer patients. Crit Rev Oncol Hematol 35:2000; 181–200. 25. Extermann M. Measuring comorbidity in older cancer patients. Eur J Cancer 2000; 36:453–71. 26. Balducci L, Extermann M. Assessment of the older patient with cancer. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M eds). London: Martin Dunitz, 2004:223–35. 27. Katz S, Ford AB, Moskowitz RW et al. Studies of illness in the aged. The index of ADL: a standardized measure of biological and psychosocial function. JAMA 1963; 185:94–9. 28. Lawton MP. Scales to measure competence in everyday activities. Psychopharm Bull 1988; 24:609–14, 789–91. 29. Crimmins EM, Saito Y, Reynolds SL. Further evidence on recent trends in the prevalence and incidence of disability among older Americans from two sources: the LSOA and the NIHS. J Gerontol 1997; 52B: S59–71. 30. Reuben DB, Siu A. An objective measure of physical function of elderly outpatients. The physical performance test. J Am Geriatr Soc 1990; 38:1105–12. 31. Tinetti ME. Performance-oriented assessment of mobility problems in elderly patients. J Am Geriatr Soc 1986; 34:119–26. 32. Reuben DB, Valle LA, Hays RD, Siu A. Measuring physical function in community-dwelling older persons: a comparison of self-adminstered, interviewer-administered, and performancebased measures. J Am Geriatr Soc 1995; 43:17–23. 33. Guigoz Y, Vellas B, Garry PJ. Mini Nutritional Assessment: a practical assessment toolfor grading the nutritional state of elderly patients. In: Facts, Research and Intervention in Geriatrics, 1997. New York: Serdi Publishing, 1997:15–60. 34. Vellas B, Guigoz Y, Baumgartner M et al. Relationships betweeen nutritional markers and the Mini-Nutritional Assessment in 155 older persons. J Am Geriatr Soc 2000; 48:1300–9. 35. Folstein MF, Folstein SE, McHugh PR. Mini Mental State: a practical method for grading the cognitive status of patients for the clinician. J Psychiat Res 1975; 12:189–98.

Practical proposals for clinical protocols in elderly patients with cancer

461

36. Murray KJ, Scott C, Zachariah B et al. Importance of the mini-mental status examination in the treatment of patients with brain metastases: a report from the Radiation Therapy Oncology Group Protocol 91–04. Int J Radiat Oncol Biol Phys 2000; 48: 59–64. 37. Extermann M, Aapro M. Assessment of the older cancer patient. Hematol Oncol Clin North Am 2000; 14:63–78. 38. Sheikh JJ, Yesavage JA. Geriatric Depression Scale (GDS): recent evidence and development of a shorter version. In: Clinical Gerontology: A Guide to Assessment and Intervention (Brink TL, ed). New York: Haworth Press, 1986:165–73. 39. Yesavage J, Brink T, Rose T et al. Development and validation of a geriatric depression screening scale: a preliminary report. J Psychiat Res 1983; 7:37–49. 40. Gill TM, Feinstein AR. A critical appraisal of the quality of life measurements. JAMA 1994; 272:619–26. 41. Guyatt GH, Cook DJ. Health status, quality of life, and the individual. JAMA 1994; 272:630–1. 42. Cella DF, Tulsky DS. Measuring quality of life today: methodological aspects. Oncology (Huntingt) 1990; 4:29–38. 43. Osoba D. Lessons learned from measuring health-related quality of life in oncology. J Clin Oncol 1994; 12:608–16. 44. Slevin ML, Plant H, Lynch D et al. Who should measure quality of life, the doctor or the patient? Br J Cancer 1988; 57:109–12. 45. Pearlman RA, Uhlman RF. Quality of life in chronic diseases: perceptions of elderly patients. J Gerontol 1988; 43:M25–30. 46. Tsevat J, Cook EF, Green ML et al. Health values in the seriously ill. Ann Intern Med 1994; 122:514–20. 47. Ruckdeschel JC, Piantadosi S. Quality of life in lung cancer surgical adjuvant trials. Chest 1994; 106(Suppl 6):324S-8S. 48. Spilker B, Molinek FR, Johnson KA et al. Quality of life bibliography and indexes. Med Care 1990; 28(Suppl 12):DS1–77. 49. Velikova G, Stark D, Selby P. Quality of life instruments in oncology. Eur J Cancer 1999; 35:1571–80. 50. Schipper H, Clinch J, McMurray A et al. Measuring the quality of life of cancer patients: the Functional Living Index-Cancer: development and validation. J Clin Oncol 1984; 2:472–83. 51. Schag CAC, Heinrich RL. Development of a comprehensive quality of life measurement tool: CARES. Oncology (Huntingt) 1990; 4: 135–8. 52. Aaronson NK, Ahmedzai S, Bergman B et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality of life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993; 85:365–76. 53. Cella DF, Tulsky DS, Gray G et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol 1993; 11:570–9. 54. Ware JE, Donald Sherbourne C. The MOS 36-Item Short Form Health Survey (SF-36). Med Care 1992; 30:473–83. 55. Selby PJ, Chapman JAW, Etazadi-Amoli J et al. The development of a method for assessing quality of life in cancer patients. Br J Cancer 1984; 50:13–22. 56. Overcash J, Extermann M, Parr J et al. Validity and reliability of the FACT-G scale for use in the older person with cancer. Am J Clin Oncol 2001; 24:591–6. 57. Schwarz R, Hinz A. Reference data for the quality of life questionnaire EORTC QLQ-C30 in the general German population. Eur J Cancer 2001; 37:1345–51. 58. Ganz PA. Quality of life considerations in the older cancer patient. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004: 291–300. 59. Dontas AS, Nissinen A, Kromhout D et al. A thirty years study of healthy middle-aged men: the Seven Countries Study. In: Proceedings ofthe World Congress of Gerontology, Adelaide, August 1997. Symposium S020: Abst 468–73.

Comprehensive Geriatric Oncology

462

60. Stuck AE, Siu AL, Wieland D et al. Comprehensive Geriatric Assessment: a meta-analysis of controlled trials. Lancet 1993; 342:1032–6. 61. Stuck AE, Aronow HU, Steiner A et al. A trial of annual in-home comprehensive geriatric assessments for elderly people living in the community. N Engl J Med 1995; 333:1184–9. 62. Silverman M, Musa D, Martin DC et al. Evaluation of outpatient geriatric assessment: a randomized multi-site trial. J Am Geriatr Soc 1995; 43:733–40. 63. Reuben DB, Borok GM, Wolde-Tsadik G et al. A randomized trial of comprehensive geriatric assessment in the care of hospitalized patients. N Engl J Med 1995; 332:1345–50. 64. Landefeld CS, Palmer RM, Kresevic DM et al. A randomized trial of care in a hospital medical unit especially designed to improve the functional outcomes of acutely ill older patients. N Engl J Med 1995; 332:1338–44. 65. Repetto L, Venturino A, Gianni W. Prognostic evaluation of the older cancer patient. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:309–19. 66. Overcash J. Interdisciplinary teams in geriatric oncology. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:853–62. 67. Extermann M, Chen H, Cantor AB et al. Predictors of toxicity from chemotherapy in older patients: a prospective pilot study. Eur J Cancer 2002; 38:1466–73. 68. Monfardini S, Ferrucci L, Fratino L et al. Validation of a multidimensional evaluation scale for use in elderly cancer patients. Cancer 1996; 77:395–401. 69. Extermann M, Meyer J, McGinnis R et al. A comprehensive geriatric intervention detects multiple problems in older breast cancer patients. Crit Rev Oncol Hematol 2004; 49:69–75. 70. Cova D, Balducci L. Cancer chemotherapy in the older patient. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004: 463–88. 71. Lichtman SM, Egorin M, Rosner GL et al. Clinical pharmacology of paclitaxel in relation to patient age: CALGB 9762. Proc Am Soc Clin Oncol 2001; 20:67a. 72. Yamamoto N, Tamura T, Kamiya Y et al. Correlation between docetaxel clearance and estimated cytochrome P450 activity by urinary metabolite of exogenous cortisol. J Clin Oncol 2000; 18: 2301–8. 73. Loprinzi CL, Ravdin PM, De Laurentiis M, Novotny P. Do American oncologists know how to use prognostic variables for patients with newly diagnosed primary breast cancer? J Clin Oncol 1994; 12: 1422–6. 74. Prostate Cancer Trialists Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomised trials with 3283 deaths in 5710 patients. Lancet 1995; 346:265–9. 75. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet 1998; 351:1451–67 76. Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998; 352:930–42 77. Extermann M, Balducci L, Lyman GH. What threshold for adjuvant therapy in older breast cancer patients? J Clin Oncol 2000; 18: 1709–17. 78. Loprinzi CL, Thome SD. Understanding the utility of adjuvant systemic therapy for primary breast cancer. J Clin Oncol 2001; 19: 972–979. 79. Ravdin PM, Siminoff LA, Davis GJ et al. Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J Clin Oncol 2001; 19:980–91. 80. Miles BJ, Kattan MW. Computer modelling of prostate cancer treatment. A paradigm for oncologic treatment? Surg Oncol Clin North Am 1995; 4:361–73. 81. Silvestri G, Pritchard R, Welch HG. Preferences for chemotherapy in patients with advanced non-small cell lung cancer: descriptive study based on scripted interviews. BMJ 1998; 317:771– 5.

Practical proposals for clinical protocols in elderly patients with cancer

463

82. Russell LB, Gold MR, Siegel JE et al. The role of cost-effectiveness analysis in health and medicine. JAMA 1996; 276:1172–7. 83. Siegel JE, Weinstein MC, Russell LB, Gold MR. Recommendations for reporting costeffectiveness analyses. JAMA 1996; 276: 1339–1341. 84. Weinstein MC, Siegel JE, Gold MR et al. Recommendations of the panel on cost-effectiveness in health medicine. JAMA 1996; 276: 1253–8. 85. Lubitz J, Beebe J, Baker C. Longevity and Medicare expenditures. N Engl J Med 1995; 332:999–1003. 86. Hillner BE, Weeks JC, Desch CE, Smith TJ. Pamidronate in prevention of bone complications in metastatic breast cancer: a cost-effectiveness analysis. J Clin Oncol 2000; 18:72. 87. Dranitsaris G, Hsu T. Cost utility analysis of prophylactic pamidronate for the prevention of skeletal related events in patients with advanced breast cancer. Support Care Cancer 1999; 7:271–9. 88. Gulati SC, Bitran JD. Cost-effectiveness analysis: sleeping with an enemy or a friend? J Clin Oncol 1995; 13:2152–4. 89. Hayman JA, Langa KM, Kabeto MU et al. Estimating the cost of informal caregiving for elderly patients with cancer J Clin Oncol 2001; 19:3219–3225.

22 Under-representation of elderly patients in cancer clinical trials: Causes and remedial strategies Joseph M Unger, Laura F Hutchins, Kathy S Albain Introduction The challenge of enrolling elderly cancer patients in clinical trials becomes more urgent as the number of elderly in the USA increases. The US Census Bureau estimates that the proportion of people aged 65 or older in the USA will increase from 12.6% in 2000 to 20% in 2030.1 Cancer incidence disproportionately impacts the elderly population, in which currently more than 60% of all new cancer cases occur; this proportion could rise to 70% by the year 2020 if current trends continue.2 Meanwhile, the overall age-adjusted mortality rate for persons aged 65 or older (1068.3 per 100000) is 15 times higher than for persons younger than 65 (67.3 per 100000).3 Although the incidence and mortality for certain cancers has recently decreased,4 the approaching boom in the elderly population could result in a pandemic of new cases of cancer and of deaths from cancer. For instance, a study by Yancik5 showed that if colon cancer incidence remains stable, the projected growth in the elderly population will result in a doubling of colon cancer prevalence by the year 2030. Clinical trials provide the critical final step in demonstrating that promising new cancer therapies or preventions are effective. Crucial to the validity of study results is the requirement that the clinical trial sample adequately represent the general cancer population with the same type of cancer. Severe selection bias for entry onto the clinical trial may threaten the generalizability of study results. Unfortunately, large clinical trials consortia have shown that the elderly are in fact severely underrepresented in clinical studies for new therapies. In a study by Hutchins et al6 for the Southwest Oncology Group (SWOG), only 25% of the 16396 consecutively enrolled patients to SWOG trials from 1992 to 1996 were 65 or older, compared with 63% in the US cancer population with the same diseases (p<0.001). Severe underpresentation was found in all of the most common cancers, including breast (9% SWOG versus 49% US), colorectal (40% SWOG cersus 72% US), lung (39% SWOG versus 66% US), and prostate (64% SWOG versus 77% US) (p<0.001 for each disease type). These results held when the age cut-off was set at 70 years and when analyzed separately by type of oncologic practice (academic versus community-based). A similar under-representation of patients aged 65 or older was also found in all trials sponsored by the US National Cancer Institute (NCI) (Table 22.1).7 Any discussion of cancer treatment in older populations benefits from a distinction between ‘fit’ elderly and ‘frail’ elderly. While comorbid conditions are prevalent among

Under-representation of elderly patients in cancer clinical trials

465

older persons, some may not impact treatment for cancer. Other persons have no other comorbid conditions

Table 22.1 Cancer incidence in the elderly versus elderly enrollment on clinical trials (%) Hutchins et al6

Trimble et al7

All patients

Men

SWOG

SEER

Bladder

56

73

Brain

19

44

Breast

9

49

Cervical

7

24

Colorectal

40

72

Head and neck

24

49

Leukemia

27

Lung

NCI

Women SEER

48

68

63

10

56

39

66

47

64

Lymphoma

14

16

Melanoma

22

37

Myeloma

22

37

Ovarian

30

48

Pancreas

38

73

46

68

Prostate

64

77

80

82

Soft tissue sarcoma

29

44

Total

25

63

39

72

NCI

SEER

17

48

46

75

44

62

35

47

60

75

26

57

p<0.001 for all comparisons except prostate and female pancreas from Trimble et al and lymphoma from Hutchins et al. SWOG, Southwest Oncology Group; SEER, Surveillance, Epidemiology, and End Results population registry; NCI, National Cancer Institute clinical trials.

and are otherwise healthy. Such patients might be considered ‘fit’. Frail elderly patients likely suffer from normal age-related changes in health status and/or have a variety of other chronic illnesses that may make them unsuitable for a cancer clinical trial and sometimes any treatment beyond palliative care. The emphasis of this chapter is on improving the enrollment of the growing population of fit elderly in cancer clinical trials, although the potential for enrolling frail elderly patients in clinical trials designed specifically for them is also discussed.

Comprehensive Geriatric Oncology

466

To date, only limited clinical trials research efforts have specifically targeted older cancer patients, resulting in a dearth of proven treatments for this patient group. The combination of the existing under-representation of the elderly in clinical trials and the approaching boom in the elderly population serve only to heighten the need for clinical research targeted to the accrual of elderly patients. Improving clinical trial enrollment in general is an issue for cancer researchers, and has had some targeted study. However, the particular problems of enrolling fit elderly patients on cancer clinical trials, or of designing trials for older frail cancer patients, have received little attention. In this chapter, we shall investigate the potential causes of under-representation of elderly patients in clinical trials, and suggest possible remedial strategies. The general problem of enrollment on clinical trials Estimates of the proportion of cancer patients who enroll in clinical trials are generally less than 3%,8 despite the fact that more than 75% of physicians consider clinical trials to offer better care for patients.9 The causes of under-enrollment on clinical trials for patients of all ages have been studied.9–13 Here, we present three of these studies, which are summarized in Tables 22.2 and 22.3.10–12 Table 22.2 shows rates of clinical eligibility and protocol enrollment on clinical trials; Table 22.3 shows reasons

Table 22.2 Rates of clinical eligibility and protocol enrollment on clinical trials for patients of all ages; results of prior studies (%) Begg et al10

Hunter et al11

Klabunde et al12

78

40

40

Clinically ineligible

56

44

39

Clinically eligible

44

56

61

On a protocol

52

34

30

Not on a protocol

48

66

70

Protocol available for disease site/stage

Clinically eligible and:

Table 22.3 Reasons for clinically eligible patients (of all ages) not participating in a clinical trial: results of prior studies (%) Readon

et al10 Hunter et al11 Klabunde et al12

Physician decision

52

51

17

Patient refusal

19

32

38

Under-representation of elderly patients in cancer clinical trials

467

Reasons for patient refusal: Experimentation

10

15

Toxicity

4

5

Costs

2

5

Other

16

13

Follow-up difficulty/concomitant medical problems

17

10

22

Other

12

7

22

for not entering clinical trials. Begg et al10 sampled 3534 new and repeat patients from institutions affiliated with the Eastern Cooperative Oncology Group (ECOG). Because of the emphasis on clinical trials participation at ECOG institutions, the rate of protocol availability for patients with a specified disease site and stage was quite high (78%) (Table 22.2). Among these patients, 56% were clinically ineligible, whereas 44% were clinically eligible. Nearly half (48%) of the patients clinically eligible for a protocol did not enroll on one. The most often cited reasons for non-participation (Table 22.3) were the physician’s preference for specific treatment or alternative therapy (52%), patient refusal (19%), significant concomitant medical problems or anticipated difficulty with follow-up (17%), and other non-specified reasons (12%). A similar study by Hunter et al,11 restricted to new patients of all ages in community hospitals, sampled 44156 patients. Fewer protocols of the appropriate disease site and stage were available (40%). Although more than half of the patients were clinically eligible (56%), two-thirds of these patients did not participate in a clinical trial. Again, the most often cited reasons for non-participation were physician decision (51%), followed by patient refusal (32%), anticipated difficulty with follow-up or concomitant medical problems (10%), and other reasons (7%). A more recent study by Klabunde et al,12 in which 2339 new and repeat patients of all ages in community hospitals were sampled, found similar rates of protocol availability, clinical eligibility, and nonparticipation as in Hunter et al.11 Similar reasons for non-participation were also found, although in this study patient refusal (38%) outweighed physician decision (17%). For all three of these reports (Table 22.2), the most common reason for patient ineligibility for available protocols was rigid eligibility criteria. Patients were excluded for a number of reasons, including the presence of other illnesses (including second malignancies), poor performance status, abnormal laboratory tests, and prior therapy. Other studies have found similar reasons for patient ineligibility.14,15 Are the elderly any different? It is reasonable to assume that many of these barriers to clinical trial enrollment are similar for older persons, but that other barriers may be present or predominate. The studies cited above indicate areas upon which to focus investigation in older populations. The most common reason that patients with a protocol available do not enroll on a clinical trial is clinical ineligibility. Older patients, who often have a variety of concurrent

Comprehensive Geriatric Oncology

468

illnesses, are less likely to qualify for trial participation. Among eligible patients, the predominant reason for not enrolling on a clinical trial is physician decision. Understanding that older patients may generally be less tolerant of intense interventions, either because of concurrent illness or because of normal age-related decline, physicians may be more likely to decide against clinical trial participation. Often this bias is not based on documented research, especially in the fit elderly population. Patients also decide of their own accord to refuse clinical trial participation. It is reasonable to assume that age would play a role in patient refusal as well. Older persons may have less exposure to educational resources regarding clinical studies, raising concerns about experimentation and toxicity. In addition, older persons are much more likely to be retired and living on fixed incomes—therefore, cost could be an issue. The logistics of following older persons on a clinical study could be problematic, since they are less mobile. Other factors may also play a role; the informed consent procedure, for instance, would be particularly problematic for older patients with visual, auditory, or cognitive impairment. Also, older patients often express greater fear of ‘becoming a burden’ to those they love. Each of these issues is in some way correlated with the increasing frailty and functional decline that comes with greater age, and which is also often associated with the presence of one or more chronic illnesses. Together, these conditions often render older patients ineligible for existing clinical trials for cancer. Eligibility criteria The studies by Begg et al,10 Hunter et al,11 and Klabunde et al12 showed that 39–56% of patients (of any age) with a protocol available for the disease site and stage were considered clinically ineligible. These and other studies have found the most common reason for patient ineligibility for available protocols to be rigid eligibility criteria.10– 12,14,15 Cancer clinical trials typically exclude patients with comorbid illness, including second malignancies. Other reasons (which also point to the presence of comorbidity) include prior therapy (either for cancer or a related condition) and poor performance status. Prestudy laboratory tests outside of acceptable ranges, indicating that vital organs are not functioning properly, are also used to exclude patients from clinical trials, regardless of the regimen under study. Specific drugs (e.g. platinum-based chemotherapies) may require even more stringent laboratory test results to enhance patient safety. Together, these exclusions may often affect the older otherwise-healthy patient more than the younger patient because of normal age-associated decline in organ function. The presence of comorbid illnesses then adds additional impact to this eligibility screening. Comorbidity and measures of functional impairment Chronic conditions and chronic illness are much more prevalent in older persons than in younger persons. The National Health Interview Survey (NHIS), a national household interview survey coordinated by the US National Center for Health Statistics (NCHS),

Under-representation of elderly patients in cancer clinical trials

469

estimates arthritis as the most prevalent chronic condition among adults aged 65 or more (48.3%), followed by hypertension (36.4%) and heart disease (26.9%).16 Prevalence rates for younger age groups (45–64 and less than 45) are much lower for each of these conditions (Table 22.4). In fact, it is estimated that four out of five older persons has one or more chronic conditions.17 The comorbidity profile of the cancer patient has only recently received comprehensive investigation. In 1992, the US National Institute on Aging (NIA) and the NCI

Table 22.4 Prevalence of selected major chronic conditions in the USA(%)a Age group Condition

<45

45–64

65+

Arthritis

3.1

24.0

48.3

Hypertension

3.0

21.4

36.4

Heart disease

3.3

11.6

26.9

Diabetes

0.8

5.8

10.0

Hearing impairment

3.0

13.2

30.3

Visual impairment

1.7

4.8

8.4

Cataracts

0.2

2.3

17.2

Deformity or orthopedic impairment

8.4

17.8

15.8

a

Data from the National Health Interview Survey (1996).

began a study with the goal of gathering data on comorbid conditions in patients registered to the NCI’s SEER (Surveillance, Epidemiology, and End Results) program. Data on comorbidities for more than 7600 older cancer patients (aged 55–74) with various malignancies were abstracted from hospital medical records and combined with corresponding data on each patient’s malignancy recorded in the SEER database.18 A subsequent study by Yancik5 showed that the most prominent concomitant major illnesses were hypertension (42.9%), heart-related conditions (39.1%), arthritis (34.9%), and gastrointestinal problems (31.0%). The mean number of comorbidities increased with age, from 2.9 for patients aged 55–64, to 3.6 for patients aged 65–74, to 4.2 for patients aged 75 or more. Less than 10% of patients had no comorbid conditions. In large part owing to the prevalence of significant chronic illnesses, older patients are ‘expected’ to have much greater difficulty tolerating standard therapeutic regimens, and are not ‘expected’ to respond to treatment as well as their younger counterparts. This expectation has historically biased physicians and patients against seeking either standard therapy or experimental therapy for the treatment of older cancer patients.19–23 Samet et al21 found that the proportion of patients receiving definitive therapy declined with age, even among patients who lived at least 1 year from diagnosis, suggesting that definitive therapy was more likely to be withheld from even good-prognosis older patients. Mor et

Comprehensive Geriatric Oncology

470

al19 found a similar inverse relationship between age and treatment in breast, lung, and colorectal cancer patients—even after adjusting for comorbidity and stage of disease. Even within the 65 and over group, age plays a role. In the adjuvant breast cancer setting, Newschaffer et al20 found that women aged 85 or older were less than one-third as likely to receive surgery for their cancer as women aged 65–74. In addition to comorbidity, a progressive loss in the functional reserve of multiple organ systems may compromise the tolerance of elderly patients for clinical trials, resulting in increased complications of chemotherapy (see Chapter 32 of this volume24). In particular, myelotoxicity may increase with age25 (see Chapter 39 of this volume26). However, studies investigating the effect of age on tolerance or response to therapy have shown mixed results. An important early retrospective study by the Eastern Cooperative Oncology Group (ECOG) in studies of lung, breast, and colorectal cancer found no increase in the frequency or severity of the toxicity of chemotherapy among older patients, and no decrease in response rates.27 More recent results are inconclusive. In adjuvant treatment for breast cancer, one study found increased toxicity and decreased response in older patients,28 while another found similar toxicity and response in older patients.29 In a large adjuvant breast trial, there was no interaction between age and benefit of chemotherapy.30 Whether an older cancer patient tolerates or responds to treatment as well as a younger patient will depend largely on the extent of the patient’s comorbid burden. For some diseases, otherwise-healthy older patients may receive satisfactory treatment with standard therapies, or the normal age-related changes in pharmacokinetics may dictate reduced doses or alternative therapies. Patients with significant chronic illnesses may require even further dose reductions or no therapy at all. But only prospective clinical trials in the older cancer population that are adequately defined by geriatric risk groups will be able to determine which type and dose of treatment is appropriate. To quantify the comorbid burden in older cancer patients, an elderly comorbidity index will be required. This then would be used as either an eligibility or a stratification criterion in clinical trials. Some non-age-specific comorbidity indexes have already been developed. One of the most widely used is the Charlson Index developed to classify comorbid conditions that might predict the risk of mortality in longitudinal studies.31 In the initial study validating this scale, 1-year mortality rates were shown to increase in a stepwise fashion from 12% for patients with zero comorbid conditions to 85% for patients with five or more comorbid conditions. The Charlson scale has had ample validation in such varied settings as arthritis, dialysis, and HIV.31–39 Other indices based on the categorization of clinical disease include the Cumulative Illness Rating Scale (CIRS),40 the Kaplan-Feinstein Scale,41and the Index of Coexistent Disease (ICED).42,43 In the cancer setting, comorbidity scales have been used to retrospectively assess the effect of comorbidity on outcome for cancer patients, and, as expected, comorbidity has been found to predict survival.31,44–49 Satariano and Ragland46 studied 936 women aged 40–84 with primary breast cancer. Seven comorbid conditions were selected for analysis. Patients with three or more comorbid conditions had a fourfold higher rate of mortality, independent of age, stage, and other factors. In colon cancer, Yancik et al49 studied 1610 patients with colon cancer as part of the NIA/NCI SEER study. Again an increasing number of comorbid conditions was highly predictive of worse survival—independently of age, stage, and sex. Other studies have found similar negative impacts of comorbidity

Under-representation of elderly patients in cancer clinical trials

471

on survival in women with breast cancer, including two that specifically used the Charlson Index to assess the extent of comorbidity.45,47 In order to perform appropriate trials in older persons, tools for assessment of functional status will also be required. The use of performance status to determine risk groups for response to treatment and survival for patients of all ages is familiar to oncologists. Performance status scales, such as the ECOG, Karnofsky, and Zubrod scales, are known predictors of outcome. However, these give an incomplete evaluation of older persons.50 Importantly, scales designed to assess Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) have also been found to correlate with longevity.51–53 These latter scales have been shown to have little or no correlation with comorbidity scales,50 and to be independent predictors of mortality.37 Level of social or caregiver support has been shown to impact outcome in cardiovascular patients, even after controlling for other measures of functional status and comorbidity.54–58 In the field of cancer, few studies have been performed, although there is evidence that marital status, as a surrogate for level of caregiver support, independently predicts survival.59,60 To the extent that the older cancer patient is more likely to lack social support—whether because of the death or incapacity of a spouse, increased isolation due to lack of mobility, or other reasons—prognosis could be differentially adversely impacted. As such, together with existing scales of performance status and ADL/IADL, it may also play an important role in defining elderly patient populations. The exclusion of patients with serious concurrent illnesses in cancer clinical trials, in addition to insuring safety, is designed to isolate the cancer as the primary source of morbidity in the patient. Therefore, any response to therapy can be concluded to be a response to the therapy that is specifically targeting the cancer. The development of new agents requires such an approach, and in this context it is appropriate to exclude patients with significant concomitant illnesses. However, the future of cancer therapy promises to be more complex, with the predominant setting not an otherwise-healthy patient with a single well-defmed malignancy, but a patient (generally older) with a variety of concomitant conditions, which will complicate not only the clinical picture but also the interpretation of the toxicity and outcome of the clinical trial. Thus, trials to study standard and new agents in a fit, older population, as well as trials targeted to patients (of all ages) with comorbidities, are needed. Physician decision Patients newly diagnosed with cancer are beset with a number of potentially life-altering decisions that must be made in a short period of time. The prospect of clinical trial participation is unlikely to be of primary concern, especially among older patients who may be less familiar with such trials. It becomes incumbent upon the physician, therefore, to introduce the option of a clinical trial. Yet physicians are often unwilling to urge participation, even though, as suggested in a survey of 60 patients by Kemeny et al,61 older cancer patients may be as likely as younger patients to accept clinical trial participation when offered. In an important study by Benson et al9 for the Illinois Cancer Center, investigators surveyed 437 physicians for their attitudes to clinical trials participation for patients of all ages. Although fully 78% of

Comprehensive Geriatric Oncology

472

physicians felt that patients receive better care on randomized clinical trials, physicians nonetheless expressed a number of concerns about trial participation. In fact, despite the conviction that patients receive superior care in the clinical trial environment, this same study found that 55% of physicians sometimes treat otherwise-eligible patients offprotocol with one arm of the trials, without actually entering the patient on the trial. A number of factors were found to deter physician recommendation for participation. Although nearly all respondents believed that informed consent was necessary (98%), 23% indicated that the requirement of obtaining informed consent was a barrier to enrolling patients onto clinical trials. Inconvenience (23%) and high financial burden (29%) were also cited as factors that deterred enrollment, as well as excessive time required for patient follow-up (26%) (Table 22.5). Physicians expressed a number of concerns about the doctor-patient relationship that, although not necessarily preventing trial enrollment, were noted with surprising frequency. A majority of physicians (55%) were uncomfortable discussing whether a clinical trial is the right treatment. Equally prevalent was the fear of undermining the patient’s belief in the physician’s knowledge and decision-making power (51%). In addition, more than a quarter of the physicians were uncomfortable treating the patient as a research subject (28%). A similar study by Taylor et al62 surveyed the principal investigators at all 94 member institutions of the National Surgical Adjuvant Breast and Bowel Project (NSABP) for attitudes towards clinical trial participation for patients of all ages. As in the study by Benson et al,9 the majority of physicians were concerned that participation in a randomized clinical trial undermined the doctor-patient relationship, and cited this as a reason for not entering eligible patients on trials (73%). Other major reasons were

Table 22.5 Reasons for physicians deciding not to enroll eligible patients (of all ages) on clinical trials: results of prior studies (%) Reasons for not enrolling patients:

Benson et al9 Taylor et al62

Undermines doctor-patient relationship Informed consent Dislike of open discussions about uncertainty

73 23

38

7

23

Conflict between physician as clinician and as scientist

18

Practical difficulties/inconvenience

29

9

Concerns about non-standard treatment or unequal treatments

29

8

Concerns about cost for patient

23

Rigid protocol design

36

Excessive time for patient follow-up

26

trouble with informed consent (38%), dislike of open discussions about uncertainty (23%), conflict between the physician as clinician and the physician as scientist (18%),

Under-representation of elderly patients in cancer clinical trials

473

practical difficulties in trial procedures (9%), and feelings of personal responsibility if treatments are unequal (8%) (Table 22.5). Physician attitude is a powerful determinant in the older cancer patient’s choice of medical care.63 Unfortunately, no studies have specifically profiled physician attitudes about clinical trial participation for the older cancer patient. Nonetheless, we can infer that the concerns noted by physicians in both of these studies are likely to exist, and perhaps be amplified, in the consideration of the clinical trial option for the elderly patient. The fear that clinical trial participation will undermine the doctor-patient relationship could have a large impact on enrolling older patients on clinical trials. Patients look to their physicians for expertise in treatment decision-making, trusting that this decision will represent the best course of treatment for the particular patient. Again, increasing age will only complicate this issue. Older patients, who are often less informed about modern treatment options than their younger counterparts, may be even more dependent on physician’s discretion for treatment selection. But randomization onto a phase III trial or a recommendation for a phase II trial (against a standard care approach) implies uncertainty regarding what is the best treatment, and physicians may anticipate that the introduction of uncertainty will subvert patient confidence in the physician’s expertise, even if, as indicated by the existence of a randomized clinical trial, multiple treatments of similar efficacy (until proven otherwise) are available. Physicians may already believe in the superiority of standard treatment; indeed, many express concerns about non-standard or unequal treatments in the randomized setting. New treatments for older patients will be developed in the coming decades as research into geriatric cancer intensifies. For the fit older patient, for example, some of these treatments may be reduced doses or altered schedules of standard treatments for younger patients. Even if adequately piloted in phase II trials, such treatments may ‘appear’ inadequate to the task of effectively treating an older patient’s cancer, and physicians might thus be reticent to encourage an older patient to participate in a randomized trial in which standard therapy serves as control. Conversely, physicians may have a bias that standard therapies are too toxic for the fit older patient, even if pilot data suggest otherwise. In both scenarios, an existing bias regarding treatment of older cancer patients could lead a physician to decide not to propose a randomized clinical trial. Physicians’ perception of a conflict between their role as clinician and their role as scientist may also be complicated in the older cancer patient. Older patients are often beset by complicating conditions that might at first appear to render the patient unsuitable for experimental therapy, even if new therapies have proven efficacy in similar patients. The change in policy regarding Medicare coverage for clinical trials in the elderly should alleviate physician concerns regarding costs for older cancer patients (although some issues remain; see the section below on ‘Cost’). Physicians, however, have their own concerns about costs. The time spent attending to the details of clinical trial enrollment, as well as explaining clinical trials to the patient, is in general not adequately compensated for in most clinical trials.64 Logistic difficulties also play a role. In a study of physician attitudes and expectations that influenced clinical trial enrollment, oncologists who considered the paperwork time-consuming or who otherwise thought the trial effort would be extra work were less likely to refer a patient to a clinical trial.23 Hjorth et al65 confirmed this, noting that the physician’s perception of the simplicity of

Comprehensive Geriatric Oncology

474

the study protocol was significantly correlated with increased clinical trial enrollment. However, new trials for older cancer patients, which must take into account comorbidity and other issues discussed here, may require additional protocol-specified workups and questionnaires, and may also require that the oncologist coordinate with physicians of other disciplines (who are actively treating the patient’s other illnesses) regarding protocol requirements. In the absence of other attempts at protocol simplification, new trials for older patients promise to be more rather than less complex. Consent The obtaining of informed consent is an issue both subtle and complex, and continues to be a barrier for patients of any age under consideration for a clinical trial. The debate regarding concerns for all ages will be summarized first. In the study by Taylor et al,62 38% of all investigators considered the obtaining of informed consent as an obstacle to accrual—the second most-cited reason. Other studies have found similar results.9,66 Perhaps this is not surprising, given that consent forms historically have been written at a level that is difficult for most patients to read. In a study by Grossman et al,67 137 consent forms were reviewed and analyzed to assess readability. Readability at or below an 8th-grade level was found in only 1–6% of all forms. Even when patients reported that they were satis- fied with the consent process, many failed to comprehend critical information such as non-standard treatment and the risks and uncertainty associated with clinical trial participation.68,69 Davis et al70 tested 183 adults for their ability to comprehend a consent form written at the 16th-grade level (college graduate) versus a simplified version written at the 7th-grade level. While participants found the simplified version easier to read, understanding of the content of the consent form did not improve. But does comprehension of informed consent improve enrollment on clinical trials? In one study, the conventional process of obtaining consent—a written consent form containing full disclosure of the risks of potential treatments—was compared with verbal disclosure at the oncologist’s discretion.71 Patients who received full disclosure through written consent had a better understanding of the proposed trial. They were also noted to have greater anxiety regarding the trial and were less likely to agree to randomization. In contrast, a study in women being screened for breast cancer or with newly diagnosed breast cancer indicated that women with a better understanding of the issues and risks of clinical trials are more likely to participate in a randomized trial.72 Perhaps recognizing such contradictions, many physicians do not view the informed consent process as an appropriate means of conveying information,9,66 and many also fear that patients will withdraw from participating in a clinical trial if they are informed of the risks in the great detail required by informed consent.73 Patients themselves report refusal to enter clinical trials because of fears of experimentation that the consent form failed to allay.11,12,74 Clearly the issue of informed consent is complex, whether the patient is young or old. The requirement of full disclosure of the risks of potential treatments results in consent forms that are difficult to read; even when they are readable, patients do not necessarily understand their content; yet a better understanding of the content may discourage

Under-representation of elderly patients in cancer clinical trials

475

participation in a clinical trial. Physician concerns about the consent process span the age spectrum. Although these factors pertain to patients of all ages, it is not unreasonable to assume that these issues, already complex, are further confounded by age. However, there have been no specific studies on the consent process for cancer-specific treatment trials in older patients. Studies in other disciplines have found that comprehension of the consent form is negatively associated with age,75–77 a phenomenon amplified further by chronic or acute medical illness.75 Methods for improving patient comprehension of potential treatments for cancer have been investigated. A number of studies have investigated the approach of sending patients of all ages taped recordings of the oncology consultation,78–82 in each of which patients showed a positive response to taped recordings and generally preferred them over letters.82 Patients reported improved understanding through at-home review of the consultation tapes,80–81although there was little evidence that the audiotapes increased recall of either diagnosis or treatment plan.79,82 Physicians themselves, meanwhile, generally prefer sending individualized letters rather than audiotapes,83,84—an approach that has been shown to improve recall of the consultation.85 Another approach considered to enhance understanding is the addition of a videotape to the consent process.86–88 Thomas et al88 provided patients with a videotape after the initial consultation, and found that it significantly reduced the anxiety and depression associated with follow-up discussions of treatment options. Follow-up telephone contacts have had some success. Aaronson et al89 performed a study in 180 patients who were randomized to standard informed consent procedures versus standard informed consent procedures plus a follow-up telephone contact with an oncology nurse. The group of patients receiving the follow-up phone call were better informed about the risks and sideeffects of potential treatments and the nature of randomization. Importantly, however, this approach had no effect on rates of clinical trial participation. While none of the above studies focused on older patients, methods for improving comprehension of consent specifically for the elderly have been undertaken in noncancer-specific settings.90–92 All of these studies represent important first steps in the attempt to better prepare patients for potential participation in cancer clinical trials. Patients with explicitly diagnosed dementia or other ailments associated with cognitive impairment provide yet a further degree of complexity. The prevalence of dementia increases from 2.8% for adults aged 65–74 to 28% for those 85 or older.93 Treatment itself may induce cognitive decline. One study found that 19% of advanced breast cancer patients who signed a clinical trial consent form had at least moderate cognitive failure due to treatment.94 While methods of gaining consent from patients with dementia have been proposed,95 it could be a substantial impediment to clinical trial participation in such patients. For patients with later-stage dementia, in most cases the treatment decisions would be made by a family member or other proxy. Here, the decision to treat or not to treat is difficult in and of itself, and the clinical trial option adds yet another dimension.

Comprehensive Geriatric Oncology

476

Cost The costs associated with the treatment of the elderly with cancer promise to increase dramatically in the coming decades. One study estimated that Medicare costs for the ‘oldest old’ (those 85 and older) will increase sixfold by the year 2040,93 and the US Government Accounting Office estimates that total Medicare spending will double as a share of the US gross domestic product by 2035.96 But while increased expenditures for cancer treatment as a whole are inevitable, there is little indication that the cost of clinical trial therapy either is more expensive now or will be more expensive in the future than non-protocol therapy. Despite this, treatment providers have historically had difficulty in obtaining reimbursement from health insurers.97 These policies have discouraged patients and physicians from seeking prior approval for trial enrollment, hindering clinical trial participation.98 Physicians report that the cost of clinical trials is a major impediment to recommending trials to their patients.9,99 In a survey of physicians at the Illinois Cancer Center by Benson et al,9 79% indicated that clinical trials impose a high financial burden on the patient, and 29% said this reason had caused them not to place patients on a trial. Patients have similar concerns, reflected in the studies by Hunter et al11 and Klabunde et al12 (see Table 22.3), where one of the measurable components of patient refusal was cost concerns. Historically, health insurers have not covered the costs of what was considered to be ‘experimental’ therapy, including clinical trials for cancer, for patients of any age, citing two assumptions: (i) that alternative therapies promoted in clinical trials could be potentially harmful to the patient and (ii) that clinical trials cost much more than standard therapy. Although some physicians believe that patients receive inferior care on clinical trials or have concerns about the relative efficacy of experimental compared with standard treatments,9 most understand that any well-designed clinical trial compares standard therapy with an alternative therapy that as good as or better than standard therapy (phase III), or otherwise offers a phase II trial that is state-of-the-art. However, acknowledgement of this notion may not be universal, and continued education is warranted. Furthermore, participation in clinical trials does not significantly increase the cost of care for cancer patients.100–104 Bennett et al101 studied the 6-month direct medical charges for 35 clinical trial participants and 35 matched controls from five cancer centers. The total estimated mean charges for the clinical trial participants were $57542, while those for the controls were $63721. Similarly, a study at the Mayo Clinic by Wagner et al104 investigated 61 matched pairs. Total costs for the clinical trial patients were similar to costs for their matched controls at 1 month, 3 months, 6 months, 1 year, and 5 years. Other studies have found similar cost-efficacy for clinical trials.100,102,103 These studies, the largest of which used 135 matched pairs, are summarized in Table 22.6. A much larger trial (the Costs of Cancer Treatment (CCT) study), planned by Goldman and colleagues at RAND Corporation and the NCI, will use data from 750 patients enrolled in NCI-sponsored phase II or III trials and their matched pairs.105

Under-representation of elderly patients in cancer clinical trials

477

Older persons in the USA are almost entirely covered by Medicare. In 2000, 34 million beneficiaries aged 65 or older were covered by Medicare,106 which represents nearly all (98%) of those 65 or older.1 Prior to 2000, however, Medicare did not cover the routine costs of clinical trials—a major barrier to enrollment for older patients. The decade-long advocacy of organizations such as the American Society for Clinical Oncology (ASCO) had raised awareness of the potential impact of this Medicare policy, although the extent of the impact was

Table 22.6 Costs or charges of cancer clinical trials compared with non-trial treatmenta Study

No. of Year Phase Units patients

Quirk et al103 77 (MSKCC)

Bennett et al101 (AACI)

Fireman et al102 (Kaiser Permanente)

Wagner et al104 (Mayo Clinic)

35

135

61

1995

II/III

1996– II 98

1994– III 96

1988– II/III 94

Costs

Group

Total costs or charges (US$) 1 mo 3 mo

6 mo 1 yr

Control

37055

CT patients

30775

% difference

−17%

Charges Control

63721

CT patients

57542

% difference

−10%

Costs

Costs

Control

15516

CT patients

17003

% difference

+10%

2 yr

Control

3820

7499 10073 14762

26797

CT patients

3457

7421 12200 16819

27090

% −10% −1% +21% +14% difference Barlow et al100 (GHC)

69

1990– II/III 96

Costs

5 yr

+1%

Control

25000

CT patients

30000

Comprehensive Geriatric Oncology

478

% difference Goldman et 750 al105 (RAND/NCI)

1998

III

Costs

+20% Results pending

CT, chemotherapy. a Adapted from Bennett CL, Adams JR, Knox KS et al. Clinical trials: Are they a good buy? J Clin Oncol 2001; 19:4330–9.

not entirely known. But in 1999, the US Institute of Medicine (IOM) issued a report highlighting issues regarding ethnic minorities and the medically under-served, including reference to the severe under-representation of the elderly in clinical trials as found in the SWOG,6 noting that ‘Medicare…coverage of costs associated with enrollment in a clinical trial is poor and inconsistent, limiting the ability of populations covered by these plans to enter clinical trials’, and recommending that the Health Care Financing Administration (HCFA) ‘coordinate to address funding for clinical trials’.107 The accumulation of evidence of the degree to which this policy hindered clinical advances for elderly cancer patients, combined with evidence of the cost-effectiveness of clinical trials compared with non-protocol therapy, resulted in a subsequent IOM report in 2000, ‘Extending Medicare Reimbursement in Clinical Trials’, explicitly recommending that ‘Medicare should reimburse routine care for patients in clinical trials’.108 In June 2000, President Clinton issued an executive memorandum directing Medicare to revise its payment policy to reimburse providers whose patients participate in clinical trials.109 This change in policy will likely increase accrual of older patients to cancer clinical trials. However, implementation of the plan has presented some unexpected stumbling blocks; in particular, providers may be unsure about how to code the claims submitted to Medicare for clinical trials services. ASCO has advocated for clarification of this issue.110 In addition, Medicare will not cover the investigative item or service itself, items or services provided for data collection, or items and services provided at no charge by the trial sponsor.111 Thus, there are other potential costs not covered in the current Medicare plan. To date, Medicare has received fewer claims for clinical trials reimbursement than were expected.110 This is probably due in part to the lack of familiarity with the new policies. But there may also be uncertainty or confusion, among both physicians and patients, about what exactly is covered by Medicare. Clarification of these issues, and education of providers, could remove these final cost barriers to clinical trial enrollment for older patients. Patient refusal While efforts toward reducing eligibility, physician, informed consent, cost, and other barriers to clinical trials are critical, the ultimate decision regarding trial participation rests with the patient, and the often-complex decision-making process will reflect a patient’s personal biases and attitudes, together with those of his or her family and close

Under-representation of elderly patients in cancer clinical trials

479

friends. Altruistic motivations regarding contributions to research do influence a proportion of patients, but the majority are (appropriately) primarily concerned with finding the best possible treatment for their disease.112,113 In the absence of other barriers, a patient who believes that the best possible treatment option is to be found in a clinical trial is more likely to participate in that trial. Focus group studies of older patients consistently find that fear and anxiety underlie attitudes towards cancer.114–116 Older patients are particularly fearful of the experimental aspect of clinical trials.11,12 This fear is likely rooted in a history of testing new therapies on human subjects that is earmarked by instances of abuse. The Tuskegee Syphilis Study is perhaps the most well-known example. Over a period of 40 years, from 1932 to 1972, a cohort of 399 African-Americans were denied treatment for syphilis and deceived by the physicians in charge of the study.117 A study by Shavers et al118 has shown that knowledge of the Tuskegee Study resulted in distrust of research in both AfricanAmericans and Whites: 46% of African-Americans and 34% of Whites indicated that this would affect future research participation. Knowledge of the history of human experimentation with radiation in the USA following the Second World War may also have induced fear of research.119 Attention in the last several decades to the process of rigorous consent has likely reduced these fears for younger generations of patients. But for older patients, history’s examples of experimental abuse are likely to be influential. A secondary component of fear of experimentation is the process of randomization. There is perhaps no stronger indication that a patient is about to undergo an experiment than the revelation that the patient will be randomly allocated to one of two or more treatments. The introduction of chance in the treatment process may only confirm already-existing fears and distrust of a clinical trial. A study by Llewellyn-Thomas et al120 specifically addressed reasons patients would refuse entry to a clinical trial for colonic adenocarcinoma. Fully 63% of the patients who would refuse participation reported an aversion to randomization as their primary reason for trial refusal. Other studies confirm patient concerns about randomization.11,12,121,122 Recognizing this, some physicians avoid the word ‘randomization’, relying instead on analogy to describe the randomization process.123 This may explain in part why even patients who are randomized on a trial sometimes do not understand that they have been randomized. In one survey study of patients already randomized to a trial of adjuvant therapy for breast cancer, only 23% knew that they had been randomized according to a follow-up questionnaire.124 In the non-randomized trial setting, only 33% of patients surveyed by Daugherty et al113 were able to state the purpose of the phase I trial in which they were participating. Fears of toxic effects of chemotherapeutic drugs will preclude the participation of older patients more than younger patients, even though these fears should pertain whether the treatment is offered on a clinical trial or not. As already discussed, older cancer patients are much more likely to have significant chronic illnesses than their younger counterparts. Only further research into new treatments targeted towards the frail elderly will establish whether cancer therapies can be safely administered to this population. Even if they can, it may be difficult to convince an older patient with significant comorbidities that treatment for their cancer (either on or off trial) is warranted. One last reason pertains to the fatalism many associate with the word ‘cancer’. Reared at a time when there were few treatments for cancer, older patients tend to perceive their

Comprehensive Geriatric Oncology

480

prognosis in fatalistic terms.115,116 Older patients without cancer, in fact, sometimes state that they would prefer not to know about a cancer diagnosis.115,116 In this context, even therapies shown to be tolerable for older patients may, especially in the face of other illness, be rejected in favor of no therapy. Clearly the need for extra attention and extra information to alleviate the misapprehensions and concerns of older patients about clinical trials is crucial. Unfortunately, it has been found that physician recommendations of clinical trials were not as effectively communicated as non-trial treatments.125 Various approaches for enhancing communication have been investigated. For instance, Albrecht et al126 videotaped 48 patient-physician interactions at the H Lee Moffitt Cancer Center. In each session, the possibility of a clinical trial was presented to the patient. Physicians who verbally presented items normally included in an informed consent document and who ‘behaved in a reflective, patient-centered, supportive and responsive manner’ were more successful at eliciting patient participation. Fallowfield et al127 studied 315 patients with cancer at two major cancer centers in the UK. Initially, more than half of the patients (55%) refused participation if treatment was randomized. But when additional information about the randomization procedure was provided, 68% of the patients initially refusing participation said that they would change their minds about trial participation. In addition, patients in general have been found to be more willing to participate in clinical trials if they feel involved in the decision-making;72,120,125,128 unfortunately, at least one study has found that shared decision-making decreases with age.129 Patients may refuse participation for other reasons unrelated to attitudes regarding experimentation, randomization, toxicity, or perceived lack of efficacy. Transportation and other logistic issues can be more burdensome for the older patient. Increased age correlates with decreased capacity to drive, even for patients with normal cognitive function.130 The prevalence of deformity or orthopedic impairment contributes to driving difficulties (Table 22.4). Thus, the elderly will more often rely on others for transportation. This may be a limiting factor to trial participation, especially for those trials that require frequent follow-up visits for trial monitoring (although often at no increased frequency compared with standard care options). Other physical limitations (e.g. auditory or visual) may interfere with multiple components of clinical trial participation, including transportation and the obtaining of consent. The NHIS identifies hearing impairment (30.3%) as a common chronic condition in persons 65 or older, as well as visual impairment (8.4%) and cataracts (17.2%) (Table 22.4).16 The simple but necessary task of opening medication containers presents a barrier for some older patients, especially those with decreased cognitive function, poor vision, and low manual dexterity.131,132 Family decision Research has shown strong correlation between a patient’s treatment status and the psychological well-being of the family.133 Caregivers often report heightened symptoms of anxiety and depression.134 A study by Covinsky et al135 using data obtained for 2129 patients from the Study to Understand Prognoses and Preferences for Outcomes and

Under-representation of elderly patients in cancer clinical trials

481

Risks of Treatment (SUPPORT) found that many families of seriously ill patients suffer severe caregiving and financial burdens. For the otherwise-fit older patient, who is fully capable and competent to decide on his or her own treatment, the personal impact of the patient’s treatment status on family well-being will likely play a role in the treatment decision. In fact, the influence of family members often outweighs the influence of medical professionals. A study by Smitt and Heltzel136 in women with breast cancer choosing between mastectomy and breast-conserving therapy found that a patient’s spouse ranked behind surgeons and primary care physicians but ahead of radiation and medical oncologists in terms of influence on the patient’s treatment decision. A majority of the patients consulted with their spouse before making a treatment decision. Overarching these issues is the very strong desire of the older person (even if fit) not to be a burden to others.137,138 In those instances where the patient is unable to make a treatment decision—due to diminished consciousness, to cognitive impairment, or to other reasons—a proxy or surrogate, generally designated by the patient, has the responsibility of making the treatment decision. Family members have traditionally had moral and legal standing as the most appropriate surrogate for incompetent patients, both because family members usually act in accordance with patients’ wishes and because family members are usually most affected by the treatment decisions.139 Studies in other disease settings have shown that at least 90% of patients designate a family member as surrogate.140,141 Patients who are incapable of making their own treatment decisions are more likely to have other significant comorbidities. Here the primary decision is likely to be whether to treat the patient at all; the added complexities of clinical trial participation could be prohibitive. However, some patients with cognitive impairment are otherwise healthy. For patients such as these, a family member acting as surrogate decision-maker may be presented with the option of a cancer clinical trial. A standard approach for attempting to replicate the treatment decision that a patient would make were the patient competent involves the method of substituted judgment. A surrogate is asked to take into account (to the extent possible) known and supposed patient preferences and attitudes and to predict the patient’s treatment decision under a specific set of circumstances. The effectiveness of this approach, however, is in dispute. Studies in other disease settings show that substituted judgment has reasonable success,142,143 while others indicate that surrogates’ ability to predict patient preference is no better than chance alone.144–146 One study by Libbus and Russell147 showed good agreement between patients and their surrogates in all diseases except cancer, where surrogates were significantly more likely to choose treatment than patients. The imperfect accuracy of surrogate decision-making through substituted judgment has encouraged patients and families to consider making their treatment decisions known beforehand through advanced directives, in which a competent person delineates specific medical interventions that might be considered under specific scenarios if the person loses decision-making capacity. The presumption of enhanced self-determination through this approach has been refuted by at least one study, however. A randomized survey trial by Ditto et al140 compared the accuracy of surrogate decision-making with no advanced directive involvement with the accuracy after different advanced directive implements were utilized to assist the surrogate. The results showed that none of the advanced-

Comprehensive Geriatric Oncology

482

directive interventions produced significant improvements in the accuracy of surrogate decision-making. Similar results were found by Coppola et al.148 A study by Ling et al149 found that, among cancer patients of all ages recruited for possible participation in clinical trials for palliative care, one of the most common reasons for unwillingness to participate was family objection. But research on the specific factors that influence a family against deciding to allow an incompetent patient, or to urge a competent patient, to participate in a clinical trial is minimal. This very important area must be addressed in clinical research. Remedial strategies Although the research on all these areas regarding barriers to clinical trial accrual with particular emphasis on the elderly is very thin, we offer some strategies that may improve participation. First, the interaction between comorbidity and malignancy, in terms of both treatment tolerability and outcome, will need to be considered in future trials. There is, for instance, evidence of synergistic effects of combinations of certain cancers and certain non-cancer illnesses on outcome. A study by Newschaffer et al150 looked specifically at the interaction of comorbidity and breast cancer in older women. Mortality for women with breast cancer and comorbidity was 17% greater than would have been expected were there no interaction between the two. Since most elderly cancer patients have at least one other chronic illness, the ability to define elderly patient prognostic groups must depend in part on comorbidity assessment. As yet, however, no comorbidity index has been developed or adapted specifically for use in cancer patients, nor has a comorbidity index been used in a prospective fashion as part of a clinical trial. Functional status has also been shown to independently predict survival. The development of a geriatric cancer performance index, which likely includes measures of both comorbidity and functional status, is a necessary hurdle that must be overcome in order to facilitate the future study of cancer in the elderly—both to define eligibility for trials targeted to either the fit or the more frail elder, and to stratify within trials. Physician influence is a critical factor in clinical trial enrollment, especially among the elderly, who may be less familiar with such research and will rely to a greater degree upon the physician’s discretion in selecting treatment. Among all patients, physicians are deterred from entering patients on trials for various reasons, including fear that presentation of a clinical trial will undermine the doctor-patient relationship, difficulties obtaining informed consent, dislike of open discussions about uncertainty, and concerns about costs, logistics, and study design. While multiple studies have investigated physician attitudes towards clinical trials in patients of all ages, prospective studies that specifically profile physician attitudes towards enrolling elderly patients on cancer clinical trials are needed. Of particular concern are prior survey studies showing physician concern that clinical trials offer outdated or uninteresting therapies, or that clinical trials offer non-standard or (in the randomized setting) unequal treatments. The dearth of clinical trials in older cancer patients might only accentuate these existing concerns. In fact, clinical trials are designed to offer therapy that is state of the art. Continued emphasis in the oncology community on the beneficial aspects of clinical trials is warranted. In addition, concerns

Under-representation of elderly patients in cancer clinical trials

483

about the practical difficulties of clinical trial participation inhibit participation in many instances. Emphasis on the importance of designing ‘user-friendly’ trials (both for fit patients of all ages and for the patient with comorbid diseases) is also needed. The complex issue of obtaining informed consent has been the subject of study in cancer and other fields among patients of all ages—however, evidence regarding the particular problems of informed consent in older cancer patients is lacking. Studies to ascertain the extent of the problem should be conducted; meanwhile, efforts to improve patient comprehension of treatment options through follow-up letters, follow-up phone contacts, or audio- or videotape recordings of the initial consultation (which have had some success in patients of all ages) may also have success in older patients. The detrimental effects of lack of cost-coverage of clinical trials should be alleviated in the future for elderly patients in the USA as a result of changes in Medicare policy. However, accrual rates of elderly patients to clinical trials need to be monitored to assess whether this change actually correlates with increased elderly enrollment. It is likely that not all patients and physicians are fully aware of the opportunity for clinical trials coverage that Medicare now provides. In addition, some reimbursement issues remain, which may cause confusion among patients and physicians regarding coverage. Clarification of these issues could remove these final cost barriers to clinical trial enrollment for older patients. Education of the older patient population and their families with respect to the nature of clinical trials is critical to alleviating potential fears and anxieties. While instances of abuse have occurred in the past, the more recent advances in the areas of informed consent and clinical trial regulation have led to trials that are more transparent, especially with regard to the fact that participation is completely voluntary and the patient can always terminate participation at his or her discretion. In addition, it should be emphasized to the patient (not just the physician) that a clinical trial involves the administration of a treatment that is not worse than standard therapy and may be better. Difficulties in communication with older patients—whether due to decreased functional (e.g. auditory or visual) or mental status changes, or other reasons—negatively impact the informed consent process. Prospective research into the consent process, targeted specifically at the older cancer patient, is required, to assess both the extent of the problem (in particular, lack of comprehension) and remedial approaches (i.e. taped recordings of the consultation). Difficulties in communication also imply a greater role for family members in treatment decision-making. The extent to which families influence treatment choice for older patients needs to be assessed. In addition, discussion of clinical trial participation as a potential treatment option should be discussed early in the diagnostic process (since patients may lose decisionmaking capacity if their disease or comorbid conditions progress), both with the patient and with family members. Most physicians anticipate that patients get better care in clinical trials; this prospect alone may influence family decisions in favor of clinical trial participation. Conclusions The NIA, in cooperation with the NCI, has initiated program grants for clinical trials, specifically targeting treatment of cancer in the elderly.151 Strategy sessions and

Comprehensive Geriatric Oncology

484

workshops for cancer centers and cooperative groups are underway. The initiation of these grants and programs represents a growing awareness of the current (and increasing) burden of cancer in the elderly population, and of the need for increased clinical research targeted toward this patient group. Studies have illustrated the severe under-representation of the elderly in clinical trials. In this chapter, we have investigated some of the potential major barriers to clinical trial participation. Elderly patients are likely hindered from clinical trial enrollment because of eligibility criteria that exclude them; often, these eligibility criteria concern the presence of comorbid illness, which is much more prevalent in older persons. A historic bias against enrolling older patients on clinical trials is still prevalent among physicians, due, perhaps, to a dearth of good data on older patient tolerance and response to standard and newer therapies. Older patients may refuse trial participation themselves, often because of fears of research or logistic concerns such as transportation to and from the clinic. Difficulties with consent, which are prevalent for patients of any age, are particularly so in older persons. Cost concerns may still exist, although these should be less of a barrier in future US trials owing to new Medicare funding. Finally, family influence is of particular importance. But research on these barriers to cancer clinical trials for older patients is lacking; indeed, in order to explore issues in elderly patients, it is sometimes necessary to use data from other disciplines, or, within the field of cancer, to use data from patients of any age. Thus, prospective studies of barriers to cancer clinical trials for elderly patients are clearly required. The results of such studies will indicate where and how to target efforts to increase clinical trial enrollment for the elderly, so that we may begin to rectify this important barrier to clinical cancer research. References 1. Day, JC. Population Projections ofthe United States by Age, Sex, Race, and Hispanic Origin: 1995 to 2050. Washington, DC: US Government Printing Office, Current Population Reports, P25–1130, 1996. 2. Balducci I, Balducci L, Extermann M. Cancer and aging. An evolving panorama. Hematol Oncol Clin North Am. 2000; 14:1–16. 3. Ries LAG, Eisner MP, Kosary CL et al (eds). SEER Cancer Statistics Review, 1973–1998. Bethesda, MD: National Cancer Institute, 2001. 4. Howe HL, Wingo PA, Thun MJ et al. Annual report to the nation on the status of cancer (1973 through 1998), featuring cancers with recent increasing trends. J Natl Cancer Inst 2001; 93:824–42. 5. Yancik R. Cancer burden in the aged: an epidmiologic and demographic overview. Cancer 1997; 80:1273–83. 6. Hutchins LF, Unger JM, Crowley JJ et al. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 1999; 341:2061–7. 7. Trimble EL, Carter CL, Cain D et al. Representation of older patients in cancer treatment trials. Cancer 1994; 74(7 Suppl):2208–14. 8. Tejeda HA, Green SB, Trimble EL et al. Representation of African-Americans, Hispanics, and Whites in National Cancer Institute cancer treatment trials. J Natl Cancer Inst 1996; 88:812–6. 9. Benson AB 3rd, Pregler JP, Bean JA et al. Oncologists’ reluctance to accrue patients onto clinical trials: an Illinois Cancer Center study. J Clin Oncol 1991; 9:2067–75.

Under-representation of elderly patients in cancer clinical trials

485

10. Begg CB, Zelen M, Carbone PP et al. Cooperative groups and community hospitals. Measurement of impact in the community hospitals. Cancer 1983; 52:1760–7. 11. Hunter CP, Frelick RW, Feldman AR et al. Selection factors in clinical trials: results from the Community Clinical Oncology Program Physician’s Patient Log. Cancer Treat Rep 1987; 71:559–65. 12. Klabunde CN, Springer BC, Butler B et al. Factors influencing enrollment in clinical trials for cancer treatment. South Med J 1999; 92: 1189–93. 13. Lara PN Jr., Higdon R, Lim N et al. Prospective evaluation of cancer clinical trial accrual patterns: identifying potential barriers to enrollment. J Clin Oncol 2001; 19:1728–33. 14. McCusker J, Wax A, Bennett JM. Cancer patient accessions into clinical trials. Am J Clin Oncol 1982; 5:227–36. 15. Simon MS, Brown DR, Du W et al. Accrual to breast cancer clinical trials at a universityaffiliated hospital in metropolitan Detroit. Am J Clin Oncol 1999; 22:42–6. 16. Adams PF, Hendershot GE, Marano MA. Current estimates from the National Health Interview Survey, 1996. National Center for Health Statistics. Vital Health Statist 1999; 10(200). 17. US Senate Special Committee on Aging, American Association of Retired Persons, Federal Council on Aging, US Administration on Aging. Aging America: Trends and projections. Washington DC: US Department of Health and Human Services, 1991. 18. Havlik RJ, Yancik R, Long S et al. The National Institute on Aging and the National Cancer Institute SEER collaborative study of comorbidity and early diagnosis of cancer in the elderly. Cancer 1994; 74(7 Suppl):2101–6. 19. Mor V, Masterson-Allen S, Goldberg RJ et al. Relationship between age at diagnosis and treatments received by cancer patients. J Am Geriatr Soc 1985; 33:585–9. 20. Newschaffer CJ, Penberthy J, Desch CE et al. The effect of age and comorbidity in the treatment of elderly women with nonmetastatic breast cancer. Arch Intern Med 1996; 156:85– 90. 21. Samet J, Hunt WC, Key C et al. Choice of cancer therapy varies with age of patient. JAMA 1986; 255:3385–90. 22. Silliman RA, Guadagnoli E, Weitberg AB, Mor V. Age as a predictor of diagnostic and initial treatment intensity in newly diagnosed breast cancer patients. J Gerontol 1989; 44:M46–50. 23. Siminoff LA, Zhang A, Colabianchi N et al. Factors that predict the referral of breast cancer patients onto clinical trials by their surgeons and medical oncologists. J Clin Oncol 2000; 18:1203–11. 24. Balducci L, Cox CE, Greenberg H et al. Management of cancer in the aged patient. In: Comprehensive Geriatrk Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:391–8. 25. Balducci L, Mowry K. Pharmacology and organ toxicity of chemotherapy in older patients. Oncology (Hungtingt) 1992; 6 (Suppl):62–8. 26. Cova D, Balducci L. Cancer chemotherapy in the older patient. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004: 463–88. 27. Begg CB, Cohen JL, Ellerton J. Are the elderly predisposed to toxicity from cancer chemotherapy? An investigation using data from the Eastern Cooperative Oncology Group. Cancer Clin Trials 1980; 3: 369–74. 28. Crivellari D, Bonetti M, Castiglione-Gertsch M et al. Burdens and benefits of adjuvant cyclophosphamide, methotrexate, and fluorouracil and tamoxifen for elderly patients with breast cancer: the International Breast Cancer Study Group Trial VII. J Clin Oncol 2000; 18:1412–22. 29. Christman K, Muss HB, Case LD, Stanley V. Chemotherapy of metastatic breast cancer in the elderly. The Piedmont Oncology Association experience. JAMA 1992; 268:57–62. 30. Albain K, Green S, Ravdin P et al. Overall survival after cyclophosphamide, Adriamycin, 5FU, and tamoxifen (CAFT) is superior to T alone in postmenopausal, receptor (+), node (+)

Comprehensive Geriatric Oncology

486

breast cancer: new findings from phase III Southwest Oncology Group intergroup trial S8814 (INT-0100). Proc Am Soc Clin Oncol 2001; 94. 31. Gharlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40:373– 83. 32. Beddhu S, Bruns FJ, Saul M et al. A simple comorbidity scale predicts clinical outcomes and costs in dialysis patients. Am J Med 2000; 108: 609–13. 33. Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidimiol 1994; 47:1245–51. 34. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9CM administrative databases. J Clin Epidemiol 1992; 45:613–9. 35. D’Hoore W, Sicotte C, Tilquin C. Risk adjustments in outcome assessment: the Charlson Comorbidity Index. Meth Inf Med 1993; 32:382–7. 36. Fried L, Bernardini J, Piraino B. Charlson Comorbidity Index as a predictor of outcomes in incident peritoneal dialysis patients. Am J Kidney Dis 2001; 37:337–42. 37. Gabriel SE, Crowson CS, O’Fallon WM. A comparison of two comorbidity instruments in arthritis. J Clin Epidemiol 1999; 52: 1137–42. 38. Poses RM, McClish DK, Smith WR et al. Prediction of survival of critically ill patients by admission comorbidity. J Clin Epidimiol 1996; 49:743–7. 39. Skiest DJ, Rubinstien E, Carley N et al. The importance of comorbidity in HIV-infected patients over 55: a retrospective case-control study. Am J Med 1996; 101:605–11. 40. Linn BS, Linn MW, Gurel L. Cumulative Illness Rating scale. J Am Geriatr Soc 1968; 16:622– 6. 41. Kaplan MH, Feinstein AR. The importance of classifying initial co-morbidity in evaluating the outcome of diabetes mellitus. J Chron Dis 1974; 27:387–404. 42. Greenfield S, Apolone G, McNeil BJ, Cleary PD. The importance of co-existent disease in the occurrence of postoperative complications and one-year recovery in patients undergoing total hip replacement. Comorbidity and outcomes after hip replacement. Med Care 1993; 31:141–54. 43. Greenfield S, Blanco DM, Elashoff RM, Ganz PA Patterns of care related to age of breast cancer patients. JAMA 1987; 257:2766–70. 44. Fleming ST, Rastogi A, Dmitrienko A, Johnson KD. A comprehensive prognostic index to predict survival based on multiple comorbidities: a focus on breast cancer. Med Care 1999; 37:601–14. 45. Newschaffer CJ, Bush TL, Penberthy LT. Comorbidity measurement in elderly female breast cancer patients with administrative and medical records data. J Clin Epidemiol 1997; 50; 725– 33. 46. Satariano WA, Ragland DR. The effect of comorbidity on 3-year survival of women with primary breast cancer. Ann Intern Med 1994; 120:104–10. 47. West DW, Satariano WA, Ragland DR, Hiatt RA. Comorbidity and breast cancer survival: a comparison between Black and White women. Ann Epidemiol 1996; 6:413–9. 48. Yancik R, Wesley MN, Ries LA et al. Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older. JAMA 2001; 285:885–92. 49. Yancik R, Wesley MN, Ries LA et al. Comorbidity and age as predictors of risk for early mortality of male and female colon carcinoma patients: a population-based study. Cancer 1998; 82:2123–34. 50. Extermann M, Overcash J, Lyman GH et al. Comborbidity and functional status are independent in older cancer patients. J Clin Oncol 1998; 16:1582–7. 51. Katz S. A standardized measure of biological and psychosocial functions. JAMA 1963; 185:914–19. 52. Katz S, Branch LG, Branson MH et al. Active life expectancy. N Engl J Med 1983; 309:1218– 24.

Under-representation of elderly patients in cancer clinical trials

487

53. Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 1969; 9: 179–86. 54. Berkman LF, Leo-Summers L, Horwitz RI. Emotional support and survival after myocardial infarction. A prospective, population-based study of the elderly. Ann Intern Med 1992; 117:1003–9. 55. Greenwood DC, Muir KR, Packham CJ, Madeley RJ. Coronary heart disease: a review of the role of psychosocial stress and social support. J Public Health Med 1996; 18:221–31. 56. Oxman TE, Freeman DH Jr., Manheimer ED. Lack of social participation or religious strength and comfort as risk factors for death after cardiac surgery in the elderly. Psychosom Med 1995; 57:5–15. 57. Penninx BW, van Tilburg T, Kriegsman DM et al. Effects of social support and personal coping resources on mortality in older age: the Longitudinal Aging Study Amsterdam. Am J Epidemiol 1997; 146: 510–9. 58. Ruberman W, Weinblatt E, Goldberg JD, Chaudhary BS. Psychosocial influences on mortality after myocardial infarction. N Engl J Med 1984; 311:552–9. 59. Butow PN, Coates AS, Dunn SM. Psychosocial predictors of survival in metastatic melanoma. J Clin Oncol 1999; 17:2256–63. 60. de Graeff A, de Leeuw JR, Ros WJ et al. Sociodemographic factors and quality of life as prognostic indicators in head and neck cancer. Eur J Cancer 2001; 37:332–9. 61. Kemeny MM, Muss HB, Kornblith AB et al. Barriers to participation of older women with breast cancer in clinical trials. Proc Am Soc Clin Oncol 2000; 2371. 62. Taylor KM, Margolese RG, Soskolne CL. Physicians’ reasons for not entering eligible patients in a randomized clinical trial of surgery for breast cancer. N Engl J Med 1984; 310:1363–7. 63. Fox SA, Roetzheim RG, Kington RS. Barriers to cancer prevention in the older person. Clin Geriatr Med 1997; 13:79–85. 64. Mansour EG. Barriers to clinical trials. Part III: Knowledge and attitudes of health care providers. Cancer 1994; 74(9 Suppl): 2672–5. 65. Hjorth M, Holmberg E, Rodjer S, et al. Physician’s attitudes toward clinical trials and their relationship to patient accrual in a Nordic multicenter study on myeloma. Control Clin Trials 1996; 17:372–86. 66. Taylor KM, Shapiro M, Soskolne CL, Margolese RG. Physician response to informed consent regulations for randomized trials. Cancer 1987; 60:1415–22. 67. Grossman SA, Piantadosi S, Covahey C. Are informed consent forms that describe clinical oncology research protocols readable by most patients and their families? J Clin Oncol 1994; 12:2211–5. 68. Joffe S, Cook EF, Cleary PD et al. Quality of informed consent in cancer clinical trials: a crosssectional survey. Lancet 2001; 358: 1772–7. 69. White DR, Muss HB, Michielutte R et al. Informed consent: patient information forms in chemotherapy trials. Am J Clin Oncol 1984; 7: 183–90. 70. Davis TC, Holcombe RF, Berkel HJ et al. Informed consent for clini cal trials: a comparative study of standard versus simplified forms. J Natl Cancer Inst 1998; 90:668–74. 71. Simes RJ, Tattersall MH, Coates AS et al Randomised comparison of procedures for obtaining informed consent in clinical trials of treatment for cancer. BMJ 1986; 293:1065–8. 72. Ellis PM, Butow PN, Tattersall MH et al. Randomized clinical trials in oncology: understanding and attitudes predict willingness to participate. J Clin Oncol 2001; 19:3354–61. 73. Lynoe N, Sandlund M, Jacobsson L. Clinical cancer research—some aspects on doctors’ attitudes to informing participants. Acta Oncol 1996; 35:749–54. 74. Ellis PM, Dowsett SM, Butow PN, Tattersall MH. Attitudes to randomized clinical trials amongst out-patients attending a medical oncology clinic. Health Expect 1999; 2:33–43. 75. Christensen K, Haroun A, Schneiderman LJ, Jeste DV. Decision-making capacity for informed consent in the older population. Bull Am Acad Psychiatry Law 1995; 23:353–65.

Comprehensive Geriatric Oncology

488

76. Krynski MD, Tymchuk AJ, Ouslander JG. How informed can consent be? New light on comprehension among elderly people making decisions about enteral tube feeding. Gerontologist 1994; 34:36–43. 77. Stanley B, Guido J, Stanley M, Shortell D. The elderly patient and informed consent. Empirical findings. JAMA 1984; 252:1302–6. 78. Deutsch G. Improving communication with oncology patients: taping the consultation. Clin Oncol 1992; 4:46–7. 79. Dunn SM, Butow PN, Tattersall MH et al. General information tapes inhibit recall of the cancer consultation. J Clin Oncol 1993; 11: 2279–85. 80. Hogbin B, Fallowfield L. Getting it taped: the ‘bad news’ consultation with cancer patients. Br J Hosp Med 1989; 41:330–3. 81. Johnson IA, Adelstein DJ. The use of recorded interviews to enhance physician-patient communication. J Cancer Educ 1991; 6:99–102. 82. Tattersall MH, Butow PN, Griffin AM, Dunn SM. The take-home message: patients prefer consultation audiotapes to summary letters. J Clin Oncol 1994; 12:1305–11. 83. McConnell D, Butow PN, Tattersall MH. Audiotapes and letters to patients: the practice and views of oncologists, surgeons and general practitioners. Br J Cancer 1999; 79:1782–8. 84. Stockler M, Butow PN, Tattersall MH. The take-home message: doctors’ views on letters and tapes after a cancer consultation. Ann Oncol 1993; 4:549–52. 85. Damian D, Tattersall MH. Letters to patients: improving communication in cancer care. Lancet 1991; 338:923–5. 86. Agre P, McKee K, Gargon N, Kurtz RC. Patient satisfaction with an informed consent process. Cancer Pract 1997; 5:162–7. 87. Jimison HB, Sher PP, Appleyard R, LeVernois Y. The use of multimedia in the informed consent process. J Am Med Inform Assoc 1998; 5:245–56. 88. Thomas R, Daly M, Perryman B, Stockton D. Forewarned is forarmed—benefits of preparatory information on video cassette for patients receiving chemotherapy or radiotherapy—a randomized controlled trial. Eur J Cancer 2000; 36:1536–43. 89. Aaronson NK, Visser-Pol E, Leenhouts GH, et al. Telephone-based nursing intervention improves the effectiveness of the informed consent process in cancer clinical trials. J Clin Oncol 1996; 14: 984–96. 90. Dunn LB, Lindamer LA, Palmer BW et al. Enhancing comprehension of consent for research in older patients with psychosis: a randomized study of a new novel consent procedure. Am J Psychiafty 2001; 158:1911–3. 91. Rikkert MG, van den Bercken JH, ten Have HA, Hoefnagels WH. Experienced consent in geriatrics research: a new method to optimize the capacity to consent in frail elderly subjects. J Med Ethics 1997; 23:271–6. 92. Taub HA, Kline GE, Baker MT. The elderly and informed consent: effects of vocabulary level and corrected feedback. Exp Aging Res 1981; 7:137–46. 93. Schneider EL, Guralnik JM. The aging of America. Impact on health care costs. JAMA 1990; 263:2335–40. 94. Bruera E, Spachynski K, MacEachern T, Hanson J. Cognitive failure in cancer patients in clinical trials. Lancet 1993; 341:247–8. 95. Fellows LK. Competency and consent in dementia. J Am Geriatr Soc 1998; 46:922–6. 96. New Spending Estimates Underscore Need for Reform. Medicare Publication GAO-01–1010T, July 2001. 97. Fleming ID. Barriers to clinical trials. Part I: Reimbursement problems. Cancer 1994; 74(9 Suppl):2662–5. 98. NIH Clinical Trials: Various Factors Affect Patient Participation. Washington, DC: US General Accounting Office, Publication HEHS-99–1821, 1999. 99. Fisher WB, Cohen SJ, Hammond MK et al. Clinical trials in cancer therapy: efforts to improve patient enrollment by community oncologists. Med Pediatr Oncol 1991; 19:165–8.

Under-representation of elderly patients in cancer clinical trials

489

100. Barlow W, Taplin S, Seger D et al. Medical care costs of cancer patients on protocol. NCI Meeting, Bethesda, MD, July 7, 1998. 101. Bennett CL, Stinson TJ, Vogel V et al. Evaluating the financial impact of clinical trials in oncology: results from a pilot study from the association of American Cancer Institutes/Northwestern University Clinical Trials Costs and Charges Project. J Clin Oncol 2000; 18:2805–10. 102. Fireman BH, Fehrenbacher L, Gruskin EP, Ray GT. Cost of care for patients in clinical trials. J Natl Cancer Inst 2000; 92:136–42. 103. Quirk J, Schrag D, Radzyner M et al. Clinical trial costs are similar to and may be less than standard care and inpatient (INPT) charges at an academic medical center (AMC) are similar to major, minor, and non-teaching hospitals. Proc Am Soc Clin Oncol 2000; 19:433a (Abst 1696). 104. Wagner JL, Alberts SR, Sloan JA et al. Incremental costs of enrolling cancer patients in clinical trials: A population-based study. J Natl Cancer Inst 1999; 91:847–53 [Erratum 2000; 92:164–5]. 105. Goldman DP, Schoenbaum ML, Potosky AL et al. Measuring the incremental cost of clinical cancer research. J Clin Oncol 2001; 19: 105–10. 106. Medicare National Enrollment Trends for 1966–1999. Health Care Financing Administration. Internet address: http://www.hcfa.gov/stats/stats.htm. 107. Haynes MA, Smedley BD (eds). The Unequal Burden of Cancer: An Assessment of NIH Research and Programs for Ethnic Minorities and the Medically Underserved. Washington, DC: National Academy Press, 1999. 108. Aaron HJ, Gelband H (eds). Extending Medicare Reimbursement in Clinical Trials. Committee on Routine Patient Care Costs in Clinical Trials for Medicare Beneficiaries. Washington, DC: National Academy Press, 2000. 109. President Clinton takes new action to encourage participation in clinical trials. Medicare will reimburse for all routine patient care costs for those in clinical trials. White House Press Release. Washington, DC: Office of the Press Secretary, The White House, June 7, 2000. 110. Medicare coverage of clinical trials. ASCO News, Policy Watch. January 2002. 111. Medicare and Clinical Trials. Health Care Financing Administration Publication HCFA02226, January 2001. 112. Cassileth BR, Lusk EJ, Miller DS, Hurwitz S. Attitudes toward clinical trials among patients and the public. JAMA 1982; 248:968–70. 113. Daugherty C, Ratain MJ, Grochowski E et al. Perceptions of cancer patients and their physicians involved in phase I trials. J Clin Oncol 1995; 13:1062–72. 114. Beeker C, Kraft JM, Southwell BG, Jorgensen CM. Colorectal cancer screening in older men and women: qualitative research findings and implications for intervention. J Community Health 2000; 25:263–78. 115. Sutton SM, Eisner BA, Burklow J. Health communications to older Americans as a special population. The National Cancer Institute’s consumer-based approach. Cancer 1994:74(7 Suppl):2194–9. 116. Zapka JG, Berkowitz E. A qualitative study about breast cancer screening in older women: Implications for research. J Gerontol 1992; 47(Special Issue):93–100. 117. Jones JH. Bad Blood: The Tuskegee Syphilis Experiment. New York: Free Press, 1993. 118. Shavers VL, Lynch CF, Burmeister LF. Knowledge of the Tuskegee Study and its impact on the willingness to participate in medical research studies. J Natl Med Assoc 2000; 92:563–72. 119. Lederer S. Subjected to Science: Human Experimentation in America after the Second World War. Baltimore: Johns Hopkins University Press, 1995. 120. Llewellyn-Thomas HA, McGreal MJ, et al. Patients’ willingness to enter clinical trials: measuring the association with perceived benefit and preference for decision participation. Soc Sci Med 1991; 32:35–42. 121. Jenkins V, Fallowfield L. Reasons for accepting or declining to participate in randomized clinical trials for cancer therapy. Br J Cancer 2000; 82:1783–8.

Comprehensive Geriatric Oncology

490

122. McQuellon RP, Muss HB, Hoffman SL et al. Patient preferences for treatment of metastatic breast cancer: a study of women with early-stage breast cancer. J Clin Oncol 1995; 13:858–68. 123. Jenkins VA, Fallowfield LJ, Souhami A, Sawtell M. How do doctors explain randomized clinical trials to the patients? Eur J Cancer 1999; 35:1187–93. 124. Hietanen P, Aro AR, Holli K, Absetz P. Information and communication in the context of a clinical trial. Eur J Cancer 2000; 36: 2096–104. 125. Siminoff LA, Fetting JH, Abeloff MD. Doctor-patient communication about breast cancer adjuvant therapy. J Clin Oncol. 1989; 7: 1192–200. 126. Albrecht TL, Blanchard C, Ruckdeschel JC et al. Strategic physician communication and oncology clinical trials. J Clin Oncol 1999; 17: 3324–32. 127. Fallowfield LJ, Jenkins V, Brennan C et al. Attitudes of patients to randomised clinical trials of cancer therapy. Eur J Cancer 1998; 34: 1554–9. 128. Buchanan J, Borland R, Cosolo W et al. Patients’ beliefs about cancer management. Support Care Cancer 1996; 4:110–7. 129. Kaplan SH, Gandek B, Greenfield S et al. Patient and visit characteristics related to physicians’ participatory decision-making style. Results from the Medical Outcomes Study. Med Care 1995; 33: 1176–87. 130. Barbas NR, Wilde EA. Competency issues in dementia: medical decision making, driving, and independent living. J Geriatr Psychiatry Neurol 2001; 14:199–212. 131. Nikolaus T, Kruse W, Bach M et al. Elderly patients’ problems with medication. An inhospital and follow-up study. Eur J Pharmacol 1996; 49:255–9. 132. Thwaites JH. Practical aspects of drug treatment in elderly patients with mobility problems. Drugs Aging 1999; 14:105–14. 133. Cassileth BR, Lusk EJ, Strouse TB et al. A psychological analysis of cancer patients and their next-of-kin. Cancer 1985; 55:72–6. 134. Iconomou G, Viha A, Kalafonos HP, Kardamakis D. Impact of cancer on primary caregivers of patients receiving radiation therapy. Acta Oncol 2001; 40:766–71. 135. Covinsky KE, Goldman L, Cook EF et al. The impact of serious illness on patients’ families. SUPPORT Investigators. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment. JAMA 1994; 272:1839–44. 136. Smitt MC, Heltzel M. Women’s use of resources in decision-making for early-stage breast cancer: results of a community-based survey. Ann Surg Oncol 1997; 4:564–9. 137. Hansdottir H, Gruman C, Curry L, Judge JO. Preferences for CPR among the elderly: the influences of attitudes and values. Conn Med 2000; 64:625–30. 138. Hare J, Pratt C, Nelson C. Agreement between patients and their self-selected surrogates on difficult medical decisions. Arch Intern Med 1992; 152:1049–54. 139. Brock DW. What is the moral authority of family members to act as surrogates for incompetent patients? Milbank Q 1996; 74: 599–618. 140. Ditto PH, Danks JH, Smucker WD et al. Advance directives as acts of communication: a randomized controlled trial. Arch Intern Med 2001; 161:421–30. 141. Hines SC, Glover JJ, Babrow AS et al. Improving advance care planning by accomodating family preferences. J Palliat Med 2001; 4:481–9. 142. Covinsky KE, Fuller JD, Yaffe K et al. Communication and decision-making in seriously ill patients: findings of the SUPPORT project. The Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments. J Am Geriatr Soc 2000; 48(5 Suppl):S187–93. 143. Sulmasy DP, Haller K, Terry PB. More talk, less paper: predicting the accuracy of substituted judgments. Am J Med 1994; 96:432–8. 144. Seckler AB, Meier DE, Mulvihill M, Paris BE. Substituted judgment: how accurate are proxy predictions? Ann Intern Med 1991; 115:92–8. 145. Suhl J, Simons P, Reedy T, Garrick T. Myth of substituted judgment. Surrogate decision making regarding life support is unreliable. Arch Intern Med 1994; 154:90–6.

Under-representation of elderly patients in cancer clinical trials

491

146. Zweibel NR, Cassel CK. Treatment choices at the end of life: a comparison of decisions by older patients and their physician-selected proxies. Gerontologist 1989; 29:615–21. 147. Libbus MK, Russell C. Congruence of decisions between patients and their potential surrogates about life-sustaining therapies. Image J Nurs Sch 1995; 27:135–40. 148. Coppola KM, Ditto PH, Danks JH, Smucker WD. Accuracy of primary care and hospitalbased physicians’ predictions of elderly outpatients’ treatment preferences with and without advance directives. Arch Intern Med 2001; 161:431–40. 149. Ling J, Rees E, Hardy J. What influences participation in clinical trials in palliative care in a cancer centre? Eur J Cancer 2000; 36: 621–6. 150. Newschaffer CJ, Bush TL, Penberthy LE et al. Does comorbid disease interact with cancer? An epidimiologic analysis of mortality in a cohort of elderly breast cancer patients. J Gerontol 1998; 53: M372–8. 151. National Institute on Aging/National Cancer Institute. Pharmacology of anticancer drugs in advanced age. NCI-5 U10 CA 85443, 2000.

23 Radiotherapy in the elderly: The achievements of the Geriatric Radiation Oncology Group (GROG) Patrizia Olmi, Giampiero Ausili Cefaro, Anna Marie Cerrotta Introduction The life-expectancy of most elderly patients is longer than the expected survival from common cancers (the lifeexpectancy of a healthy woman aged 70 is 15 years, and of a man approximately 11 years). It is reasonable to treat older individuals with cancer with the aim of improving their survival. The treatment of the older person needs to be individualized, based on life-expectancy, treatment tolerance, and aggressiveness of the tumor. More than chronologic age, attention should be paid to comorbidities, function, and cognitive status, which may influence both the life-expectancy and the treatment tolerance of an older person. Cancer is the second most common cause of death after age 65,1 and most common cancers (Table 23.1) become more common with age. Thirty-five percent of cancer deaths in men and 46% in women occur at age 75 or after. Radiotherapy plays a major role in the primary treatment and the palliation of cancer in older individuals. Thanks to easy tolerability, it may represent a suitable alternative to surgery and chemotherapy in frail older individuals. For this reason, a number of hospital-based radiation oncologists throughout Italy formed the Geriatric Radiation Oncology Group (GROG), which is a cooperative group focusing on the treatment of individuals aged 70 and older. Radiotherapy appears to be a very suitable form of cancer treatment for older patients, presenting the advantages of negligible acute mortality, treatability of patients whose general conditions and concomitant diseases contraindicate other forms of cancer treatment (aggressive surgery and chemotherapy), organ and function preservation, and acceptable acute and late sequelae. After a review of recent advances in radiation oncology and treatment of common tumors in the elderly, we shall describe the GROG experience as a reference for other investigators interested in the management of older individuals.

The achievements of the Geriatric Radiation Oncology Group (GROG)

493

Advances in external radiation oncology Conformal radiotherapy Radiotherapy appears very suitable for older patients because it is effective for curative and palliative purposes and has limited systemic toxicities. As locoregional failure

Table 23.1 Mortality from all cancers and selected site by age, Italy 1990–94 Type of cancer

Gender Deaths in age group 15– 44

All cancers

Lung

35

70.3

Females

12996

75260 81 613 144359

46

73.4

1950

44099

49006

33265

26

68.3

639

6232

7512

9212

39

71.6

1057

11158

14482

20634

44

72.9

957

8310

10890

25445

56

76.8

—

—

—

—

—

—

3755

20431

13686

17931

32

67.5

Males

30

2594

8328

20963

23.2

78.5

Females

—

—

—

—

—

—

Males

Males

Males Females

Prostate

75+

12721 127250 145940 157012

Females Breast

Median age of death

Males

Females Colon-rectum

45–64 65–74

%age 75+

Table 23.2 Estimated local failure as major cause of death Primary tumor site

Actual deaths (1994)

No. of patients

Percent-age

Brain/central nervous system

12600

11970

95

Prostate

38000

23180

61

Cervix/uterus

4600

2760

60

Corpus uterus

5900

3481

59

Esophagus

19400

6136

59

Bladder

10600

5724

54

Head and neck

19650

8056

41

Comprehensive Geriatric Oncology

494

Breast

46300

6482

14

Lung

153000

16830

11

is a major problem in radiation oncology, and may lead to reduced survival and distant metastasis, improvement of locoregional cancer control is a major focus of investigations.2 In a significant number of patients, the failure to control the tumor locoregionally is the major contributing factor to death (Table 23.2).3 Higher doses can now be delivered using three-dimensional (3D) conformal radiotherapy: that is, an external-beam radiotherapy in which the prescribed dose volume conforms closely to the target volume. This approach is expensive and time-consuming, because it requires multiple steps and a substantial time investment, but produces superior curative results. In older patients, the use of 3D conformal radiotherapy also results in improved tolerability, and may be safely combined with chemotherapy. Conformational 3D radiation is commonly applied to prostate, rectal, lung, head and neck, and bladder cancers. An important new modality of conformal radiotherapy is intensity-modulated radiation therapy (IMRT), which allows delivery of higher radiation doses to the tumor than conventional 3D conformal radiotherapy, while sparing normal tissues. Brachytherapy Brachytherapy plays a very significant and clearly established role in cancer management, and is particularly suitable to older individuals owing to its limited toxicity, lower investment in time, and lower cost than externalbeam irradiation. Brachytherapy provides a unique opportunity to deliver a very high dose of radiation to tumor tissue while sparing surrounding normal structures because of the rapid fall-off of the absorbed dose at increasing distance from the source.4 For cancers with a steep dose-response ratio, brachytherapy is superior to conformal techniques.5 A second advantage, particularly important for elderly patients, is the overall short treatment time due to the high specific activity of the radio-active sources and their short half-lives.6 Interstitial implants consist of radioactive needles, wires, or small encapsulated sources called seeds, directly inserted in the tumor or in tissue very close to the lesion. This type of implant is widely used for intraoral and superficial cancers or for tumors located in easily accessible organs such as the prostate gland. Intracavitary implants are composed of applicators bearing the radioactive sources positioned in a body cavity close to the target tissue, and are mostly used for the treatment of cervical or endometrial cancers. Intraluminal brachytherapy refers to the placement of radioactive sources into a lumen, such a bile duct or an airway.7 According to Report 38 of the International Commis sion on Radiation Units and Measurements (ICRU), the dose rate is defined as low, medium, or high. Low-dose-rate (LDR) implants deliver doses of 0.4–2 Gy/h, medium dose-rate brachytherapy uses dose rates of 2–12 Gy/h, while high-dose rate (HDR) brachytherapy uses dose rates greater than 12 Gy/h.8 Although not recognized by ICRU Report 38, the ultralow dose rates, ranging from 0.01 to 0.3 Gy/h, are of great importance, since these are the dose rates used in permanent implants with iodine-125 (125I) and palladium-103 (103Pa) seeds.4

The achievements of the Geriatric Radiation Oncology Group (GROG)

495

In the last few decades, the HDR technique has allowed new possibilities, such as endoscopic and intraoperative brachytherapy for tumor sites including bronchus, esophagus, and bile ducts. Moreover, HDR brachytherapy offers the undoubted advantage of a very short treatment time, radioprotection for personnel, avoidance of general anesthesia, and avoidance of prolonged bed confinement.9 The last two points seem particularly beneficial for elderly patients with multiple comorbidities, subject to the complications of anesthesia and risk of thromboembolism and deconditioning. Finally, pulsed-dose-rate (PDR) brachytherapy has been developed with the intention of utilizing the advantages of HDR computer-controlled remote after-loading technology while maintaining the potential benefits of LDR. A continuous low dose rate is replaced by a pulse of about 0.5 Gy, delivered for 10 minutes every hour, so the average dose rate is maintained and the overall treatment time for a given total dose remains fixed.7 Management of common cancers in the elderly Breast cancer Breast cancer is the most frequent tumor in aged woman: according to data from the US National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results

Table 23.3 Ten-year overall survival (OS), diseasefree survival (DFS), locoregional relapse-free survival (RFS), and distant metastases-free survival (MFS) rates in breast cancer patients aged 70 or older Categorya

No. of patients OS (%)b

pT1

263

68 (0.00000) 89 (0.00000) 91 (0.0003)

90 (0.00000)

pT2

322

42

73

81

73

pT3

32

49

69

86

66

pT4

105

37

63

79

65

pN0

360

60 (0.00000) 87 (0.00000) 90 (0.0001)

89 (0.00000)

pN1

310

43

66

1–3 nodes

175

47 (0.00000) 79 (0.00000) 89 (0.00000) 78 (0.00000)

4–9 nodes

76

40

60

77

59

>10 nodes

56

19

33

50

33

ER/PgR-positive

45

58 (NS)

88 (NS)

91 (NS)

91 (NS)

ER/PgR-negative

69

—

83

84

79

a

ER, estrogen receptor; PgR, progesterone receptor. p-values in parentheses (NS, not significant).

b

DFS (%)b

67

RFS (%)b

80

MFS (%)b

Comprehensive Geriatric Oncology

496

(SEER) program, comparing the years 1975–77 with 1989–91 in the USA, the incidence rate of localized disease in elderly people increased by 89.5% in the age group 60–69 years and by 90.1% in the age group 70–79 years. These increases were almost double those observed in younger women. Re-analysis of data from the Breast Cancer Detection Demonstration Project, which analyzed 280 000 American women in 1975, showed that screening diagnosed 1 tumor in 1000 women aged 35–39, but 12.9 tumors in 1000 women aged 75–79. In Europe, the crude rate is 19.3 for women aged 44 or less, 156.5 for the 45–64 age group, and 224.5 for the group aged over 65; the mortality rates for the three groups are respectively 4.3, 59.8, and 118.2.10 The use of radiotherapy in the management of breast cancer falls into the following categories: • adjuvant radiotherapy after conservative surgery; • post-mastectomy adjuvant radiotherapy (chest wall± nodal chains); • palliative radiotherapy for distant metastases (mainly bone and brain metastases). Breast-conserving surgery has become routine practice also in the elderly; radiotherapy can reduce locoregional relapse and cancer mortality also in this age group. The impact of radiotherapy on survival is controversial owing to the increase in non-cancer-related death, especially in the group of older patients. At the Istituto Nazionale Tumori of Milan, in a group of 408 TINO patients aged 70– 94 operated on with wide excision, the 10-year local relapse rate was 6.5% for irradiated patients and 15.2% for unirradiated ones.11 Other data in the literature12,13 (somewhat contradictory) would seem to confirm that the irradiation of elderly patients may be beneficial, even if subgroups with favorable prognostic factors (e.g. Tla-b, grade 1, no involved axillary nodes, or negative sentinel lymph node) might be spared radiotherapy. Irradiation of the whole breast after breast-conserving surgery is a treatment of mild toxicity. Things may be different if the target volume includes the chest wall. In this case, the risk of toxicity to the lung and the heart may increase. The decision to administer radiotherapy to the chest wall and the axilla should be based on a positive benefit-risk ratio; in particular, the risk of morbidity and mortality from breast cancer must be higher than the risk of cardiovascular and therapeutic complications. In a retrospective analysis of a group of 746 patients aged 70 or more referred to the Radiation Oncology Department of the University of Florence in the period 1970–1998, the 10-year overall survival rate was 50%, and 78% of the patients were free of tumor and other major diseases. Overall survival, disease-free survival, locoregional relapsefree, and distant metastasis-free survival data for this group of patients aged 70 years or more are reported in Table 23.3. All the main prognostic factors analyzed in the study (tumor stage, nodal status, and number of involved nodes) are highly significant with relation to overall and disease-free survival, as well as to locoregional and distant relapse-free survival, apart from endocrine receptor status. It is well known that receptor status is a good predictor of treatment response, but has only a moderate prognostic value for survival at 5 years that is not always confirmed at 10 years; the data from Florence seem to support this. In the same series, a second tumor was detected in 59 of 746 patients (7.9%). Most second tumors were contralateral breast cancer or breast cancer in the same breast but in a different quadrant (30 out of 749 cases; 4%); colorectal cancer was the second most

The achievements of the Geriatric Radiation Oncology Group (GROG)

497

common site (11 of 746; 1.4%). Among the sites that less frequently developed second cancers, stomach, bladder, endometrium, skin, lung, and larynx were recorded. Prostate cancer Prostate cancer is a disease of older men: more than 80% of cases are diagnosed in men aged 65 and older.14 Prostate cancer is the most common cancer in men in the USA and the second most common cause of cancer-related death. In men aged 65–70, the benefit of early diagnosis (prostate-specific antigen, PSA) and aggressive treatment must be balanced against the high risk of complications and the small improvement in survival.15,16 The patients with the highest probability of success have well or moderately differentiated tumors confined to the organ, but, at the same time, these patients have a low probability of disease progression. The optimal management of prostate cancer—whether surgery or radiotherapy—is still controversial: in the elderly, the most common therapeutic approach consists of radiotherapy and hormonal therapy. Improvements in radiotherapy techniques and strategies over the last 10 years have led physicians to choose radiation treatment more and more frequently. In fact, until the use in clinical routine of 3D conformal radiotherapy, radiation-induced complications were dose-limiting. Acute side-effects such as proctitis and cystitis and late effects such as urethral stricture, bladder ulcer, incontinence, rectal urgency, and stricture are reduced by conformal radiotherapy.17–20 This technique developed in the last decade for sparing organs at risk and delivering high doses of radiation to the target tissue (~76 Gy with conventional fractionation) has now become the standard of care. With the use of conformal radiotherapy in routine practice, dose escalation with more than 74–76 Gy is still under study. In addition, to further reduce toxicity to critical pelvic organs and improve the dose, intensity-modulated radiotherapy (IMRT) can be used. Brachytherapy allows the delivery of the highest dose of radiation within the prostate and sparing of close critical normal tissue, in particular the anterior rectal wall and bladder base, due to the rapid fall-off of dose outside the implanted area, and can offer an alternative option of treatment. Brachytherapy for prostate cancer may be used as a single treatment modality or as a boost after a course of external-beam irradiation,21and can be delivered either with permanent seed implants or with temporary, removable implants. If brachytherapy alone is chosen, permanent implants with 125I or 103Pd are normally used, whereas when it is used to give a boost dose, either permanent implants with gold198 (198Au) seeds or, usually, removable implants (often delivered at high dose-rate with iridium wires) are used. Brachytherapy as a single treatment is considered optimal for good-prognosis patients (PSA ≤10), Gleason score ≤6, T1b-2a): long-term results in the literature show that treatment results with permanent implants alone are equal to those of radical prostatectomy or dose-escalated 3D conformal radiotherapy in this group of patients.22 Combined therapy is usually used in the case of medium- and high-risk patients: the rationale for adding external radiotherapy consists in extending the treatment to potential untreated extracapsular disease. The long-term treatment results are favorable using either LDR or HDR brachytherapy.23,24 Brachytherapy with high-risk patients may be proposed for salvage after failure of external-beam radiation, when patients initially

Comprehensive Geriatric Oncology

498

presented with good-prognosis disease, the relapse occurred several years after the first treatment, and the disease was still localized.25 In conclusion, in patients with localized disease, the treatment aim must be cure. In particular, radical radiotherapy—3D conformal radiotherapy, delivering total doses of 74–76 Gy, or brachytherapy—in selected patients, can also be adopted in the elderly with no major toxicity. Locally advanced cancer is more appropriately treated with externalbeam radiotherapy, for a total dose of 70 Gy or more according to the treated volume, and androgen deprivation can be used prior to or in combination with radiotherapy. Lung cancer Lung cancer is one of the most frequent neoplasms in the elderly: more than 50% of cases of this disease are diagnosed in patients over the age 65 and about 40% in those over 70.26,27 The incidence of lung cancer is expected to increase in the next few years. Two-thirds of patients present with advanced disease at diagnosis, and the majority die of cancer despite a multimodality therapeutic approach. More than two-thirds of patients dying of lung cancer are aged over 65,28 and in Europe the outcome of elderly patients is worse than that of younger ones, as shown by the 5-year relative survival rates according to Vercelli et al.29 It can be seen from Table 23.4 that there is a decrease in survival from 65 to 84 years: a greater advantage for the younger age group (ratio >1.5) is evident in both genders. Non-small cell lung cancer Non-small cell lung cancer (NSCLC) accounts for 75–80% of all lung cancer cases: in patients with stage I and II NSCLC, surgery is the standard therapy also in the elderly, but adequate patient selection, in terms of cardiac and respiratory function, is mandatory. For inoperable patients, radiotherapy plays an important role: the 5-year survival rate is around 20% (up to 30% in tumors smaller than

Table 23.4 One-year and 5-year relative survival rates in elderly lung cancer patients: pooled Italian Registries Data (1978–89) by sex and age group, together with ratio between relative survival rates in 55–64 versus 65–84 age groups Age (years)

55–64 vs 65 ratio

65–69

70–74

75–79

80–84

32

31

24

21

1.2

8

6

4

3

1.8

Males (6503 cases) 1-yr relative survival rate (%) 5-yr relative survival rate (%)

The achievements of the Geriatric Radiation Oncology Group (GROG)

499

Females (1198 cases) 1-yr relative survival rate (%)

30

27

21

22

1.5

5-yr relative survival rate (%)

7

7

7

6

1.9

3cm).30 Radical irradiation, limited to the tumor volume and adjacent mediastinal region, up to doses of 60–65 Gy, with conventional fractionation is recommended. Only a very small number of patients with advanced NSCLC (stage III and IV) can be cured with surgery, while radiotherapy is the most widely used treatment. In stage IIIA and IIIB cases, the 5-year survival rate with exclusive radiotherapy in the elderly is 10%, which is comparable to that in younger subjects.31 Pignon et al,32 analyzing the data from 871 patients receiving chest irradiation for lung cancer, concluded that, with respect to overall survival, age had no influence and that all patients with good performance status should receive the same treatment irrespective of age. Normal lung tissue is susceptible to the complications of radiotherapy: pneumonitis is the most frequent acute effect, with an incidence of 5–15%,33 usually occurring 1–3 months after completion of treatment. The risk of penumonitis increases with total dose, treated volume, dose per fraction, and length of therapy. The use of 3D computerized treatment plans may minimize the amount of normal tissue irradiated. Late pericardial disease may occur several months or years after completion of treatment and can often remain asymptomatic. Age does not influence tolerance of radiotherapy or the occurrence of overall or severe toxicity.32 The results of several randomized trials have showed encouraging improvement in survival with a combined modality of chemo- and radiotherapy, as compared with radiotherapy alone.34 This approach needs validation in older individuals. Brachytherapy may be used to treat small endobronchial cancers with curative intent,35 or as a boost after a course of external radiotherapy. Small cell lung cancer For small cell lung cancer (SCLC), which accounts for approximately 20% of lung neoplasms, radiotherapy, as a local treatment, plays a secondary role, owing to the rapid proliferation rate and the early metastatic spread characteristic of this disease. However, radiotherapy may be added to chemotherapy to control the chest disease, improving the disease-free interval, or to prevent brain metastases. A few studies have been reported with the aim of minimizing toxicity in elderly patients: Canadian researchers investigated, for limited disease and selected extensive disease, a combination of the PAVE (cisplatin, doxorubicin, vincristine, etoposide) regimen plus chest irradiation (20– 40 Gy) during the second cycle, with low haematologic complications and with response rates and median survival times comparable to those obtained for standard regimens.36 From a palliative point of view, the role of radiotherapy becomes particularly important when relief of symptoms with minimal discomfort to the patient is necessary. Radiotherapy achieves good palliation in 60–85% of clinical problems due to the primary tumor, including dyspnea, haemoptysis, mediastinal syndrome, and major locoregional tumor extent. Brachytherapy, especially with the introduction of HDR afterloading

Comprehensive Geriatric Oncology

500

devices, represents an interesting modality of symptom palliation in the case of bleeding or cough, which negatively impact quality of life. This modality consists in the endobronchial insertion of a catheter loaded with a high-dose iridium source delivering a high radiation dose to the bronchial tumor. Colorectal cancers Colorectal cancers are frequent in the elderly population, with 50% of deaths occurring in patients over 75.37 The incidence of these neoplasms increases progressively with age up to 80. Some authors report an earlier stage at diagnosis in elderly compared with younger patients;38 for others, obstructing neoplasms are more frequent in the elderly,39 while the incidence of metastasis is lower.40 Surgery is considered the best therapeutic approach for colorectal cancer. Age and advanced disease are not a contraindication for colon surgery,41 but the type of surgical resection depends on the position of the tumor and whether the surgery is elective or in an emergency. Particularly for rectal cancer, even though surgery represents the main treatment option, during the past 10–20 years, radiotherapy, and recently radiochemotherapy, have been more and more frequently employed in combination with surgery in locally advanced cancers. In the management of this disease, several endpoints must be considered: cure, local tumor control, and anorectal sphincter preservation, which must be performed, whenever possible, in both younger and aged patients. Especially in the elderly, organ preservation should, in fact, represent a critical goal of treatment, owing to its impact on quality of life. Therefore, radiotherapy assumes a determining role in the following situations: to improve local tumor control and survival in resectable cancers, to allow surgery with a sphincterpreserving procedure for tumors of the inferior third of the rectum, and to cure patients with very small tumors that are inoperable for medical reasons. However, several aspects are yet to be defined: whether preoperative radiotherapy is preferable to postoperative radiotherapy and which drugs are more effective in association with radiotherapy. The rationale for using preoperative irradiation is based on the theoretical consideration that the probability of microscopic residual disease in the perirectal space can be decreased, reducing the development of local recurrence and the dissemination of cells at the time of surgery; such radiotherapy, requiring smaller treatment volumes, presents a lower risk of radiation toxicity. Large randomized trials have reported that preoperative radiotherapy can substantially decrease local failure42 and improve overall survival.43,44 Also, dose and fractionation seem to be important: a significant improvement in local control has been shown using a total dose higher than 34 Gy with conventional fractionation. The introduction of total mesorectal excision has allowed an improvement in local control in resectable rectal cancer, reducing the local recurrence rate to 5% or less.45 The role of short-term preoperative radiotherapy in combination with this surgical approach has been investigated, and initial data show a beneficial effect on local recurrence risk.46 The toxicity associated with preoperative radiotherapy with conventional fractionation is generally low and represents one of the main advantages: the bowel is more likely to be mobile, with fewer subsequent radiation complications. Acute neuropathic pain has been reported occasionally; it appears to be related to the volume of radiation and the dose, and is generally reversible.

The achievements of the Geriatric Radiation Oncology Group (GROG)

501

The rationale for the use of postoperative irradiation is based on the possibility to select patients at higher risk of locoregional recurrence according to pathologic stage and operative findings. Randomized trials have shown that the postoperative option may decrease local recurrences, but without any influence on overall survival.47 The toxicity in this case is rather important, reaching 18% in some series.48 Several authors report intestinal obstruction after postoperative radiotherapy due to injury to small-bowel loops adherent in the pelvic cavity;49 thus, a number of techniques have been investigated to prevent and reduce small-bowel irradiation. Another late effect related to the volume of small bowel included in the treatment field is chronic diarrhea, which is more frequent than in the preoperative setting. Radiotherapy may also be detrimental to sphincter function.50 Chemoradiation consists in concomitant administration of chemotherapeutic agents and radiotherapy with the aim of a spatial cooperation and intensification of the effects of radiotherapy. This approach has been investigated in several trials, and has shown a tendency to improve local control rates and survival.51 The schedules applied are not contraindicated in elderly patients, since no major complications have been reported.52 Furthermore, an Italian randomized multicentric study with preoperative chemoradiotherapy plus or minus postoperative chemotherapy in locally advanced rectal cancer enrolled 614 patients. The preoperative treatment consisted of 45 Gy with conventional fractionation plus concomitant chemotherapy with 5-fluorouracil (5-FU; 375mg/m2×5 days×2 cycles) and folinic acid (FA, leucovorin; 10mg/m2×5 days in both cycles). After surgery, the patients were randomized to receive or not to receive chemotherapy (5-FU 375mg/m2+FA 100mg/m2). Out of the 614 patients, 92 were aged 70 or more. From a treatment point of view, the group of older patients was similar to the younger patients in terms of compliance with preoperative radiotherapy treatment, chemotherapy, and major toxicity (Table 23.5) with a slightly higher acute morbidity (Table 23.6). Table 23.7 shows the type of surgery in three oatient age groups,

Table 23.5 Compliance with preoperative treatment in rectal cancer Age <60 (236 pts)

61–70 (216 pts)

>70 (92 pts)

Not treated

6 (2.5%)

5 (2.3%)

1 (1.1%)

Radiotherapy <45 Gy

8 (3.4 %)

12 (5.5%)

6 (6.5%)

Chemotherapy <2 cycles

14 (21%)

13 83%)

12 (13%)

Toxicity >grade 2

49 (21%)

47 (22%)

35 (38%)

Table 23.6 Acute morbidity of preoperative treatment in rectal cancer Age <60 (236 pts)

61–70 (216 pts)

>70 (92 pts)

Comprehensive Geriatric Oncology

502

Epitheliolysis

8.5%

7.4%

13%

Diarrhea

9.3%

9.7%

22%

Hematologic complications

5.5%

6.9%

8.7%

Cystitis/proctitis

5.9%

2.7%

4.3%

Others

2.9%

3.2%

4.3%

Deaths

0.8%

1.8%

1.0%

21.0%

21.7%

38.0%

Total events

Table 23.7 Surgical modality performed in rectal cancer after preoperative treatment Age <60 (224 pts)

61–70 (200 pts)

>70 (84 pts)

Abdominal-perineal

29.4%

37.5%

36.9%

resection

60.7%

52.5%

55.9%

Hartman

2.7%

2.0%

2.4%

Transrectal excision

4.9%

5.5%

2.4%

Palliative surgery

2.2%

1.0%

2.4%

Table 23.8 Perioperative morbidity and mortality in rectal cancer Age <60 (215 pts)

61–70 (194 pts)

>70 (81 pts)

Dehiscence

8.0%

7.0%

12.0%

Infection

4.0%

2.0%

2.4%

Vascular complications

0.9%

1.0%

4.0%

Other

1.8%

1.5%

5.0%

Deaths

0.4%

1.5%

1.2%

16.7%

17.0%

29.0%

Total events

which is very similar. The perioperative morbidity and mortality by age (Table 23.8) show that the older patients had more total events than younger patients—but still an acceptable number. An alternative therapeutic option to sphincter-sparing surgical procedures is represented by endocavitary brachytherapy. This approach can be applied in an outpatient setting, without general anesthesia, and is particularly favorable in elderly patients with a high surgical risk. Tolerance of the treatment is good: acute side-effects consist in

The achievements of the Geriatric Radiation Oncology Group (GROG)

503

tenesmus, frequent stools, and diarrhea; late toxicity includes intermittent rectal bleeding and asymptomatic superficial ulceration of the rectal mucosa.53 In conclusion, comorbidities and functional status must be taken into account in the management of the elderly group of patients; therefore, careful selection is necessary. In general, for patients with stage I rectal cancer, radical surgical therapy should be considered the exclusive treatment, followed by postoperative radiotherapy in the case of low-lying small lesions treated with a transanal approach. Preoperative radiation with concomitant chemotherapy if possible, as neoadjuvant treatment, should be given to stage II and III patients to achieve a high rate of sphincter preservation. The treatment of aged patients with extrapelvic disease is still controversial, and should be individualized: chemotherapy should be used according to the evaluation of concomitant diseases and functional status; palliative hypofractionated radiotherapy can be effective for painful bone metastases or for rectal bleeding.54 Head and neck cancer Head and neck cancer is quite common in the elderly. The incidence peaks between the sixth and seventh decades of life. Overall, the age distribution of this type of tumor in the general population indicates that patients older than 70 account for 24%,55 even though the percentage varies among the different series. In a retrospective survey conducted by the GROG, it was found out that 9422 elderly patients aged 70 and older had been referred to 47 radiotherapy centers in 1992, of whom 112 patients (12%) had head and neck cancer; 24 out of the 112 were aged over 80.56 These data were confirmed by a prospective GROG study performed in 1994 on 2060 patients aged 70 or older, which showed that 12.6% of patients were affected by this type of neoplasm,57 with the following distribution: larynx 103 patients, pharynx 63, oral cavity 35, lips 24, salivary glands 12, nasal cavity, and paranasal sinuses. Hirano and Mori58 from the Kurume University Hospital reported that 29.9% of head and neck cancer patients examined were older than 70 and that 5.9% were older than 80. The most frequent site of origin is the larynx, followed by the oral cavity and oropharynx; lesions are usually diagnosed in an advanced stage. Epidermoid lesions are the most common histologic type, and no differences have been found in tumor differentiation between younger and older patients.59 It is difficult to describe biological features of these tumors that are specific to the elderly. Koch et al60 has specifically studied p53 gene abnormalities in aged patients with head and neck carcinomas: they found a significantly lower rate of p53 mutation in this group. No statistical correlation was shown between age and a high or low angiogenic status in tissue samples.61 Surgeons and radiotherapists have always played the leading role in the management of head and neck cancer, but divergent opinions and controversies still exist. The selection is often based on the assessment of comorbidity and performance status, mainly for conservative surgery. Consequently, for patients with an excessively high surgical risk, radiotherapy represents the only choice. The Comprehensive Geriatric Assessment (CGA) is a method for classifying patients with functional limitations, and could allow the most appropriate therapeutic decision for each case. Comorbidities, such as cardiac or vascular diseases and chronic obstructive broncopneumopathies, are very frequent in the

Comprehensive Geriatric Oncology

504

elderly, and, in particular with respect to head and neck cancer, only 15% of patients did not show a previous history of disease.59 Zachariah et al,62 in their report on patients aged 80 and over, showed that both curative and palliative radiotherapy are highly effective and well tolerated by the oldest old patients. Baumann63 reported that, in a series of 679 patients, 88.2% received radiation with curative intent. Moreover, definitive radiotherapy should be considered even in patients older than 90; Ogushi et al64 reported, in fact, that this group of patients, with a good performance status, may well tolerate curative treatment: acute toxicity and local control seem to be almost the same as those expected for younger patients, although the healing of acute effects requires a longer period. Based on this finding, there is no indication of dose reduction because of age. In the first prospective study carried out by GROG, on 103 patients with laryngeal cancer, most (71%) were given radiotherapy alone with curative intent: the mean dose was 63.4 Gy, cutaneous and mucosal tolerance was good, and grade 3–4 toxicity (according to the Radiation Therapy Oncology Group (RTOG) scale) was observed in only 6 cases.57 Lusinchi et al,59 too, showed no real impact of age on mucosal tolerance: 17% of 331 patients had severe mucositis. A study by Nozaki et al65 performed in 1998 on 90 patients older than 80 reported that radiotherapy was completed in 90% of cases, with an 82% rate of clinical response. Olmi et al,66 in a retrospective study of head and neck cancers treated with radiotherapy, at 5 years, observed similar results in terms of local control and survival among patients younger and older than 70. The prospective GROG study planned in 1997 on 394 elderly Italian head and neck patients showed that radiotherapy plays a major role in the global therapeutic strategy, either alone or as adjuvant treatment. Definitive radiotherapy was given to 155 patients, 18 received palliative treatment, and 92 adjuvant radiotherapy. When cure was the aim, a median dose of 66 Gy to the primary tumor was delivered and 58 Gy to neck nodes; a median dose of 60 Gy was administered to the primary site and 54 Gy to the nodes if postoperative treatment was planned; the median dose for palliation was 30 Gy. Tolerance of radiotherapy is well quantified: only 18 patients did not complete the planned therapy, and grade 3–4 toxicity was observed in 22 patients. Of the 155 patients treated with curative intent, 64.5% reached a complete response 2 months after the end of the treatment; at a median follow-up of 23 months, 39.6% were alive and disease-free. After a median follow-up of 20.2 months, 62% of the 92 patients treated with adjuvant irradiation were still alive without disease.67 Allal et al68 reported the results for 39 aged patients treated with an accelerated radiotherapy course. These results confirmed the belief that radical radiotherapy can be performed successfully in elderly people, and suggest that even accelerated fractionation schedules are feasible in those who are physically healthy. The acute and late complications are similar to those observed in younger patients, and treatment outcome seems to be comparable. Radiotherapy combined with chemotherapy is not used frequently, because of the potential high toxicity;69 Bourhis et al,70 in a meta-analysis, reported that more sideeffects and more toxicity-related deaths may occur in the elderly.

The achievements of the Geriatric Radiation Oncology Group (GROG)

505

Esophageal cancer Esophageal cancer is rather frequent in older patients, and its incidence is increasing substantially.71 Peracchia et al72 and Hishikawa et al73 reported a higher frequency of this tumor in elderly women than among younger patients; moreover, they noted that the middle and lower thoracic esophagus were involved by cancer more frequently in the aged group. This neoplasm is rarely superficial, and very often, especially in elderly patients, it is locally advanced and inoperable (often because of concomitant disease). Surgery represents the best treatment option that is able to provide prolonged survival for lesions of the lower third of the thoracic esophagus and the gastro-esophageal junction. For cervical and upper-mid-thoracic tract lesions, surgery and radiotherapy can give the same results. With surgery, resection of the entire esophagus is required, and this is particularly challenging in the elderly. Therefore, radiotherapy has become an important treatment modality for this group of patients as well as for younger ones. Several authors have reported that age is not a significant prognostic factor, showing that radiotherapy plays an important role in the therapeutic approach to esophageal cancer, although survival is not satisfactory.32,74,75 In fact, despite recent advances in radiation techniques, definitive radiotherapy alone achieves poor results.76 Combination of chemotherapy with radiotherapy allows a significant increase in overall survival, and represents the standard of care in non-surgical treatment;77 however, for elderly patients, because of treatment intolerance, the combined approach is not yet considered current standard therapy.78 The role of pre- and post-operative radiotherapy is controversial: if it is true that these modalities allow improvements in local control, there is no evident benefit on survival.79 In general, radiotherapy alone is considered in a few clinical conditions: for superficial esophageal carcinoma, for inoperable cancer, for patients medically unable to receive chemotherapy, and for palliation of symptoms. In the first case, in a selected group of patients, radiotherapy provides excellent local control and survival, particularly if a boost of intraluminal brachytherapy is delivered after 50–60 Gy of external-beam radiotherapy. In advanced cancer, the outcome of radiotherapy alone is disappointing: the 5-year survival rates are inferior to 10%, despite recent advances in irradiation technique. External dose is considered the most important factor for esophageal cancer, with significant effects on local control and survival. An external dose of 60 Gy or more is necessary for the treatment of this type of tumor, and it can be safely used in elderly patients, preferably with four-field treatment or 3D conformal radiotherapy. The occurrence of acute and late toxicities is correlated with radiotherapy parameters such as treated volume, number of fields, dose per fraction, and length of treatment.32 Intraluminal brachytherapy as a boost dose for curative intent after external radiotherapy, with the introduction of the HDR devices, is considered one of the most effective treatment options, even for elderly patients,73 because it allows delivery of a higher dose to the tumor, sparing the critical nearby organs. An acute complication is esophagitis, which occurs nearly 2 weeks after the beginning of a conventional course of radiotherapy; it is characterized by retrosternal pain or burning on swallowing, with consequent limitation of food intake if pain control is not achieved, fatigue, and weight loss (more significant in elderly patients); pneumonitis and perforated esophagus are rare.

Comprehensive Geriatric Oncology

506

When late toxicity is considered, the most frequent events are stenosis and stricture, while fistulae are rare.80 Although these patients have a short life-expectancy, age does not influence the occurrence of severe complications.73 Radiotherapy is particularly used for palliative treatment: dysphagia, caused by tumor obstruction, is the most common and earliest symptom of advanced disease. Moderate doses of radiotherapy provide excellent relief of dysphagia with few side-effects. Intraluminal brachytherapy is a valid instrument in palliative treatment, alone or as a boost after a reduced external-beam course of radiotherapy. The primary aim of this modality is rapid and lasting relief of symptoms. Intraluminal HDR brachytherapy consists in the use of very small and thin iridium sources, loaded on different, long, flexible applicators, according to the anatomic situation. In order to reduce the volume of irradiation in the esophageal wall and the danger of perforation and bleeding, different applicators have been constructed. This modality restores swallowing in 50–80% of patients for a period of 4–6 months. Cervical cancer Cervical cancer is one of the most common gynecologic malignancies in old women; about 27% of patients are over 65.81 Treatment and prognosis depend especially on the clinical stage of the tumor at diagnosis. For early-stage cervical cancer, radical surgery is most often the treatment of choice, while radiotherapy represents the only curative approach in the majority of locally advanced neoplasms for adult patients. It is controversial whether age influences the prognosis of patients with carcinoma of the cervix, but several studies indicate that age should be a contraindication neither for radical hysterectomy82 nor for radical radiotherapy.83 After these procedures, the survival of older and younger women is comparable (p=0.41).84 Nevertheless, age and comorbidities may have a role to play in choosing different treatments: 50–75 % of elderly patients may suffer pre-existing medical problems, discouraging the surgical option; for this group, radiotherapy is of particular benefit and often brachytherapy alone may be a valid treatment approach.85 Radical radiotherapy involves external photon-beam irradiation combined with brachytherapy, which is an essential part of the treatment, delivered as a boost dose in order to obtain the best local control and survival.86 External irradiation is used to treat the whole pelvis, including the common iliac lymph nodes and the parametria; high-energy photon beams (≥15 MeV) are generally chosen, to provide a more homogeneous dose distribution in the central pelvis. Early reactions appear for most patients for doses of 40 Gy and more.87 The cervix, vagina, and medial parametria are adequately treated with brachytherapy, which allows delivery of a high dose to these structures for rapid dose fall-off. In recent years, HDR brachytherapy has entered into the clinical routine: outpatient treatment is an unquestionable advantage; moreover, the short immobilization time reduces complications such as pulmonary embolism and thrombophlebitis. This modality seems particularly important for elderly patients, and may well increase the percentage of old women with cervical cancer receiving curative therapy. A large number of elderly patients enrolled in trials of the European Organization for Research and Treatment of Cancer (EORTC) carried out from 1975 to 1991 were evaluated by Pignon et al.88 These authors investigated the outcome of patients receiving

The achievements of the Geriatric Radiation Oncology Group (GROG)

507

radiotherapy for pelvic malignancies, including cervical cancer. They reached the conclusion that survival and local control were comparable to those of the youngest patients. In recent years, this opinion has appeared in several papers. Mitchell et al83, Mitsuhashi et al,89 and Sakurai et al90 reported that survival rates after radiotherapy for cervical cancer, consisting of external-beam irradiation of the entire pelvis and two or three sessions of LDR intracavitary brachytherapy, even for patients aged 80 and older, were not worse than those for patients from the youngest group. Lindegaard91 maintains that age per se is not a significant factor for treatment outcome, and, whenever possible, combined external-beam radiotherapy and brachytherapy should be applied. With regard to acute and late toxicity, the age-related risk is controversial. A high incidence of acute sequelae in this group of patients has been reported by some authors. Sablinska92 and Grant et al93 found a high frequency of acute morbidity, with as many as 32–41% of patients unable to complete treatment. Pignon et al88 noted a higher incidence of acute bladder sequelae in older patients, but, after adjusting for radiation dose, no difference was observed for each age group. In contrast, in several other papers, no differences in the frequency and severity of acute radiation toxicity, as functions of age, were reported.83,89,91 A reduction in dose of 5–10% for patients older than 65,94 or a reduction of field size for patients aged 80 and older,62 is recommended by some authors. An interesting study has suggested the use of intensity-modulated radiotherapy (IMRT) to reduce the volume of small bowel affected when the whole pelvis is included.95 The literature on late radiation complications is very scanty, and comparison between different studies is not easy because of various scoring systems and variability of statistical methods. The risk of major late radiation toxicity ranges between 3% and 5% for stage I-IIA, and between 10% and 15% for stage IIB-III.85,91,96 Mitchell et al83 and Mitsuhashi et al89 noted similar rates of severe chronic rectal, small-bowel, and bladder sequelae in the elderly and non-elderly groups (9–10%). Perez et al,94 too, reported no difference in the incidence of late toxicity in elderly patients. The most important factors associated with rectal complications are a history of diabetes and pelvic doses above 50 Gy.97 Pignon et al88 remarked that only overall urinary effects were significantly more frequent in aged patients, but an analysis adjusted for dose levels established that the complications were dose-related and independent of age. Invasive bladder carcinoma Invasive bladder carcinoma is a rather frequent neoplasm: it is the fourth most common cancer in elderly men, although it is less frequent in women. It is typically multifocal, and in 25% of cases it is invasive from the beginning. Recently, owing to therapeutic advances, the death rate from bladder cancer has decreased, passing from the fourth to the seventh most common cause of death. Treatment options with curative intent are surgery or radiotherapy, but the outcome is still disappointing owing to local failure and distant metastasis. Currently the surgical approach considered the best treatment option is radical cystectomy as the standard treatment for locoregionally advanced and for refractory highgrade superficial bladder cancer, with a well-recognized but acceptable risk of perioperative complications and minimal operative mortality. Several authors support this

Comprehensive Geriatric Oncology

508

choice even in elderly patients. Navon et al98 reported on 21 patients at least 75 years old, treated with radical cystectomy and continent urinary diversion: the overall postoperative complication rate was 28%. Other authors99,100 have shown similar results with radical surgery, with morbidity similar to that of younger adults and minimal mortality. In fact, Figueroa et al99 evaluated 404 patients aged 70 or older, and concluded that aggressive radical surgery is a viable treatment in selected patients treated with radical cystectomy and urinary diversion. The same results on toxicity were obtained in a group of patients aged 80 or older. The overall survival rate at 5 years was 53% in the group of older patients (n =404), in comparison with the group of younger patients (n=762), for whom the rate was 63% (p=0.3). Chang et al100 are in agreement about the same aspects of toxicity after the same surgical approach in elderly patients with comorbidity. In the last few decades, multimodality organ-sparing treatments have been investigated: especially in older patients, bladder preservation could represent an essential endpoint; moreover, this group of patients is often inoperable because of frequent concomitant diseases. In several institutions, radiotherapy is used as definitive treatment, with cystectomy as salvage therapy. During the 1960s, radiotherapy in the preoperative setting was studied, but randomized trials did not show a definitive benefit. In fact, irradiation alone can give durable results in less than 50% of cases. In order to increase local control, organ preservation, and survival, combined treatments have been investigated, especially concomitant cisplatin-based chemoradiotherapy. Fellin et al101 reported the results of a study on invasive transitional cell bladder cancer treated with radiotherapy combined or not with chemotherapy from 1989 to 1994. A group of 66 patients with a median age of 59, suitable for radical surgery and chemotherapy, received two courses of methotrexate, cisplatin, and vinblastine (MVAC), followed by 40 Gy of pelvic radiotherapy, with conventional fractionation, associated with two courses of concomitant cisplatin: a boost of 24 Gy was given to completely responding patients. A second group of 64 patients (median age 72), not suitable for surgery or chemotherapy owing to local or general inoperability, advanced age, or poor performance status, received fulldose radiotherapy (55–70 Gy in 5–8 weeks). In both groups, bladder and bowel toxicity was frequent during irradiation, but no patients required interruption of treatment. Bladder function was good in patients without local recurrence, and with a mean follow-up of 43 months, 32 maintained a functional bladder. The Geriatric Radiation Oncology Group (GROG) experience Over the last few years, several papers have been published reporting therapeutic results in terms of locoregional control and survival in the treatment of cancer in the elderly with radiotherapy. Acute toxicity as a possible factor limiting the rate of success has been especially highlighted. Information from general clinical trials is scarce, because only a limited number of highly selected older individuals were enrolled in these trials. Furthermore, these trials provide little information related to the variables that define older individuals, including function, comorbidity, cognition, social support, and emotional status. The main goal of GROG was to acquire information specific to older cancer patients.

The achievements of the Geriatric Radiation Oncology Group (GROG)

509

GROG originated from the initiative of some pioneering radiation oncologists who realized the extent of the problem of cancer in the elderly. They shared the vision that this problem would become increasingly central to the practice of oncology, including radiation oncology, and that it could only be dealt with by a systematic uniform approach. To this end, a series of meetings were held to define the most important questions of cancer and aging and to spread the word about this impending epidemic. GROG involves 70 hospital-based radiation centers throughout Italy, which are also reference centers for the Italian National Health System. It is led by a combined chairmanship and involves a protocol committee and a safety and efficacy committee empowered to perform interim analyses. It holds annual meetings to review ongoing progress and new proposals. The original questions defined by the members of GROG were the following: • Can we use existing data to establish that radiotherapy is safe and effective in older cancer patients? • What is the feasibility of prospective clinical trials in older individuals, assessing a number of age-relevant parameters, such as function, comorbidity, cognition, social support, and polypharmacy? • Are there special approaches to cancer in the older individual? The first question was addressed in 1992: a review of the practice of the original GROG members revealed that almost 3000 patients were older than 70. This analysis showed that the more than 90% of these patients had been able to complete the planned course of treatment without undue toxicity, and established that age by itself was not a contraindication to radiation treatment. The second question was addressed by a study conducted in 1994 that recruited 2060 patients in 7 months.102 All patients underwent a CGA. In addition to establishing the feasibility of a prospective study in older cancer patients with a common and uniform evaluation, this study also provided a profile of cancer patients aged 70 and older referred to radiation centers throughout Italy (Table 23.9). As can be seen, the majority of patients referred for radiotherapy were in good or excellent general condition. This may be explained in one of two ways: either the patients were highly selected or cancer involves preferentially a fringe of older individuals whose health is well preserved, as suggested by other studies. The comor

Table 23.9 GROG study: age and gender of 2060 patients No. of patients Age 70–80 yrs

1623 (79%) (mean 76.2; range 70–103)

>80 yrs

437 (21%)

Comprehensive Geriatric Oncology

510

Gender Male

1137 (55%)

Male 70–80 yrs

926 (82%)

Male >80 yrs

211 (18%) (M/F ratio 1.2/1)

Female

923 (45%)

Female 70–80 yrs

697 (75%)

Female >80 yrs

226 (25%)

Table 23.10 GROG study: Activities and Instrumental Activities of Daily Living (ADL/IADL) ADL/IADL

Yes

No

Dressing

1224 (89%)

144

Bathing

1215 (89%)

153

Eating

1303 (95%)

65

Walking

809 (59%)

478

Cooking

690 (50%)

678

Shopping

663 (48%)

707

Housework

629 (46%)

739

Phone use

1050 (77%)

317

892 (65%)

472

Money management No data

692

bidities encountered are listed in Table 23.10. For the first time, cancer and patient characteristics were complemented with an analysis of Eastern Cooperative Oncology Group (ECOG) Performance Status and an evaluation of coexisting comorbidities (even if without score—only presence or absence), of daily activities, and of instrumental daily activities that patients were able to do. The data demonstrated that treatment intents were quite similar to those in younger patients and that tolerance was good in the majority of older individuals. The doses delivered in exclusive radiotherapy were lower than those used in younger adults, while the same total dose was used in adjuvant and palliative radiotherapy (Table 23.11). Table 23.12 shows the data on dose delivered according to therapy intent and tumor site. Encouraged by these results, the GROG investigators planned a number of diseasespecific studies in older individuals. The second prospective survey103 was focused on

The achievements of the Geriatric Radiation Oncology Group (GROG)

511

bone metastases in 1995–96: in the participating centers, 29 and 347 patients were collected in 6 months.

Table 23.11 GROG study: total delivered tumor dose of radiotherapy Treatment intent

No. of patients

Mean dose (Gy)

Range (Gy)

Curative alone

558

57.2

15–74

Curative with surgery/ chemotherapy

471

52.0

7–90

Palliative

767

35.9

3–52

Table 23.12 GROG study: delivered dose of radiotherapy according to intent and tumor origin Tumor site No. of patients

Curative intent: mean dose (Gy)

Adjuvant radiotherapy after surgery: mean dose (Gy)

Larynx

65

63.4

Lung (NSCLC)

82

55.5

Breast

138

Prostate

48*/25**

Rectal

71

48.6

Endometrial

54

48.9

Bladder

43

58.7

55.7 66.7*

58.6**

The pain intensity was scored according to the Visual Analogue Scale before treatment, on completion, after 1 month, and after 6 months, and pain relief was evaluated at the same intervals according to World Health Organization (WHO) criteria, using the ThreePoint Analgesic Scale. The treatment parameters and acute toxicity according to the RTOG core system were analyzed. The authors concluded that external radiotherapy was useful for palliation in elderly patients with bone metastases, allowing significant pain relief, which was evident soon after the end of irradiation, remained stable at 1 month after treatment, and had a slight decrease at 6 months. The quality of life was improved, and consequently analgesic consumption decreased. The study did not identify an optimal treatment schedule or fraction dose, even though in most cases (43%) hypofractionation was used: overall doses varied between 8 and 49 Gy administered in 1–20 fractions. A third study104 was dedicated to lung carcinoma in order to assess the indications for radiation treatment, compliance with treatment plans, and quality of life in a group of patients with NSCLC. All patients referred to the 20 participating centers over a period of 6 months in 1996 were recruited. Clinical characteristics and previous therapy were recorded for every patient, and a mini test was performed on patients’ life activity, using parameters

Comprehensive Geriatric Oncology

512

Table 23.13 GROG study: radiotherapy doses according to intent of care in 182 patients Dose (Gy)

Radical radiotherapy Planned

Palliative radiotherapy

Delivered

Planned

Delivered

<30

0

0

6

6

30–50

7

8

56

47

50–60

38

34

9

10

60–70

64

57

2

1

Table 23.14 GROG study: characteristics of 394 patients affected by head and neck cancer aged 70 or older No. of patients

Percentage

Gender: Male

305

77.4

89

22.6

70–74

183

46.4

75–79

113

28.7

98

24.9

Females Age (years):

>80

aimed at exploring a number of functional indexes. The test was performed before radiotherapy, after completion, and quarterly during follow-up. One-hundred and ninetysix patients were entered into the study: 109 underwent radiotherapy with radical intent (radiotherapy alone in 75 patients and postoperative radiotherapy in 34 patients), 73 were treated with palliative intent, and in 14 cases treatment was foregone. Most patients were classified as stage III, which explains why 40% of them underwent palliative radiotherapy; doses ranging from 50 to 70 Gy were given when the intent was radical, and 91% of patients completed the planned treatment with a toxicity similar to that observed in younger patients (Table 23.13). The fourth and last study105 was performed in 1997, and investigated head and neck cancer in the elderly, involving 22 Italian radiotherapy centers. In this study, 394 patients were recruited (305 males and 89 females), aged between 70 and 92 with a mean age of 76.6 (Table 23.14). For 79.6% of the patients, the Karnofsky Performance Status was equal to or superior to 80, and in most cases the comorbidities were grade 1–2 (Table 23.15). In 74.4% of the patients, a weight loss less than 5 kg was registered. Three hundred and three patients with squamous cell carcinoma were evaluable and subdivided as in Table 23.16 according to the site of origin. The mean radio-

The achievements of the Geriatric Radiation Oncology Group (GROG)

513

Table 23.15 GROG study: comorbidities in 394 patients with head and neck tumors aged 70 or older Comorbidity

Grade 1–2 (%)

Grade 3–4 (%)

Cardiovascular

74.6

25.4

Neurological

93.5

6.5

Respiratory

86.8

13.2

Gastrointestinal

91.5

8.5

Urinary

95.9

4.1

Osteoarticular

91.2

8.8

Table 23.16 GROG study: distribution of head and neck tumors according to site of origin: a series of 394 patients Site

No. of patients

Percentage

Nasopharynx

16

4

Oropharynx

51

13

Hypopharynx

24

6

Larynx

187

47.5

Oral cavity

83

21

Paranasal sinuses

21

5.5

Salivary glands

12

3

therapy dose was 66 Gy for treatments with curative intent and radiotherapy alone, and 60 Gy when radiotherapy was adjuvant after surgery. The acute and late toxicities were similar to those in younger patients. The actuarial overall survival rate at 50 months was 50%. The GROG studies clearly established that: • Radiotherapy is well tolerated and effective in the majority of older individuals, and there are no clear differences from the practice in younger adults. • A uniform language, based on CGA, can be used in large cooperative clinical trials. • Older individuals are willing to participate in clinical studies. • A cooperative group dedicated to studying older cancer patients stands an excellent chance of gathering a large amount of data over a short time period. While we cannot say that the experience of GROG is transferable to other healthcare settings, its success suggests that this possibility be explored. Currently, GROG is

Comprehensive Geriatric Oncology

514

involved in incorporating new insights on aging into clinical trials and in establishing cooperation with medical oncology cooperative groups also focused on cancer and age. Palliative radiotherapy Palliative care and symptom management in patients with advanced disease represent a large part of radiotherapeutic practice, with an essential primary role in any comprehensive palliative care program. Cancer-related bone pain, neurological deficit consequent to spinal cord compression, brain metastases, superior vena cava obstruction, and bronchial obstructions can be palliated effectively with radiotherapy in order to improve quality of life. These aspects are particularly important in elderly patients because they add to age-related comorbidities and vulnerability.106 From the few data in the literature concerning palliative radiotherapy in the elderly, we can estimate that 40– 50% of all radiotherapeutic treatments are delivered with palliative aim. In the prospective study for elderly patients conducted in 1994 by GROG, 767 out of 1809 irradiated patients were treated with palliative radiotherapy, accounting for 42.5%.102 Wasil et al,107 in a retrospective study on 183 patients aged 80 and older, treated with radiotherapy, reported that 51% of the patients received a palliative course of radiotherapy, and 73% of them completed the planned course. Mitsuhashi et al108 published data on 32 patients aged 90 or older treated with radiotherapy: 9 of them were treated with palliative intent. In a GROG study of 196 elderly patients affected with NSCLC, palliative radiotherapy was delivered to 40% of patients, mainly for dyspnea and pain.104 In 1995, GROG conducted a nationwide survey on the use of radiotherapy in elderly patients with bone metastases: 347 patients were enrolled in the study during a period of 6 months.103 Doses varied between 8 and 40 Gy; hypofractionation was used in most patients (49%), flash therapy in 17%, split-course therapy in 11%, and conventional fractionation in the remaining cases. Many patients with other cancer-related symptoms may benefit from short therapy schedules, and this is true for these elderly cancer patients who are unfit for curative treatment. References 1. Franceschi S, La Vecchia C. Cancer epidemiology in the elderly. Crit Rev Oncol Hematol 2001; 39:219–26. 2. Leibel Sa, Ling CC, Kutcher GJ et al. The biological basis for conformal three-dimensional radiation therapy. Int J Radiat Oncol Biol Phys 1991; 21:805–11. 3. Emami B. Graham MV, Michalski JM, Perez CA. Three-dimensional conformal radiation therapy: clinical aspects. In: Principles and Practice of Radiation Oncology (Perez CA, Brady LW, eds). Philadelphia: Lippincott-Raven, 1997:371–86. 4. Williamson JF. Physics of brachytherapy. In: Principles and Practice of Radiation Oncology (Perez CA, Brady LW, eds). Philadelphia: Lippincott-Raven, 1997:405–67. 5. Hanks GE, Liebel SA, Krall JM et al. Patterns of care studies: dose-response observations for local control of adenocarcinoma of the prostate. Int J Radiat Oncol Biol Phys 1985; 11:153–57.

The achievements of the Geriatric Radiation Oncology Group (GROG)

515

6. Pierquin B. Précis de Curietherapie, Endocurietherapie et Plésiocuriethérapie. Paris: Masson, 1994. 7. Perez CA, Grigsby PW,Williamson JF. Clinical applications of brachytherapy I: Low dose-rate. In: Principles and Practice of Radiation Oncology (Perez CA, Brady LW, eds). Philadelphia: LippincottRaven, 1997:487–559. 8. International Commission on Radiation Units and Measurements. Dose and Volume Specification for Reporting Intracavitary Therapy in Gynecology. Bethesda, MD: ICRU Report 38, 1985. 9. Martinez AA, Stitt JA, Speiser BL, Perez CA. Clinical applications of brachytherapy II: high dose-rate. In: Principles and Practice of Radiation Oncology (Perez CA, Brady LW, eds). Philadelphia: LippincottRaven, 1997:561–82. 10. Aapro M, AusiliCefaro G, Nole F, Pacini P. Carcinoma mammario. Argomenti Oncol 1999; 20:137–42. 11. Cerrotta AM, Lozza L, Kenda R et al. Current controversies in the therapeutic approach to early breast cancer in the elderly. RAYS 1997; 22(1 Suppl1):66–8. 12. Fowble B. An assessment of treatment options for breast conservation in the elderly women with early breast cancer. Int J Radiat Oncol Biol Phys 1995; 31:1015. 13. Veronesi U. Luini A Del Vecchio M et al. Radiotherapy after breast-preserving surgery in women with localized cancer of the breast. N Engl J Med 1993:328:1587–90. 14. De Antoni EP, Crawford ED. Pretreatment of metastatic disease. Cancer 1994; 74(Suppl):2182–7. 15. Chodak GW. The role of conservative management in localized prostate cancer. Cancer 1994; 74(Suppl):2178–81. 16. Wingo PA, Ries LA, Rosenberg HM et al. Cancer incidence and mortality 1973–1995: a report card for the US. Cancer 1998; 82: 1197–207. 17. Duncan W, Warde P, Catton CN. Carcinoma of the prostate: results of radical radiotherapy (1970–1985). Int J Radiat Oncol Biol Phys 1993; 26:203–10. 18. Dearnaley DP, Khoo VS, Norman A et al. Comparison of radiation side-effects of conformal and conventional radiotherapy in prostate cancer: a randomized trial. Lancet 1999; 353:267–72. 19. Malinverni G, Mandoliti G, Ausili-Cefaro G et al. Tolerance and feasibility of radical conformal radiotherapy for prostate cancer in elderly patients. A multicentric study of the Italian Geriatric Radiation Oncology Group. In: Proceedings of Conference on Cancer in the Elderly, Lyon, 2001:Abst 69. 20. Villa S, Gramaglia A, Cerrotta A et al. Radical radiotherapy in the treatment of prostate carcinoma in the elderly (over 80): What is the problem? Tumori 2001; 87(Suppl 1):141. 21. Stone NN, Stock RG. Prostate brachytherapy: treatment strategies. J Urol 1999; 162:421–6. 22. Blasko JC, Grimm PD, Sylvester JE, Cavanagh W. The role of external beam radiotherapy with I 1257 Pd 103 brachytherapy for prostate carcinoma. Radiat Oncol 2000; 57:273–8. 23. Stromberg JS, Martinez AA, Horwitz EM et al. Conformal high dose-rate iridium-192 boost brachytherapy in locally advanced prostate cancer: superior prostate-specific antigen response compared with external beam treatment. Cancer J Sci Am 1997; 3:346–52. 24. Martinez AA, Kestin LL, Stromberg JS et al. Interim report of image guided conformal high dose-rate brachytherapy for unfavourable prostate cancer: the William Beaumont phase II dose escalating trial. Int J Radiat Oncol Biol Phys 2000; 47:343–52. 25. D’Amico AV. Analysis of the clinical utility of the salvage brachytherapy in patients who have a rising PSA after definitive external beam radiation therapy. Urology 1999; 54:201–3. 26. Fry WA, Menck HR, Winchester DP. The National Cancer Data Base report in lung cancer. Cancer 1996; 77:1947–55. 27. Gridelli C, Perrone F, Monfardini S. Lung cancer in the elderly. Eur J Cancer 1997; 33:2313– 14.

Comprehensive Geriatric Oncology

516

28. Havlik RJ, Yancik R, Long S et al. The National Institute on Aging and the National Cancer Institute SEER: collaborative study on comorbidity and early diagnosis of cancer in the elderly. Cancer 1994; 74:2101–6. 29. Vercelli M, Quaglia A, Casella C, Mangone L, and the ITACARE Working Group. Cancer patient survival in the elderly in Italy. Tumori 1997; 83:490–6. 30. Dosoret DE, Katin MJ, Blitzer PH et al. Radiation therapy in the management of medically inoperable carcinoma of the lung: results and implications for future treatment strategies. Int J Radiat Oncol Biol Phys 1990; 24:3–9. 31. Giovanazzi BS, Rademaker A, Lai G, Benson AB. Treatment tolerance of elderly patients entered into phase II clinical trials: an Illinois Cancer Center study. J Clin Oncol 1994; 12:2447–52. 32. Pignon T, Gregor A, Konig CS et al. Age has no impact on acute and late toxicity of curative thoracic radiotherapy. Radiother Oncol 1998; 46:239–48. 33. Gross NJ. Pulmonary effects of radiation therapy. Ann Intern Med 1977; 86:81–92. 34. Dillman RO, Herndon J, Seagren SL et al. Improved survival in stage III non small cell lung cancer: seven year follow-up of Cancer and Leukemia Group B (CALGB) 8433 trial. J Natl Cancer Inst 1996; 88: 1210–15. 35. Marsiglia H, Baldeyrou P, Lartigau E et al. High dose rate brachytherapy as sole modality for early stage endobronchial carcinoma. Int J Radiat Oncol Biol Phys 2000; 47:665–72. 36. Westeel V, Murray N, Gelmon K et al. New combination of the old drugs for elderly patients with small-cell lung cancer: a phase II study of PAVE regimen. J Clin Oncol 1998; 16:1940–7. 37. Silverberg E, Boring CC, Squires TS. Cancer statistics, 1990. CA Cancer J Clin 1990; 40:9. 38. Goodwin JS, Samet JM, Key CR. Stage at the diagnosis of cancer varies with the age of the patient. J Am Geriatr Soc 1986; 34:20. 39. Korenaga D, Ueo H, Mochida. Prognostic factors in Japanese patients with colorectal cancer: the significance of large bowel obstruction—univariate and multivariate analysis. J Surg Oncol 1991; 47:188. 40. Suen KC, Lau LL, Yermakov V. Cancer and old age. An autopsy study of 3535 patients over 65 years old. Cancer 1974; 33:1164. 41. Fitgerald SD, Longo WE, Daniel GL, Vernava AM. Advanced colorectal neoplasia in the highrisk elderly patient: Is surgical resection justified? Dis Colon Rectum 1993; 36:161–6. 42. Stockholm Rectal Cancer Study Group. Preoperative short-term radiation therapy in operable rectal carcinoma. A prospective randomized trial. Cancer 1990; 66:49–55. 43. Swedish Rectal Cancer Trial. Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 1997; 336: 9807. 44. Camma C, Giunta M, Fiorica F et al. Preoperative radiotherapy for resectable rectal cancer: a meta-analysis. JAMA 2000; 284:1008–15. 45. Havenga K, Enker WE, Norstein J et al. Improved survival and local control after total mesorectal excision or D3 lymphadenectomy in the treatment of primary rectal cancer: an international analysis of 1411 patients. Eur J Surg Oncol 1999; 25:368–74. 46. Kapiteijn E, Marijnen CAM, Nagtegaal ID et al. Preoperative radiotherapy combined with total mesorectal excision for resectable cancer. N Engl J Med 2001; 345:638–46. 47. Glimelius B, Pahlman L. Perioperative radiotherapy in rectal cancer. Acta Oncol 1999; 38:23– 32. 48. Treurniet Donker AD, van Putten WL, Wereldsma JC. Postoperative radiation therapy for rectal cancer. An interim analysis of a prospective, randomized multicenter trial in the Netherlands. Cancer 1991; 67:2028–42. 49. Mak AC, Rich TA, Schultheiss TE et al. Late complications of postoperative radiation therapy for cancer of the rectum and rectosigmoid. Int J Radiat Oncol Biol Phys 1994; 28:597–603. 50. Lundby L, Jensen VJ, Overgaard J et al. Long-term colorectal function after postoperative radiotherapy for colorectal cancer. Lancet 1997; 350:564.

The achievements of the Geriatric Radiation Oncology Group (GROG)

517

51. Tveit KM, Guldvog I, Hagen S et al. Randomized controlled trial of postoperative radiotherapy and short-term time-scheduled 5-fluorouracil against surgery alone in the treatment of Dukes B and C rectal cancer. Br J Surg 1997; 84:1130–5. 52. Valentini V, Morganti AG, Luzi S et al. Is chemoradiation feasible in elderly patients? A study of 17 patients with anorectal carcinoma. Cancer 1997; 80:1387–92. 53. Gerard JP, Ayzac L, Coquard R, et al. Endocavitary irradiation for early rectal carcinoma T1 (T2). A series of 101 patients treated with the Papillon’s technique. Int J Radiat Oncol Biol Phys 1996; 34: 775–83. 54. Salvi G, Valentini V, Audisio RA et al. Guidelines for treatment of elderly patients with colorectal cancer. RAYS 1999; 24:76–8. 55. Muir CS, Fraumeni S, Doll R. The interpretation of time trends in cancer incidence and mortality. Cancer Surv 1994; 19/20:5–20. 56. Olmi P, Ausili-Cefaro G, Loreggian L. Radiation therapy in the elderly with head and neck cancer. RAYS 1997; 22(1 Suppl):77–81. 57. Loreggian L, Olmi P, Ausili-Cefaro G et al. Radiation therapy in elderly patients with head and neck cancer: preliminary results. RAYS, 1999; 24(2 Suppl); 44–8. 58. Hirano M, Mori K. Management of cancer in the elderly: therapeutic dilemmas. Otolaryngol Head Neck Surg 1998; 118:110–14. 59. Lusinchi A, Bourhis J, Wibault P et al. Radiation therapy for head and neck cancers in the elderly. Int J Radiat Oncol Biol Phys 1990; 18:819–23. 60. Koch WM, Patel H, Brennea J et al. Squamous cell carcinoma of head and neck in the elderly. Arch Otolaryngol 1995; 121:262–5. 61. Hedge PU, Brenski AC, Caldarelli DD et al. Tumor angiogenesis and p53 mutations. Prognosis in head and neck cancer. Arch Otolaryngol Head Neck Surg 1998; 124:80–5. 62. Zachariah B, Balducci L, Venkattaramanabalaji GV et al. Radiotherapy for cancer patients aged 80 years and older: a study of effectiveness and side effects. Int J Radiat Oncol Biol Phys 1997; 39:1125–9. 63. Baumann M. Is curative radiation therapy in the elderly patients limited by increased normal tissue toxicity? Radiother Oncol 1998; 46: 225–7. 64. Ogushi M, Ikeda H, Watanabe T et al. Experiences of 23 patients >90 years of age treated with radiation therapy. Int J Radiat Oncol Biol Phys 1998; 41/42:407–13. 65. Nozaki M, Murakami Y, Furuta M et al. Radiation therapy for cancer in elderly patients over 80 years of age. Radiat Med 1998; 16:491–4. 66. Olmi P, Fallai C, Badii D. Relationship between radiation therapy and age in head and neck cancer. In: Proceedings of 2nd Conference on Cancer in the Elderly, 1994:132–4. 67. Loreggian L, Olmi P, Ausili-Cefaro G et al. Radiation therapy in elderly Italian people with head and neck cancer: results on 394 patients observed by GROG (Gruppo di Radioterapia Oncologica Geriatrica) in 22 radiotherapy departments. Tumori 2001; 87(Suppl): 141. 68. Allal AS, Maire D, Becker M, Dulguerov P. Feasibility and early results of accelerated radiotherapy for head and neck carcinoma in the elderly. Cancer 2000; 88:648–52. 69. Kennedy BJ. Aging and cancer. J Clin Oncol 1996; 19:371–4. 70. Bourhis J, Pignon JP, Designe M et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): (1) loco-regional treatment vs same treatment+chemotherapy. Proc Am Soc Clin Oncol 1998; 17:Abst 1486. 71. Lamont DW, Gillis CR, Caird FI. Epidemiology of cancer in the elderly. In: Cancer in the Elderly (Caird FI, Brewin TB, eds). London: Butterworth, 1990:9–15. 72. Peracchia A, Bardini R, Ruol A et al. Carcinoma of the esophagus in the elderly (70 years of age or older). Indications and results of surgery. Dis Esophagus 1988; 1:147–52. 73. Hishikawa Y, Kurisu K, Taniguchi M et al. Radiotherapy for carci noma of the esophagus in patients aged eighty or older. Int J Radiat Oncol Biol Phys 1991; 20:685–8.

Comprehensive Geriatric Oncology

518

74. Kawashima M, Ikeda H, Yorozu A et al. Clinical features of esophageal cancer in the octogenarian treated by definitive radiotherapy: a multi-institutional retrospective survey. Jpn J Clin Oncol 1998; 28:301–7. 75. Ikeda H, Ishikura S, Oguchi M et al. Analysis of 57 nonagenarian cancer patients treated by radical radiotherapy: a survey of 8 institutions. Jpn J Clin Onc 1999; 29:378–81. 76. Taifu L. Radiotherapy of carcinoma of the esophagus in China. A review. Int J Radiat Oncol Biol Phys 1991; 20:875–9. 77. Al Sarraf M, Martz K, Herskovich A et al. Progress report of combined chemoradiotherapy versus radiotherapy alone in esophageal cancer: an intergroup study. J Clin Oncol 1997; 15:277–84. 78. Tanisada K, Teshima T, Ikeda H et al. A preliminary outcome analysis of the patterns of care study in Japan for esophageal cancer patients with special reference to age: non surgery group. Int J Radiat Oncol Biol Phys, 2000; 46:1223–33. 79. Gignoux M, Roussel A. The value of preoperative radiotherapy in esophageal cancer: results of a study of EORTC. World J Surg 1987; 11:426–32. 80. Gava A. Definitive radiation therapy for esophageal carcinoma treatment. Tumori 2001; 87:97– 8. 81. Baranovsky A, Myers MH. Cancer incidence and survival in patients 65 years of age and older. CA Cancer J Clin 1986; 36:26–41. 82. Geisler JP, Geisler HE. Radical hysterectomy in patients 65 years of age and older. Gynecol Oncol 1994; 53:208–21. 83. Mitchell PA, Waggoner S, Rotmensch J, Mundt AJ. Cervical cancer in the elderly treated with radiotherapy. Gynecol Oncol 1998; 71:291–8. 84. Pignon T, Scalliet P. Radiotherapy in the elderly. Eur J Surg Oncol 1998; 24:407–11. 85. Perez CA: Uterine cervix. In: Principles and Practice of Radiation Oncology (Perez CA, Brady LW, eds). Philadelphia: Lippincott-Raven, 1997:1773–834. 86. Hanks GE, Kerring DF, Kramer S. Patterns of care outcome studies: results of the national practice in cancer of the cervix. Cancer 1983; 51:959–67. 87. Kinsella TJ, Bloomer WD. Tolerance of the intestine to radiation therapy. Surg Gynecol Obstet 1980; 151:273–84. 88. Pignon T, Horiot JC, Bolla M et al. Age is not a limiting factor for radical radiotherapy in pelvic malignancies. Radiother Oncol 1997; 42:107–20. 89. Mitsuhashi N, Takahashi M, Nozaki M et al. Squamous cell carcinoma of the uterine cervix: radiation therapy for patients aged 70 years and older. Radiology 1995; 194:141–5. 90. Sakurai H, Mitsuhashi N, Takahashi M et al. Radiation therapy for elderly patients with squamous cell carcinoma of the uterine cervix. Gynecol Oncol 2000; 77:116–20. 91. Lindegaard JC, Thranov IR, Engelholm SA. Radiotherapy in the management of cervical cancer in elderly patients. Radiother Oncol 2000; 56:9–15. 92. Sablinska B. Carcinoma of the uterine cervix in women over 70 years of age. Gynecol Oncol 1979; 7:128–35. 93. Grant PT, Jeffrey JF, Fraser RC et al. Pelvic radiation therapy for gynecologic malignancies in geriatric patients. Gynecol Oncol 1989; 33:185–8. 94. Perez CA, Breaux S, Bedwinek JM et al. Radiation therapy alone in the treatment of carcinoma of the uterine cervix: analysis of complications. Cancer 1984; 54:235–46. 95. Roeske JC,Lujan A, Waggoner SE et al. Intensity-modulated whole pelvic radiation therapy in patients with gynecologic malignancies. Int J Radiat Oncol Biol Phys 2000; 48:1613–21. 96. Pedersen D, Bentzen SM, Overgaard J. Early and late radiotherapeutic morbidity in 442 consecutive patients with locally advanced carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 1994; 29:941–52. 97. Roeske JC, Mundt AJ, Halpern H et al. Late rectal sequelae following definitive radiation therapy for carcinoma of the uterine cervix: a dosimetric analysis. Int J Radiat Oncol Biol Phys 1997; 37: 351–8.

The achievements of the Geriatric Radiation Oncology Group (GROG)

519

98. Navon JD, Weinberg AC, Ahleting TE. Continent urinary diversion using a modified Indiana pouch in elderly patients. Am Surg 1994; 60:786. 99. Figueroa AJ, Stein JP, Dickinson M et al. Radical cystectomy for elderly patients with bladder carcinoma. An updated experience with 404 patients. Cancer 1998; 83:141–7. 100. Chang SS, Albert G, Cookson MS, Smith JA. Radical cystectomy is safe in elderly patients at high risks. J Urol 2001; 166:938–41. 101. Fellin G, Graffer U, Caffo O et al. The results of radiotherapy in bladder sparing strategies for invasive transitional cell carcinoma. Tumori 2001; 87:90–1. 102. Olmi P, Ausili-Cefaro G. Radiotherapy in the elderly: a multicentric prospective study on 2060 patients referred to 37 Italian radiation therapy centers. RAYS 1997; 22(1 Suppl); 53–6. 103. Mandoliti G, Polico C, Capirci C et al. Radiation therapy of bone metastases in the elderly: a multicentric survey of the Italian Geriatric Radiation Oncology Group. RAYS 1997; 22(1 Suppl): 57–60. 104. Gava A, Bertossi l, Zorat PL et al. Radiotherapy in the elderly with lung carcinoma: the experience of the Italian Geriatric Radiation Oncology Group. RAYS 1997; 22(1 Suppl):61–5. 105. Loreggian. L, Olmi P, Ausili Cefaro G et al. Radiation therapy in 394 patients with head and neck cancer observed by GROG. In: Proceedings of 6th International Conference on Geriatric Oncology, Lyon, 2001: Abst 60. 106. Saliba D, Elliott M, Rubenstein LZ et al. The Vulnerable Elderly Survey: a tool for identifying vulnerable older people in the community. J Am Geriatr Soc 2001; 49:1691–9. 107. Wasil T, Lichtman SM, Gupta V. Rush S. Radiation therapy in cancer patients 80 years of age and older. Am J Clin Oncol 2000; 23:526–30. 108. Mitsuhashi N, Hayakawa K, Yamakawa M et al. Cancer in patients aged 90 years or older: radiation therapy. Radiology 1999; 211: 829–33.

24 Quality of life considerations in the older cancer patient Patricia A Ganz Introduction Since the days of the ancient philosophers, Western societies have been concerned about the well-being of individuals.1 From an individual perspective and the philosophical tradition, the concept of quality of life (QoL) includes the idea of happiness, as well as an individual’s ability to pursue activities that are personally and subjectively valued. From a societal perspective, QoL concerns such things as quality of housing, environment, jobs, and community services, and their availability to members of society. Using QoL as viewed from a societal perspective, individual countries can be compared at a single point in time, and the well-being of individuals in society can be monitored over time. Philosophers and demographers have examined both of these aspects of QoL and wellbeing for some time. However, it is only during the past two decades or so that these considerations have been applied to health-related issues. QoL considerations were brought to the forefront of healthcare research in the late 20th century as a result of the convergence of several important factors. These include (i) prolonged life-expectancy, from the eradication of many infectious diseases and the successful treatment of other conditions (e.g. diabetes and kidney failure), (ii) the appearance of many new chronic diseases (e.g. arthritis, heart disease, cancer, and AIDS), (iii) the increasing cost and toxicities of some treatments, and (iv) concern about health outcomes beyond mortality. Coincident with these circumstances has been an emerging science of outcomes assessment,2 which borrows extensively from concurrent methodologic advances in the social sciences, enabling the quantification and evaluation of the QoL outcomes of diseases and their treatments. In this chapter, we shall have an opportunity to examine the intersection of these events from the perspective of cancer in the elderly. There are numerous textbooks and reviews that devote considerable time to the examination of QoL assessment.3–7 This chapter cannot cover all of the important topics that a reader may be interested in, and therefore reference will be made to more detailed texts. However, this chapter will provide sufficient information to allow discussion of critical issues relevant to older persons with cancer, including the definition and conceptualization of QoL, methods of measuring QoL, the role of QoL assessment in the elderly cancer patient, common cancers in the elderly, including the most important QoL issues for each, special aspects of QoL in the elderly, and future directions for research and application.

Quality of life considerations in the older cancer patient

521

Definition and conceptualization of quality of life Definition and history Although most of us intuitively understand what the phrase ‘quality of life’ connotes, it has been exceedingly difficult for social scientists, health services researchers, and clinicians to define precisely. Often ‘quality of life’ is used by the authors of scientific papers without explicit definition, and a wide range of variables are used as measures (from physiologic indicators such as weight loss, to standardized psychologic measures of emotional distress).8 ‘Quality of life’ has been a frequently abused catch phrase; however, there is growing consensus about its definition. Two research groups have proposed definitions: (i) ‘quality of life is the subjective evaluation of life as a whole’;9 (ii) ‘quality of life refers to patients’ appraisal of and satisfaction with their current level of functioning compared to what they perceive to be possible or ideal’.10 The first definition emphasizes the subjectivity of the measurement, as well as the importance of a global assessment or summary score. The second definition also highlights the subjectivity of QoL assessment, as well as the preference or value given to the person’s current health state. For example, two people with the same disability may place a different value on their current

Table 24.1 Historical aspects of health-related quality of life (HRQoL) assessment • World Health Organization (WHO) Definition of Health (1948) • Functional Health Classification Schemes (e.g. New York Heart Association, Arthritis, Karnofsky Performance Status) (1940–50) • Social Indicators Research the Great Society (1960s) • The RAND Health Insurance Experiment (1970s) • Patient’s Rights Movement (1980s)

health state. Conceptually, both of these definitions contribute to our understanding of the phrase ‘quality of life’; however, they do not necessarily indicate how one should measure it. Many recent reviews and papers have focused on the evolving conceptualization of QoL.11–14 While the concept of QoL has broad, general meaning based on its roots in ancient philosophical works,15 contemporary definitions and measurement strategies derive from historical efforts designed to measure the well-being of the population using social indicators such as general satisfaction and happiness, as well as satisfaction with housing, employment, and income,16–18 and from the World Health Organization (WHO) definition of health as a ‘state of complete physical, mental, and social well-being and not merely the absence of disease’.19 While the WHO definition was considered impossible to operationalize and measure at the time of its publication, contemporary QoL assessment tools focus on these three critical dimensions of health and QoL. Current conceptualization of QoL as measured in relationship to disease and treatment is called health-related quality of life (HRQoL), since it tends to limit the focus to dimensions of

Comprehensive Geriatric Oncology

522

QoL that are directly affected by health and/or disease states.12,20 Table 24.1 lists highlights of the history of QoL assessment. One of the first major research efforts directed at measuring the health and well-being of individuals occurred some three decades ago when Lester Breslow and colleagues studied a population sample in Alameda County, California.21 In their work, they adopted the WHO definition of health to guide their assessment of the population, focusing on the physical, emotional, and social dimensions of well-being. Although they examined some social indicators in their study sample, the main thrust of their work was on the selfreported evaluation of the three dimensions of well-being. These early QoL researchers demonstrated the feasibility of reliably asking people about these dimensions of HRQoL. In oncology practice, the Karnofsky Performance Status scale22 was an early tool that was developed to measure the functional performance of cancer patients. The scale was developed by clinicians primarily to collect and record information that was thought to be important for diagnosis, treatment, and clinical response. Although widely accepted clinically, the reliability of clinically rated scales such as the Karnofsky tends to be poor,23 which limits their use for monitoring healthcare outcomes and QoL. Although the Karnofsky Performance Status correlates highly with the physical functioning dimension of QoL questionnaires in some studies, it does not seem to correlate well with overall measures of QoL in cancer patients.24 The measure is limited further by being clinicianrather than patient-rated. However, it has the advantage of being brief, being acceptable in the clinical setting, and having a clear relationship to other important clinical variables such as mortality.22,23 Early in the 1980s, Spitzer and colleagues25 developed a tool specifically to evaluate the QoL of cancer patients. This instrument contains a uniscale for the global evaluation of QoL, along with separate components that evaluate the physical and emotional aspects of QoL. This latter 10-point scale is appealing because of its simplicity, as well as the ease with which it can be rated by an observer. For this reason, it was extensively used in cancer research during the 1980s (e.g. in the National Hospice Study). However, since then there has been growing consensus that QoL should be rated by the patient rather than by a clinician or proxy.26 Thus, many new tools have been developed to capture the patient’s own assessment of QoL. The US National Cancer Institute (NCI) has had two workshops (1990 and 1995) on the topic of QoL assessment in clinical trials,27 and now each of the clinical trials cooperative groups has clinical investigators and staff devoted to consideration of inclusion of QoL endpoints in clinical treatment trials. In addition, many pharmaceutical companies are routinely including QoL measures as part of the evaluation of new drugs. Recently, improvements in QoL (including pain and symptom relief) have been acknowledged as being relevant endpoints in the new-drug approval process. Multidimensionality of QoL Most experts in this field perceive QoL as a multidimensional construct that includes several key dimensions.13,14,20,28,29 These include physical functioning (performance of self-care activities, functional status, mobility, physical activities, and role activities such as work or household responsibilities), disease and treatment-related symptoms (specific symptoms from the disease such as pain or shortness of breath, or side-effects of drug

Quality of life considerations in the older cancer patient

523

therapy such as nausea, hair loss, impotence, or sedation), psychological functioning (anxiety or depression that may be secondary to the disease or its treatment), and social functioning (disruptions in normal social activities).

Figure 24.1 The multidimensional aspects of the quality of life construct. Adapted from reference 30. Additional considerations in the evaluation of QoL may include spiritual or existential concerns, sexual functioning and body image, and satisfaction with healthcare. Figure 24.1 represents one author’s conceptualization of the dimensionality of QoL.30 Whenever possible, HRQoL should be assessed by the patient8,31and should reflect the evaluation of a number of dimensions affecting his or her life at that moment. Although the specific dimensions that are the most satisfactory or unsatisfactory at any point in time may vary, the individual’s QoL may in fact remain stable or change depending on how these dimensions fluctuate and interact. For this reason, some have argued that both the component dimensions of QoL and a global assessment should be considered.32 Therefore, in the research or clinical settings, one should always ask what specific dimensions of QoL are likely to be affected, and choose a QoL tool based on its content relevance to the questions of interest. Measurement of QoL Data collection methods Although there is consensus that QoL should be assessed by the patient, there are a variety of ways in which this information can be obtained. The clinical interview (using structured questions from a validated instrument) is the most comprehensive approach in that it allows participation of the greatest number of individuals (e.g. those who cannot

Comprehensive Geriatric Oncology

524

read or write, and those with visual impairment or frailty). However, the personal interview is more costly in personnel and time, and there may be some bias introduced through in-person interaction. Interviews can be conducted in-person or by telephone, and can assure fewer missing data. For geriatric research, the clinical interview is a standard approach for a variety of reasons, but often because of the frailty of the target population. In contrast, most of the research on QoL in cancer patients has focused on selfadministered questionnaires. This has occurred primarily because of an interest in the inclusion of QoL assessments in clinical trials, where extensive personnel for conduct of interviews are unavailable. The advantages of the self-administered format include a limited need for personnel to collect data, more accurate responses for sensitive information, and administration at a time and place that are convenient for the patient. However, there are important limitations to self-administered instruments, which include a requirement for literacy and language translation, familiarity with completion of pencil and paper tests, and the increased likelihood of missing data. In addition, very ill patients (e.g. with Karnofsky score <60), may have difficulty completing more than the briefest scales.33 Ideally, a combination of these two approaches should be used in the assessment of QoL in cancer patients. One can start with the self-administered format, and reserve the structured research interview for those patients who tance. Even when a self-administered format is used, are unable to complete the written form without assis-however, it is important to review all questionnaires for missing data. Thus, the combination of the two approaches can lead to the greatest efficiency in terms of data completeness and personnel time. In the Medical Outcomes Study, which included a sizeable portion of outpatients over 65, the fairly lengthy survey was self-administered by the majority of subjects, with telephone interview required in the remainder.34 While, in general, results from self-report and telephone interviews are similar, there can be some variation, especially on sensitive topics, and researchers should track the mode of administration. In research studies with older cancer patients, an attempt should be made to collect the data in a single systematic format. If resources permit, the interview may be the best approach to ensure inclusion of all eligible older patients. Choice of instruments In the field of QoL assessment, there is a tension between using instruments that are highly specific to the research or clinical question at hand (e.g. a unique toxicity for a treatment) versus use of a tool that has been widely used with other samples of cancer patients or patients with other chronic conditions (e.g. diabetes, arthritis, or heart disease). The debate revolves around the use of generic measures or cancerspecific/cancer site- and phase-specific tools (Table 24.2). In considering the geriatric cancer patient, one must also consider a whole body of geriatric assessment tools as an additional reference point (e.g. the Mini-Mental State Examination and the Geriatric Depression Scale). However, for the purpose of this discussion, we shall focus on scales that have been used in a broad range of populations. Generic instruments such as the RAND measures,34–36 the Dartmouth COOP charts,37 and the Duke scales,38 all have considerable value if one wishes to compare the general

Quality of life considerations in the older cancer patient

525

impact of differing diseases and conditions on HRQoL. From a policy standpoint, this may be important in terms of preventing discrimination against cancer patients, since their functional status and QoL may exceed those of patients with other chronic conditions.39 On the other hand, the information obtained from these scales

Table 24.2 Examples of HRQoL instruments used with cancer patients Generic health status measures Sickness Impact Profile (SIP) RAND Health Insurance Experiment measures Medical Outcomes Study (MOS) instruments Nottingham Heath Profile Psychosocial Adjustment to Illness Scale (PAIS) Dartmouth COOP Charts Generic cancer-specific instruments Quality of Life Index (Spitzer) Quality of Life Index (Padilla and Grant) Functional Living Index-Cancer (FLIC) European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ) Cancer Rehabilitation Evaluation System (CARES) Functional Assessment of Cancer Therapy (FACT) Cancer site-specific instruments Breast Cancer Chemotherapy Questionnaire Linear Analogue Self-Assessment (LASA) for breast cancer Performance Parameter (head and neck cancer) Site-specific modules for the FACT and the EORTC-QLQ Symptom-oriented scales Rotterdam Symptom Checklist Symptom Distress Scale (McCorkle) Memorial Pain Assessment Card Morrow Assessment of Nausea and Emesis (MANE) scale

often lacks the sensitivity to detect impairments from cancer treatments.40,41 In contrast, the cancer-specific QoL instruments (e.g. FLIC, EORTC, CARES, and FACT) that have been developed during recent years have high reliability and validity, and are responsive to changes in treatment.42 In addition, they are more likely to capture

Comprehensive Geriatric Oncology

526

the known toxicities and concerns related to cancer treatment. Therefore, they should be a preferred choice in the comparative evaluation of cancer treatments. However, one must recognize that each of these generic cancer-specific instruments may need to be supplemented with disease-specific modules (e.g. for breast cancer, prostate cancer, and leukemia) or condition-specific questions that target specific QoL issues (e.g. pain, nausea, and sexual functioning). Thus, in designing a QoL assessment, one must carefully define the expected impacts of the disease and its treatment on QoL, and use a battery of assessment tools that are likely to reflect these effects. In considering how to assess QoL in the geriatric cancer patient, one must follow the same general principles as for other populations; however, special issues may arise in very frail elderly samples, especially those who are not routinely included in clinical trials because of other exclusion criteria. Relatively little research has been conducted with this group of cancer patients, and it is unclear whether other chronic conditions (e.g. arthritis and heart or pulmonary disease) will overwhelm any specific contribution made by the cancer. This is clearly an area ripe for further research, and is beginning to receive attention from several investigators.43,44 Role of QoL assessment in cancer treatment QoL assessment can be used for a variety of purposes: to describe the impact of cancer and its treatment on patients; to compare the outcome of different treatments in clinical trials; to identify unanticipated benefits or toxicities of treatment; to inform future treatment planning through modification of aspects that detract from QoL. Information gained from prior QoL research can help inform treatment decisions. For example, multiple studies have shown that overall QoL, and most of its dimensions, differ little among women who choose mastectomy over lumpectomy in the primary treatment of breast cancer.45 Therefore, a woman who is considering alterative surgical treatments for breast cancer can be reassured that her subsequent adjustment will not be dependent on the type of surgery she receives. However, since research has shown that there is much more body image disruption from mastectomy compared with lumpectomy,46 a woman who expresses concerns about her body image should be encouraged to consider a lumpectomy. Several studies have also demonstrated that QoL is an important prognostic factor for survival33,47 While this should not be the only variable used in considering whether a patient should receive aggressive cancer therapy, assessing patient-rated QoL could help physicians determine more systematically when only palliative care should be offered. In this regard, there is mounting evidence that physicians regularly ignore the advance directives or expressed wishes of patients regarding end-of-life support.48 Regular evaluation of a patient’s QoL over time can capture functional deterioration, which physicians assess poorly.31 Physicians’ reluctance to engage in discussions with seriously ill patients is likely to be enhanced by more objective and quantified measures of outcome. Although these issues are relevant to all cancer patients, they are particularly salient for the elderly, in whom the majority of cancer deaths occur.

Quality of life considerations in the older cancer patient

527

Common cancers in the elderly and important QoL concerns Breast cancer Breast cancer is the most common cancer in women in Western industrialized countries. The disease has a bimodal distribution, with the greatest incidence in older women.49 Older women are diagnosed with breast cancer at a more advanced stage, and this probably results directly from less frequent screening for breast cancer (mammography and physical examination).50,51 Once diagnosed, there are additional differences in the patterns of care for older versus younger women with breast cancer.52–55 All of these factors contribute to a poorer overall survival for older women with breast cancer.49 In a review of breast cancer care in old age,43 the authors point out that there is considerable vadation in the care of older women with breast cancer (e.g. lumpectomy without radiation therapy, inconsistent use of tamoxifen, and omission of axillary lymph node dissection). These variations in care may have a substantial impact on QoL as well as survival, yet they have not been studied systematically. Indeed, little is known about whether patients are actually consulted as these decisions are made, or whether physicians have assumed patient preferences (e.g. a more frequent use of mastectomy over lumpectomy in older women). There is an emerging interest in studying alternative treatment strategies for older women with breast cancer (e.g. omission of axillary node dissection). Whenever possible, these therapeutic studies should be coupled with evaluation of QoL outcomes. Although there is a growing literature on QoL in breast cancer patients, few studies have examined the relationship of age to QoL. In a series of reports from a longitudinal cohort study (227 patients) of newly diagnosed breast cancer followed in the first year after surgery, we have demonstrated better adjustment in older women with breast cancer,56 and in a predictive model for psychosocial distress in the year after breast cancer, women older than 55 fared better.57 These findings are consonant with the literature,39 and suggest that older women are resilient, in spite of increasing physical limitations that occur with age. Other variables that may be important include social support and comorbid conditions. However, as is generally the case, QoL cannot be predicted, and should be assessed directly by the patient. Therefore, although, in general, older women adapt well to breast cancer, some may not. With the increasing use of generic measures of QoL, such as the RAND and MOS measures, we shall begin to be able to compare the well-being of cancer patients with that of the general population of outpatients and individuals with other specific chronic conditions. In a study of long-term breast cancer survivors, we used the RAND 36-Item Health Survey 1.0 to evaluate QoL in 2- and 3-year breast cancer survivors.41 Compared with outpatients with chronic medical conditions, the breast cancer survivors were functioning at a higher level (range about 0.5 standard deviation for most subscales) (Figure 24.2). These findings suggest that breast cancer survivors have comparatively high levels of functioning, similar to those of other non-cancer outpatients visiting medical offices. On the other hand, in this same report, using the CARES,58 we demonstrated a substantial number of ongoing rehabilitation concerns, especially in the area of body image and sexual functioning.41 These latter observations point to the

Comprehensive Geriatric Oncology

528

greater sensitivity of a cancer-specific measure in capturing disease-specific concerns that are not readily assessed in a general population measure of QoL. In our more recent studies with breast cancer survivors, we have found that the problems with sexual functioning identified in this earlier study seemed to be more strongly associated with aging, rather than with the breast cancer treatments.59 Specifically, we found that breast cancer survivors rated their sexual functioning as similar to that of postmenopausal women without breast cancer.59,60 In more detailed analyses, the quality of the partnered relationship and the emotional health of the woman positively influenced sexual interest and satisfaction, while vaginal dryness predicted more sexual dysfunction, and this was strongly associated with past chemotherapy.61 In an intervention study with postmenopausal women, we found that addressing the menopausal symptoms of breast cancer survivors could improve these symptoms as well as sexual functioning.62

Figure 24.2 RAND 36-Item Health Survey results in breast cancer survivors who are 2 and 3 years since diagnosis compared with non-cancer outpatients. Breast cancer data are from reference 41 and non-cancer outpatient data are from reference 36. Data presented are mean and one standard deviation (bar) for each scale. Colorectal cancer Colorectal cancer ranks second to lung cancer as the most frequent cause of cancer death in the USA (with over 56700 deaths in 2001).63 It affects men and women equally, and is

Quality of life considerations in the older cancer patient

529

a particular health threat in the aging population. In contrast to breast cancer, which is often diagnosed at a localized or regional stage, colorectal cancer is diagnosed at a localized stage in only 37% of cases, and in 19% of cases it is metastatic at the time of diagnosis.63 Relatively few clinical trials have studied QoL among colorectal cancer patients. As a common disease affecting the elderly, colorectal cancer has largely been neglected. In our own work evaluating the CARES, we have studied a group of patients with colorectal cancer and have compared them with patients with lung and prostate cancer.64 All of the patient samples were older (mean age for colorectal 62.6 years, with a range of 28–89; mean for lung 61.6 with a range of 23–87; mean for prostate 69.0, with a range of 43–90). In a group of comparisons of patients with no evidence of disease, localized disease, and metastatic disease, colorectal cancer patients fared better than patients with lung cancer in many dimensions of QoL, but poorer than prostate cancer patients, except in the area of sexual functioning (Figure 24.3). This finding might be anticipated based on the more severe physical symptoms associated with lung cancer and the specific sexual problems associated with prostate cancer. In a separate study focusing on adult cancer survivors, we examined the long-term QoL of 117 colorectal cancer survivors using the CARES.65 Predictors of QoL (as measured by the CARES) in this sample of patients included Karnofsky Performance Status, the type of hospital in which treatment was received (private hospitals were most favorable), gender (males had more favorable QoL), and work status (there was a better QoL for those who were not working). In contrast to the lung and prostate cancer survivors, colorectal cancer survivors experienced improved QoL the greater the time since diagnosis, with improvements in the psychosocial dimension of QoL. However, in spite of these observations, these colorectal cancer survivors reported continuing rehabilitation concerns in a number of areas (e.g. worry about cancer recurrence, body image disruption, sexual dysfunction, atwork concerns, and financial/insurance issues).65 Lung cancer Lung cancer is the most frequent cause of cancer mortality in both men and women, and is common in the

Comprehensive Geriatric Oncology

530

Figure 24.3 Mean global CARES and CARES summary scale scores (with 95% confidence intervals) for three cancer sites (colorectal, lung, and prostate) according to extent of disease. indicates the mean value for patients who have no evidence of disease; • indicates mean value for patients with limited disease; \ indicates the mean value for patients with extensive disease. Reprinted from reference 64 with permission. elderly.63 Survival is poor in this cancer, primarily because of the advanced stage of disease in patients at diagnosis, and the limited survival benefit from chemotherapy and radiation therapy. Chemotherapy for this disease is quite toxic, and thus it may contribute to poorer QoL, especially in patients with minimal or no response to treatment. Although several meta-analyses support a modest improvement in survival from chemotherapy in advanced non-small cell lung cancer,66,67 many clinicians and patients are concerned about the QoL benefits of treatments. This remains an important area for continuing investigation in clinical trials. Several studies have demonstrated that patient-rated QoL in lung cancer patients provides additional prognostic information beyond performance status and other biologic variables.33,68 This has been demonstrated with a variety of QoL measures, including the FLIC. In a study that we completed, there was also a suggestion that social support (as measured by marital status) moderated the effects of poorer QoL on prediction of survival.33 In our study that compared the CARES in patients with colorectal, lung, and prostate cancer (see above),64 lung cancer patients demonstrated the poorest physical

Quality of life considerations in the older cancer patient

531

functioning at all phases of illness, and the metastatic lung cancer patients had substantially more impairment in overall QoL, physical functioning, psychological functioning, and marital functioning than patients with metastatic prostate cancer (Figure 24.3).64 In our examination of lung cancer survivors (average age 62.38),65 QoL was predicted by Karnofsky Performance Status only (compare with colorectal cancer patients discussed earlier), suggesting that the physical impact of the disease, treatment, and perhaps coexistent pulmonary disease have a major impact on QoL in lung cancer survivors.65 Prostate cancer Prostate cancer is primarily a disease of aging men, and now is the leading cancer in men.63 The recent increase in new prostate cancer cases is due largely to the expansion of population screening with the prostatic-specific antigen (PSA) blood test. Major controversies exist related to the benefits of PSA screening with respect to mortality, the survival benefit of treatment in men older than 70, and the morbidity associated with surgery and radiation, compared with observation. All of these controversial areas are the subjects of clinical trials, and many ongoing studies include QoL assessments. Specific QoL issues include (i) the psychological impact of a false-positive screening test, along with the physical and psychological morbidity of diagnostic tests, (ii) the sexual and urinary dysfunction associated with radical prostatectomy, (iii) the sexual, urinary, and bowel dysfunction associated with radiation therapy for prostate cancer, and (iv) the psychological and overall QoL impact of watchful waiting as a treatment strategy for prostate cancer. As it may be many years before the QoL results from ongoing clinical trials are reported, it may be useful to look at some existing information on QoL in prostate cancer patients. In our study of colorectal, lung, and prostate cancer patients,64 our sample included 288 prostate cancer patients (see above). Patients who were disease-free or had only a local recurrence had similar assessments in all dimensions assessed by the CARES. Patients with advanced metastatic prostate cancer experienced poorer overall QoL as well as poorer physicial and psychosocial functioning. Interestingly, sexual functioning was impaired in all phases of the illness and was substantially worse than in the lung and colorectal cancer patients (Figure 24.3). As noted earlier, in spite of being older, the prostate cancer patients in general had a better QoL in most dimensions than patients with the other types of cancer. In our study of the prostate cancer survivors,65 significant predictors of QoL included Karnofsky Performance Status (higher score more favorable), medical comorbidity, and time since diagnosis (both associated with poorer QoL). Psychiatric comorbidity was also associated with poorer QoL. There was a trend favoring treatment in a private hospital setting and an association with better QoL. This sample of survivors was aged on average 69.5, and the long-term survivors were aged on average 73.44. Therefore, in this aging sample of prostate cancer patients, there may be substantial interaction between cancer and other chronic illnesses.65 In another cross-sectional study of prostate cancer survivors treated for localized prostate cancer, we examined the QoL of patients receiving surgery, radiation therapy, or observation in comparison with age-matched non-cancer controls.40 In this study, we

Comprehensive Geriatric Oncology

532

used a generic measure of QoL (the RAND 36-Item Health Survey), two cancer-specific QoL instruments (CARES-SF and FACT), and a newly developed condition-specific measure targeting urinary, sexual, and bowel function.40 On average, the patients were more than 5 years since diagnosis of prostate cancer, and were elderly (surgery patients were mean age 69.7, radiation therapy patients were mean age 76.2, observation patients were mean age 75.2, and the control group were mean age 72.5). Other demographic and medical history variables were comparable across all four groups. The QoL evaluation found no difference on the RAND measure among the four groups, with the exception of lower emotional role functioning in the observation prostate cancer patients. For the two cancer-specific QoL tools, the only significant difference between the cancer patients and the controls was in sexual functioning, which was poorer in the cancer patients than in controls, and in medical interaction (e.g. communication with doctors and nurses), which was somewhat poorer in the surgically treated and observation groups. Overall, these cancer patients looked similar to their age-matched, non-cancer controls in most dimensions of QoL.40 An added value from this study, however, was the sensitivity of the new conditionspecific measure,40 in detecting treatment-related differences in functioning. Sexual functioning was poorest in the surgery group (significantly worse than observation and control), and observation patients were worse than control subjects. Urinary functioning was also poorest in the surgery group, and was significantly worse than the irradiation, observation, and control groups. Bowel functioning was most impaired in the radiation group, as might have been predicted. We concluded that physicians interacting with prostate cancer patients should advise them that treatment is unlikely to affect general health-related QoL, but it may be associated with clinically significant changes in sexual, urinary, or bowel function. Any survival gain from surgery or radiation must be balanced with expected decrements in some areas of function.40 Special aspects of QoL in the older cancer patient Assumptions have often been made about the impact of cancer and its treatment on the QoL of older patients. These include the beliefs that older patients suffer more sideeffects from treatment and have more difficulty adjusting to a cancer diagnosis. As indicated above, the elderly are quite heterogeneous, and one cannot assume that chronologic age is the primary factor affecting functioning or well-being. In a study by Kahn and colleagues,69 300 matched pairs of adult patients with cancer and their physicians were interviewed concerning the effects of disease and treatment on the patients’ QoL. The physicians overestimated the problems of the elderly cancer patients, while in actuality younger patients reported more difficulties. These authors suggest that physicians need to become more sensitized to the individualized, personal nature of their patients’ QoL and the factors that may shape or modify it.69 Thus, it is critical that healthcare providers assess the individual patient’s QoL; there is no room for paternalistic decision-making for older adults simply because of their age. Where side-effects of cancer treatment have been examined (e.g. nausea and vomiting), older patients often fare better than younger patients, requiring less antiemetic therapy.70 Some side-effects, such as diarrhea (and resultant dehydration), may be more

Quality of life considerations in the older cancer patient

533

of a problem in the older cancer patient receiving chemotherapy. Pain is an important symptom that may detract from QoL,71,72 and care should be taken to provide adequate education and treatment for this problem. Although pain research specific to the elderly is sparse,73,74 older persons with cancer are the majority of those cared for in hospice programs, where excellent palliative care is a primary goal. Several studies have documented better mental health in the elderly in general, with consistent findings among older cancer patients.39 Life experiences, as well as familiarity with the healthcare setting, allow older cancer patients to cope with a cancer diagnosis with more resiliency. With fewer responsibilities to juggle (e.g. childcare or work), as well as awareness that this is a disease experience that their peers have had, older cancer patients often are not as distressed as younger cancer patients. A specific issue for the elderly, however, may be their need for assistance of various types. In a detailed study of determinants of need and unmet need among cancer patients residing at home, Mor and colleagues75 found that physiologic factors (metastases, disease stage, and functional status) were associated with the need for assistance in the areas of personal care, instrumental tasks, and transportation. Also, older age (over 65) and low income predicted need for help with personal care, and women were more likely than men to report illness-related need for assistance with instrumental tasks and transportation. Unmet need was primarily associated with the patients’ social support system.75 Again, there may be considerable variation in the degree of social support among elderly cancer patients, and this may influence patient functioning and well-being. Healthcare providers should include evaluation of social support when considering treatment decisions as well as patients’ subjective assessment of well-being. Conclusions and future directions Although the majority of cancer patients are aged over 60, the elderly are not always adequately represented in clinical trials or QoL research. In particular, patients with comorbid conditions or physiologic abnormalities of aging (e.g. decreased renal function) are usually excluded from clinical treatment trials.76 Therefore, it may be difficult to extrapolate information obtained in clinical trials to the general elderly population. There is increasing awareness of the need for effectiveness studies (examination of which clinical practices work in the real world) to determine which treatments are best for the general community of older cancer patients. Similarly, QoL studies in older cancer patients should be conducted under these circumstances to better understand their values and estimation of QoL. These studies are particularly necessary because of the exclusion of these patients from usual clinical cancer research. Beyond research, considerable improvement in patient care will likely occur with the advancement of the outcomes movement and the integration of QoL assessments into routine care.2 Unfortunately, the tools that have been developed to monitor outcomes among groups of patients do not as yet have the precision to monitor all dimensions of HRQoL accurately in clinical practice.77 If nothing else, an acknowledgment of the value of the patient’s own subjective assessment of well-being must remain central to any considerations about cancer treatment, and physicians may use information derived from research studies to help them identify important areas for inquiry in their conversations

Comprehensive Geriatric Oncology

534

with their patients.78 Most importantly, patients care about these issues, and therefore physicians and other healthcare providers must include consideration of HRQoL issues in treatment planning for older cancer patients. References 1. Calman KC. Definitions and dimensions of quality of life. In: The Quality of Life of Cancer Patients (Aaronson NK, Beckman J, eds). New York: Raven Press, 1987; 1–9. 2. Ellwood PM. Shattuck Lecture. Outcomes management: a technology of patient experience. N Engl J Med 1988; 318:1549–56.. 3. Aaronson NK, Beckmann J (eds). The Quality of Life of Cancer Patients. New York: Raven Press, 1987. 4. McDowell I, Newell C. Measuring Health: A Guide to Rating Scales and Questionnaires, 2nd edn. New York: Oxford University Press, 1996. 5. Tchekmedyian NS, Cella DF (eds). Quality of life in current oncology practice and research. Oncology 1990; 4(5 Suppl). 6. Tchekmedyian NS, Cella DF, Winn RT (eds). Economic and quality of life outcomes in oncology. Oncology 1995; 9(11 Suppl). 7. Osoba D (ed). Effect of Cancer on Quality of Life. Boca Raton, FL: CRC Press, 1991. 8. Hollandsworth JG Jr. Evaluating the impact of medical treatment on the quality of life: a five year update. Soc Sci Med 1988; 26:425–34. 9. De Haes JCJM. Quality of life: Conceptual and theoretical considerations. In: Psychosocial Oncology (Watson M, Greer S, Thomas C, eds). Oxford: Pergamon Press, 1988:61–70. 10. Cella DF, Cherin EA. Quality of life during and after cancer treatment. Comprehensive Ther 1988; 14:69–75. 11. Cella DF, Tulsky DS. Quality of life in cancer: definition, purpose, and method of measurement. Cancer Invest 1993; 11:327–36. 12. Guyatt GH, Feeny DH, Patrick DL. Measuring health-related quality of life. Ann Intern Med 1993; 118:622–29 13. Aaronson NK. Quality of life: What is it? How should it be measured? Oncology 1988; 2:69– 74. 14. De Haes JCJM, Van Knippenberg FCE. The quality of life of cancer patients: a review of the literature. Soc Sci Med 1985; 20:809–17. 15. Aristotle. Ethics (transl JAK Thompson). Harmondsworth, UK: Penguin Books, 1976. 16. Andrews FM, Withey SB. Social Indicators of Well Being: Americans’ Perception of Life Quality. New York: Plenum Press, 1976. 17. Campbell A. Subjective measures of well-being. Am Psychol 1974; 31: 117–24. 18. Campbell A. The Sense of Well-Being in America: Recent Patterns and Trends. New York: McGraw-Hill, 1981. 19. World Health Organization. Constitution in Basic Documents. Geneva: WHO, 1948. 20. Ware JE Jr. Conceptualizing disease impact and treatment outcomes. Cancer 1984; 53(Suppl):2316–23. 21. Breslow L. A quantitative approach to the World Health Organization definition of health: physical, mental and social well-being. Int J Epidemiol 1972; 1:347–55. 22. Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer. In: Evaluation of Chemotherapeutic Agents (Macleod CM, ed). New York: Columbia University Press, 1949: 199–205. 23. Patrick DL, Deyo RA. Generic and disease-specific measures in assessing health status and quality of life. Med Care 1989; 27: S217–32.

Quality of life considerations in the older cancer patient

535

24. Adams AG, Britt DM, Godding PR et al. Relative contribution of the Karnofsky Performance Status scale in a multi-measure assessment of quality of life in cancer patients. Psychooncology 1995; 4:239–46. 25. Spitzer WO, Dobson AJ, Hall J et al. Measuring the quality of life of cancer patients. J Chron Dis 1981; 34:585–97. 26. Moinpour CM. Quality of life assessment in Southwest Oncology Group trials. Oncology 1990; 4:79–89. 27. Nayfield SG, Hailey BJ. Quality of Life Assessment in Cancer Clinical Trials. Report ofthe Workshop on Quality of Life Research in Clinical Trials, July 16–17, 1990. Bethesda, MD: US Department of Health and Human Services, Public Health Service, NIH, 1990. 28. Patrick DL, Erickson P. Assessing health-related quality of life for clinical decision making. In: Quality of Life: Assessment and Application (Walker SM, Rosser RM, eds). Lancaster: MTP Press, 1988: 9–49. 29. Schipper H, Clinch J, McMurray A, Levitt M. Measuring the quality of life of cancer patients: the Functional Living Index-Cancer: development and validation. J Clin Oncol 1984; 2:472–83. 30. Tcheckmedyian NS, Hickman M, Sian J et al. Treatment of cancer anorexia with megestrol acetate: impact on quality of life. Oncology 1990; 4:185–92. 31. Slevin ML, Plant H, Lynch D et al. Who should measure quality of life, the doctor or the patient? Br J Cancer 1988; 57:109–12. 32. DeHaes JCJM, van Knippenberg FCE. Quality of life instruments for cancer patients: Babel’s tower revisited. J Clin Epidemiol 1989; 42: 1239–41. 33. Ganz PA, Haskell CM, Figlin R et al. Estimating the quality of life in a clinical trial of metastatic lung cancer using the Kamofsky Performance Status and the Functional Living Index-Cancer (FLIC). Cancer 1988; 61:849–56. 34. Stewart AL, Ware JE (eds). Measuring Function and Well-Being. The Medical Outcomes Study Approach. Durham, NC: Duke University Press, 1992. 35. Ware JE, Sherbourne CD. The MOS 36-Item Short-Form Health Survey (SF-36): I. Conceptual framework and item selection. Med Care 1992; 30:473–83. 36. Hays RD, Sherbourne CD, Mazel RM. The RAND 36-Item Health Survey 1.0. Health Econ 1993; 2:217–27. 37. Nelson E, Wasson J, Kirk J et al. Assessment of function in routine clinical practice: description of the COOP chart method and preliminary findings. J Chron Dis 1987; 40(Suppl):55S–63S. 38. Parkerson GR, Broadhead WE, Tse CJ. The Duke Health Profile: a 17-item measure of health and dysfunction. Med Care 1990; 28: 1056–72. 39. Cassileth BR, Lusk EJ, Strouse TB, et al. Psychosocial status in chronic illness. N Engl J Med 1984; 311:506–11. 40. Litwin MS, Hays RD, Fink A et al. Quality-of-life outcomes in men treated for localized prostate cancer. JAMA 1995; 273:129–35. 41. Ganz PA, Coscarelli A, Fred C et al. Breast cancer survivors: psychosocial concerns and quality of life. Breast Cancer Res Treat 1996; 38:183–99. 42. Cella DF, Bonomi AE. Measuring quality of life: 1995 update. Oncology 1995; 9(11 Suppl):47–60. 43. Silliman RA, Balducci L, Goodwin JS et al. Breast cancer care in old age: What we know, don’t know, and do. J Natl Cancer Inst 1993; 85:190–9. 44. Goodwin JS, Hunt WC, Samet JM. Determinants of cancer therapy in elderly patients. Cancer 1993; 72:594–601. 45. Kiebert GM, de Haes JCJM, van de Velde CJH. The impact of breast-conserving treatment and mastectomy on the quality of life of early-stage breast cancer patients: a review. J Clin Oncol 1991; 9:1059–70. 46. Ganz PA, Schag CAC, Lee JJ et al. Breast conservation versus mastectomy: Is there a difference in psychological adjustment or quality of life in the year after surgery? Cancer 1992; 69:1729–38 .

Comprehensive Geriatric Oncology

536

47. Coates A, Gebski V, Bishop JF et al. Improving the quality of life during chemotherapy for advanced breast cancer. A comparison of intermittent and continuous treatment strategies. N Engl J Med 1987; 317:1490–5. 48. The SUPPORT Principal Investigators. A controlled trial to improve care for seriously ill hospitalized patients. The Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT). JAMA 1995; 274:1591–8. 49. Yancik R, Ries LG, Yates JW. Breast cancer in aging women: a population-based study of contrasts in stage, surgery, and survival. Cancer 1989; 63:976–81. 50. Fox SA, Murata PJ, Stein JA. The impact of physician compliance on screening mammography for older women. Arch Intern Med 1991; 151:50. 51. Celentano DD, Shapiro S, Weisman CS. Cancer preventive screening behavior among elderly women. Prevent Med 1982; 11:454. 52. Greenfield S, Blanco DM, Elashoff RM, Ganz PA. Patterns of care related to age of breast cancer patients. JAMA 1987; 287:2766–70. 53. Silliman RA, Guadagnoli E, Weitberg AB, Mor V. Age as a predictor of diagnostic and initial treatment intensity in newly diagnosed breast cancer patients. J Gerontol Med Sci 1989; 44:M46–50, 54. Allen C, Cox EB, Manton, KG et al. Breast cancer in the elderly. Current patterns of care. J Am Geriatr Soc 1986; 34:637. 55. Chu J, Diehr P, Feigl P et al. The effect of age on the care of women with breast cancer in community hospitals. J Gerontol 1987; 42:185. 56. Ganz PA, Lee JJ, Sim M-S et al. Exploring the influence of multiple variables on the relationship of age to quality of life in women with breast cancer. J Clin Epidemiol 1992; 45:473–86. 57. Ganz PA, Hirji K, Sim M-S et al. Predicting psychosocial risk in patients with breast cancer. Med Care 1993; 31:419–31. 58. Schag CAC, Heinrich RL. Development of a comprehensive quality of life measurement tool: CARES. Oncology 1990; 4:135–8. 59. Ganz PA, Rowland JH, Desmond K et al. Life after breast cancer: understanding women’s health-related quality of life and sexual functioning. J Clin Oncol 1998; 16:501–14. 60. Meyerowitz BE, Desmond KA, Rowland JH et al. Sexuality following breast cancer. J Sex Marital Ther 1999; 25:237–50. 61. Ganz PA, Desmond KA, Belin TR et al. Predictors of sexual health in women after a breast cancer diagnosis. J Clin Oncol 1999; 17:2371–80. 62. Ganz PA, Greendale GA, Petersen L et al. Managing menopausal symptoms in breast cancer survivors: results of a randomized controlled trial. J Natl Cancer Inst 2000; 92:1054–64. 63. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001. CA Cancer J Clin 2001; 51:15–36. 64. Ganz PA, Schag CAC, Lee JJ, Sim M-S. The CARES: a generic measure of health-related quality of life for cancer patients. Qual Life Res 1992; 1:19–29. 65. Schag CAC, Ganz PA, Wing DS et al. Quality of life in adult survivors of lung, colon, and prostate cancer. Qual Life Res 1994; 3:127–41. 66. Souquet PJ, Chauvin F, Boissel JP et al. Polychemotherapy in advanced non small cell lung cancer: a meta-analysis. Lancet 1993; 342:19–21. 67. Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials. BMJ 1995; 311:899–909. 68. Kaasa S, Mastekaasa A, Lund E. Prognostic factors for patients with inoperable non-small cell lung cancer, limited disease. The importance of patients’ subjective experience of disease and psychological well-being. Radiother Oncol 1989; 15:35.

Quality of life considerations in the older cancer patient

537

69. Kahn SB, Houts PS, Harding SP. Quality of life and patients with cancer: a comparative study of patient versus physician perceptions and its implications for cancer education. J Cancer Ed 1992; 7:241–9 70. Nerenz DR, Love RR, Leventhal H, Easterling DV. Psychosocial consequences of cancer chemotherapy for elderly patients. Health Serv Res 1986; 20:961–76. 71. Hillier R. Control of pain in terminal cancer. Br Med Bull 1991; 46: 279–91. 72. Stein WM, Miech RP. Cancer pain in the elderly hospice patient. J Pain Sympt Manage 1993; 8:474–82. 73. Portenoy RK. Pain management in the older cancer patient. Oncology 1992; 6(2 Suppl):86–98. 74. Ferrell BR, Ferrell BA, Ahn C, Tran K. Pain management for elderly patients with cancer at home. Cancer 1994; 74(7 Suppl):2139–46. 75. Mor V, Allen SM, Siegel K, Houts P. Determinants of need and unmet need among cancer patients residing at home. Health Serv Res 1992; 27:337–60. 76. Yancik R, Ganz, PA, Varricchio C, Conley B. Perspectives on comorbidity and cancer in older patients: approaches to expand the knowledge base. J Clin Oncol 2001; 19:1147–51. 77. McHorney CA, Tarlov AR. Individual-patient monitoring in clinical practice: Are available health status surveys adequate? Qual Life Res 1995; 4:293–307. 78. Ganz PA. Impact of quality of life outcomes on clinical practice. Oncology 1995; 9(11 Suppl):61–5.

25 Social support and the elderly cancer patient Cleora S Roberts Introduction The elderly person diagnosed with cancer must deal with many changes in psychological and social functioning along with the physical health problems. The social support system, which is believed to buffer the stress of illness for patients of all ages,1–3 is a critical factor for the aged, as they simultaneously experience increased need for and decreased availability of such support.4 The aging process can be accompanied by retirement, financial worries, changes in living arrangements, and bereavement in response to loss of spouse, other family members, or friends. All of these changes or losses pose threats to the patient’s social support system. There is considerable research evidence that older cancer patients suffer fewer negative psychosocial consequences than younger patients.5–8 Various explanations have been offered. Mor et al9 argued that older individuals may cope better because they have few competing demands such as jobs or children in their lives. McMillan10 found that older patients reported lower intensity of pain and physical symptoms, which are sources of emotional distress. Others5,11 have pointed out that seniors have more experience in dealing with illness and the medical setting. Massie and Holland12 observed that older patients have different health expectations, which, coupled with more experience in coping with life stresses, prepare them to confront a cancer diagnosis with less surprise and anger. Raveis and Karus13 extended our understanding of older cancer patients’ well-being by comparing them with a community sample of the same age, rather than with younger cancer patients. They reported that 26% of the older cancer patients exhibited symptoms of clinical depression, compared with 15% of similar-aged persons in the community. Although a correlation between advancing age and better psychosocial adaptation to cancer has been demonstrated, the relationship between the two variables is not a strong one. Further, as Kane14 observed, there is tremendous variability among older people and their social situations. Roberts et al15 reported that older breast cancer patients who were experiencing significant life stressors prior to their diagnosis had higher levels of psychological distress. They stressed the importance of looking beyond age differences (older versus younger patients), and looking instead at specific life circumstances of older patients as predictors of their adjustment to cancer.

Social support and the elderly cancer patient

539

Defining social support Although the term ‘social support’ is widely used by health professionals, agreement as to its specific definition is lacking. In general, social support has been defined and measured using one of two different approaches.4 Objective measures attempt to quantify an individual’s social interactions by assessing the size and density of one’s social networks. Objective definitions of social network could include reliance on relatives, frequency of contact with friends or family, or memberships in social organizations such as churches or neighborhood groups. Alternatively, social support has been defined subjectively, and focuses on the person’s perception and evaluation of the adequacy of his or her social relationships. Some researchers have concluded that the subjective measure of perceived adequacy of support is more predictive of positive outcome than objective measures of availability of support.16 Wortman17 reviewed the literature on social support and the cancer patient, and identified five types of social support: (i) expression of positive affect or caring; (ii) agreement with one’s beliefs and feelings; (iii) encouragement of open expression of beliefs and feelings; (iv) provision of material aid; and (v) inclusion in a network of mutual or reciprocal help. Wortman suggested that social support assessments of cancer patients should look at both emotional support and tangible aid (transportation to treatment appointments, help with household chores, and assistance with medications). With older cancer patients, particularly the frail elderly, the availability of tangible supports is of primary importance.18,19 Another perspective to consider is the stability of the older person’s social support network. The older person is more likely to experience the loss of emotional support from a spouse, but may be able to seek comparable support from other relatives and friends.20 Effects of social support There are two hypotheses as to how social support operates in relation to health and mental health outcomes. One posits that social support has a stress-buffering effect,2 while the other claims a direct or main effect. Ryan and Austin4 postulate that direct and buffering effects of social support may function simultaneously and that a balance between the person’s needs and available resources is the critical factor in health outcomes. In addition to these two established hypotheses, recent studies of how social support affects outcomes in cancer patients have focused on immune mechanisms.21,22 Spiegel et al22 reported that a greater quality of social support was associated with lower cortisol concentrations in women with metastatic breast cancer. These lowered levels would indicate greater neuroendocrine functioning. More definitive results may be forthcoming from studies currently in progress. Although most researchers have explored the role of social support in quality of life during illness, some have focused on social support and mortality rates. Using the US National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) data on 147000 men with prostate cancer, Krongrad et al23 found that married patients had

Comprehensive Geriatric Oncology

540

significantly longer median survival after controlling for age, stage, race, and treatment. In a sample of over 1000 Chinese subjects aged 70 or over, subjects who were widowed or never married had a 2.3-fold risk of dying compared with married subjects.24 Additionally, subjects with higher social support (defined as integration into the community, larger networks, and participation in family and social activities) had lower mortality rates. Not all researchers have reached the same conclusions regarding social support and mortality, however. Helsing et al25 found that widowed males who remarried had lower mortality rates, but widowed females who remarried did not show different mortality rates. In a prospective study of breast cancer patients, clinical and biological variables rather than social support exerted the major influence on disease progression and survival.26 Vernon and Jackson27 also found inconsistent findings in their review of literature on social support and mortality rates. Having reviewed definitions and hypothesized mechanisms of social support, we shall now examine research on the role of social support in four areas of management of cancer in older adults: (i) prevention, screening and early detection; (ii) treatment; (iii) psychosocial adaptation; and (iv) responses of family caregivers. Role of social support in cancer prevention, screening, and early detection Suarez et al28 found that older Mexican-American women rated as having strong social networks were more likely to participate in cancer screening programs. Specifically, the women with close friends were more likely to have mammography and Pap smear screening. Similarly, Wagel et al29 found that women with stronger social support practiced breast self-examination more frequently. Kang and Bloom30 noted that Black Americans suffer higher cancer mortality rates, believed to be associated with less frequent use of cancer detection tests. They examined the association of social network size with utilization of cancer screening tests among Black Americans aged 55 or older, and concluded that social support was a predictor of use of mammography and occult blood stool examinations. Similarly, Richardson et al31 found that women at high risk of breast cancer by virtue of having a twin diagnosed with breast cancer were somewhat more likely to receive mammography if they were supported by their family to do so. It is unclear what role social support plays in determining how soon a symptomatic patient seeks cancer treatment. Whereas Berkanovic32 found that lack of social support was related to patient delay in seeking treatment, Samet et al33 reported that social support was not a significant factor in careseeking among a sample of elderly New Mexican residents. Moritz and Satariano34 studied 444 breast cancer patients aged 55 or older to determine what factors were associated with being diagnosed at local versus advanced disease stage. Living arrangements were found to be a rather strong predictor, with women living alone being more likely to be diagnosed earlier at the local stage while women living with a spouse were twice as likely to be diagnosed with advanced disease. For married women, the health of the husband was an important factor, in that women with healthy husbands were less likely to be diagnosed with advanced disease while

Social support and the elderly cancer patient

541

women with husbands in poor health were more likely to have advanced disease. In a study involving both men and women, however, married subjects were more likely to be diagnosed with a local stage of cancer.35 Gotay and Wilson36 argue that programs using social support interventions have great potential to promote cancer screening, particularly for racial and ethnic minorities, for whom the traditional approaches have not worked. Utilizing strengths such as strong ties between individuals, emphasis on the importance of the family and traditional cultural values would form the basis for these strategies. Social support and cancer treatment It is generally believed that social support is a critical variable in aiding recovery from illness. After reviewing public health and nursing literature on this topic, Ryan and Austin4 concluded that lack of social support is associated with longer hospitalizations and negative emotional and cognitive changes in the elderly. In a similar vein, Berkman et al37 found that severely ill cancer patients who lived with a spouse were less likely to be placed in long-term care facilities. Based on their findings, Goodwin et al38 expressed concern that patients with poor social support networks may not receive maximal treatment because of lack of assistance in areas of transportation, medication reminders, and treatment decision-making. These researchers discovered that elderly cancer patients with lower levels of social support and limited access to transportation were less likely to receive definitive cancer treatments, particularly radiation therapy. In their study, patients who drove or lived with a driver were more than four times as likely to receive radiation treatment. They did not provide data analyses by gender, but it seems likely that the non-drivers were disproportionately female. Older persons who move, perhaps upon retirement, and are later diagnosed with cancer are deprived of their former social networks as a resource. Goodwin et al39 found that recent migrants to New Mexico, the site of their study, had increased risk for poor social support for at least 10 years after moving. They pointed to the important implications for ‘sunbelt states’ in the USA, which have a large influx of elderly immigrants. Larson et al40 analyzed the relationship between social support (measured as size and strength of the social network) and functional status of elderly lung cancer patients undergoing radiation therapy. Surprisingly, subjects with lower social support perceived themselves to have higher functional status or quality of life. The authors offer the possible interpretation that subjects with fewer social support resources may feel they have to be more self-reliant and functionally independent. In comparing functional responses to a course of therapy in their mostly male sample, patients aged over 65 did not have more therapy-related problems than the younger cohort. Larson et al caution that chronological age is not sufficient to judge a patient’s ability to undergo curative or palliative treatment regimens. These same researchers41 examined the effect of social support on a slightly younger sample (age 61 and over) that included breast (42%) and lung (58%) cancer patients, and found almost no relationship between social support and functional status. Although the authors do not address the issue, the conflicting findings

Comprehensive Geriatric Oncology

542

of the two studies may be related to gender. The majority of the lung cancer patients were males, whereas the second sample included breast cancer patients—and presumably the majority of these were females. Mor et al42 examined cancer patients’ needs and unmet needs for assistance with personal care (e.g. bathing), instrumental activities (preparing meals), transportation, and home health tasks (including high-tech care such as infusion therapy). In this longitudinal study, the prevalence of need for personal care increased at 3- and 6-month follow-up. Approximately one-third of patients reporting need for assistance at one baseline or follow-up did not have enough help. Patients older than 65 were 1.3 times more likely to have a personal assistance need. Seventeen percent of those with need for transportation had an unmet need at some point—a finding that may well affect treatment compliance. Married patients reported needing more help with personal care and household tasks. The presence of children living nearby also protected patients from having unmet needs. The data suggested that the burden of care as the illness progressed weakened informal supports such as help from neighbors over time. Psychosocial adaptation A number of studies have demonstrated a positive correlation between social support and enhanced psychological adjustment in cancer patients. Specifically, breast cancer patients with higher levels of support have fewer adjustment problems.43–45 In another study, elderly patients who were socially isolated or who experienced negative interactions with their social networks made poorer psychosocial adaptation.13 Social support was found by Ell et al46 to be a significant, though modest, predictor of psychological and functional adaptation in a sample of breast, lung, and colorectal cancer patients with an average age of 61. Patients with stronger support also had a higher personal sense of control and more positive psychological wellbeing. Persons who relied upon religion also described their support systems as being stronger. As in other studies, older patients in this sample were found to have less psychological distress. Halstead and Fernsler47 explored coping strategies of long-term cancer survivors (>5 years), and compared coping styles of elderly and middle-aged survivors. They reported that the older survivors were more likely to use and benefit from supportant strategies (‘talked problem over with family and friends’) as well as optimism (‘tried to think positively’) and palliative strategies (‘tried to keep busy’). In this sample, spiritual coping strategies were identified as helpful by 68% of the subjects, and the use of support systems was described as helpful by 42%. The role of religion and spirituality in coping with cancer is receiving increasing attention. Elderly breast cancer survivors interviewed by Feher and Maly48 reported that their faith provided an important form of social support, leading the authors to urge medical caregivers to encourage patients to seek religious support. A team of researchers led by Holland has developed a measure, the Systems of Belief Inventory, to assess religious and spiritual beliefs as a potentially mediating variable of quality of life in persons with cancer.49 In developing this instrument, they learned that subjects identified their religious communities as distinct sources of social support.

Social support and the elderly cancer patient

543

Some authors have cautioned that the relationship between social support and psychosocial adjustment to illness, although generally presumed to be causal, may in fact be correlational only. Wortman17 pointed out that a poorly adjusted person is less likely to possess, establish, or benefit from a strong support system. A study by Roberts et al50 found that when the patient’s personality variable of social desirability was controlled for, the relationships between social support and well-being were not as strong. Roberts et al concluded that patients who are highly socialized and have strong self-esteem may cultivate more satisfying social relationships and possess stronger coping mechanisms that protect them from distress. Kessler and McLeod51 also suggest that the patient’s mental health may be the causal variable that leads to establishment of a good support system or that patient well-being and social support operate in a web of mutual influence. Role of family and social network in providing care for cancer patients The growing numbers of elderly cancer patients mandate greater understanding of the impact of age on cancer management. It is necessary to focus on the social support systems of this expanding cohort,52,53 particularly in a climate of dehospitalization of cancer care that places demands on family members to manage illness and treatment sideeffects.42,54 In addition to focusing on patients’ needs, healthcare professionals must be aware of the special needs and stressors placed on caregivers, who are most frequently spouses or family members. A growing number of researchers have studied the stress experienced by caregivers of cancer patients. Oberst et al54 studied 47 family members of cancer patients, average age 61, receiving radiation therapy. Caregivers reported more stress over time as the patient experienced greater fatigue as the radiation therapy progressed. Caregivers reported that they expended the greatest time and effort in providing transportation and emotional support. Interestingly, the older caregivers saw their situation as more benign than did younger caregivers. Oberst et al suggest that older persons may be more accepting of and better prepared to cope with the illnesses that accompany aging. Caregivers with poor health, less education, and fewer financial resources reported greater stress. Kurtz et al55 also found that older caregivers of cancer patients were less depressed than their younger counter-parts and perceived caregiving as being less disruptive to their lives. These older caregivers also reported receiving more support from friends. As the patient’s illness progressed, caregivers in the Kurtz study experienced higher levels of depression and a greater impact on their own health. However, caregivers did not report a corresponding increase in support from friends during this more stressful period. In drawing conclusions, Kurtz et al cite the findings of Vachon et al,56 whose widowed subjects reported that during their spouse’s terminal cancer illness, family and friends withdrew, ‘leaving the couple to face a social death long before the physical death occurred’ (reference 56, p 1152). Given et al57 examined caregiving spouses’ reactions in a sample of 159 subjects, of whom 75% were female. The patients, who had a mean age of 74, were being treated for primary diagnoses of cancer, stroke, Alzheimer’s and Parkinson’s diseases, emphysema, diabetes, or heart disease. Spousal caregivers were assessed in four domains: negative

Comprehensive Geriatric Oncology

544

emotional reactions, feelings of responsibility for the patient, feelings of abandonment by family, and impact of caregiving on daily schedules. Negative or antisocial patient behaviors, seen less frequently in cancer patients, were correlated with negative responses by caregivers. Caregivers who perceived adequate affective and tangible support from family members reported more positive emotional reactions to their role. Grobe et al58 interviewed 30 terminally ill cancer patients (median age 63) and 28 family members to learn what services they thought were needed. Patients expressed greater need for help with symptoms and medical services, whereas families mentioned the need for respite care, emotional support, and recreation for the family members, as well as more visits by the physician. The authors conclude that the cancer patient’s family warrants increased attention during the patient’s terminal stage and that greater communication between patients and families is needed. Ferrell et al59 demonstrated that offering a pain education intervention improved the quality of life of elderly patients as well as providing important support to the family caregivers. Welch-McCaffrey60 emphasized that cancer strikes all members of the family and should be viewed as a family disease. She delineates several issues that elderly couples must confront while coping with anxiety regarding treatment outcome. Remarried older adults may have lost a previous spouse to cancer, and experience acute revival of those memories that influence negative expectations regarding the present spouse’s cancer experience. Most studies of cancer patients and their caregivers tend to assume that the two groups are mutually exclusive, when, in fact, caregivers are sometimes patients and vice versa. Older caregivers may be more challenged physically in caring for an ill spouse or sibling, and themselves may be characterized as hidden patients. Cancer patients may be caring for a spouse in poor health. Also, it is not uncommon for patients in their sixties or seventies to be caring for frail elderly parents. Persons in these dual roles of patient and caregiver require additional attention to address their complex psychosocial needs and stressors. Boyle61 points out that cancer patients who, as former caregivers, are grieving the death of family and friends to cancer and other illnesses may find it difficult to feel positive about their own chances for recovery. Boyle contends that patients whose spouse lost a battle with cancer may experience survivor guilt and feel obligated to ‘give up’. A word of caution about social support Some investigators have found that the presence of a social support system is not a guarantee of patient benefit. Further, certain behaviors by family or friends may actually have adverse effects for the patient. Revenson et al62 found that supportive behaviors may actually increase negative mood and decrease self-esteem in the cancer patient, and hypothesized that these behaviors during periods of disability may highlight the person’s inability to reciprocate that support. Wortman and Dunkel-Schetter63 observed that family and friends may hold negative feelings about the patient’s illness but believe that they should remain positive and cheerful in the patient’s presence. Such behavior precludes open communication by the patient about his or her concerns regarding the disease and its effects. In a more recent study, the notion of ‘aversive social contact’ was measured and was found to be correlated with greater mood disturbance.64

Social support and the elderly cancer patient

545

Role of the physician and health caregivers in addressing social support system of the older adult with cancer Assessment 9

Mor et al point out that as cancer care becomes increasingly dehospitalized, the nursing and clerical staff in physician’s offices may need to screen for and refer patients to community resources for unmet social service needs. They suggest that screening tools be used in the oncologist’s office or outpatient settings to identify patients in need of social services and refer to appropriate agencies in the community. Kane and Kane65 have developed questionnaires for multidimensional assessment of older patients. These checklists and questionnaires inquire about the patient’s psychological well-being as well as their social relationships and the help that they receive from others. Family members are also queried about their ability and readiness to assume caregiving tasks. Wells and Balducci18 advocate a comprehensive geriatric assessment with attention to the older cancer patient’s complex social, emotional, psychological and economic concerns. They combine the social worker’s assessment with standardized instruments such as the Geriatric Depression Scale, the Functional Assessment of Cancer TherapyGeneral Quality of Life Scale, and the Mini Mental State Examination. Welch-McCaffrey60 advocates that four categories of assessment questions be asked of the primary family support person. These questions relate to the caregiver’s perception of the cancer crises and how it has affected the caregiver, communication skills, immediate needs, and asking how the staff can be of help. Referral to social support systems If assessment determines that the patient’s natural social support system is not meeting patient needs, the health-care team should consider referral to supplemental support systems. Several resources should be considered. Volunteer organizations such as the American Cancer Society can provide information and assistance with concrete social service needs such as transportation. Also, local chapters of the American Cancer Society sponsor peer support counseling programs such as Reach For Recovery for breast cancer patients and Man-to-Man for prostate cancer patients. Area hospitals may be co-sponsors of these activities or have their own support programs. Support groups Professionally led group therapy programs may be available. Spiegel et al66 found that patients with metastatic breast cancer who met weekly for group therapy for 1 year had better mood and more adaptive coping than a control group. In a follow-up study, Spiegel et al67 reported that support group members survived longer than the control group. Shrock et al68 found that short-term psychosocial intervention in the form of health psychology classes that encouraged expression of emotion and provided social support also resulted in higher survival rates. These research findings have been widely reported, and have stimulated the formation of many new support groups for cancer patients.

Comprehensive Geriatric Oncology

546

The psychological benefits of support groups have been demonstrated in a number of studies. In spite of this, Guidry et al69 found that fewer than half of the cancer patients surveyed were asked to joint a support group. They suggest that healthcare professionals should provide information about these groups and their potential benefits. Individual counseling Another resource to be considered for the older cancer patient is individual counseling, preferably with a social worker or other mental health professional with experience with oncology patients. Some older patients may reject such a referral, since they consider it a stigma to ‘need’ psychological help. Anticipating this reaction, some physicians refrain from making referrals to a psychotherapist and thus deprive the patient of potentially beneficial treatment. Based on my experience in medical settings with patients in need of mental health services, I recommend the following approach. A brief inquiry about a history of treatment for depression or questions about current symptoms of depression should be made. If the answers indicate the presence of depressive illness, the physician should recommend consultation with a psychiatrist for evaluation (or a mental health professional who works in collaboration with psychiatrists), explaining that treatments such as counseling and/or medications are very effective in most cases of depression. It is best to recommend a particular professional with whom one is familiar and convey one’s confidence in working with that person on the patient’s behalf. When done in a straightforward and optimistic manner, many patients, particularly those suffering from severe or unremitting depression, will accept the referral immediately. Some patients may feel hurt, insulted, or rejected by the suggestion, and will ask ‘Do you really think I need it?’ My recommended response is ‘I believe you can continue to handle the stresses of cancer without counseling. At the same time, counseling could help you and your family and improve your overall quality of life, and I would like to see you take advantage of it’ If the patient continues to voice resistance, one can suggest that he or she think it over. Some patients will mull this over for several weeks or months before deciding to followup with the referral. Many patients need reassurance that the physician’s relationship with them will not be diluted or changed by their receiving psychological care. Social support from medical caregivers This discussion of the role of social support in the care of the older cancer patient would not be complete if the role of medical caregivers were omitted. Some investigators have conceptualized support from the healthcare team as a very important type of both informational and emotional support.70–72 For example, Roberts et al73 discovered that the physician’s use of interpersonal skills and provision of information during the cancer diagnostic interview was a significant predictor of a breast patient’s subsequent psychological adjustment, whereas social support from family and friends was not. Similarly, in another study, older women with breast cancer reported that they relied heavily on their physicians for information. Further, perceptions of their ability to communicate with their physicians was associated with better emotional health.74 These

Social support and the elderly cancer patient

547

and similar findings underscore the importance of physicians’ and allied health professionals’ use of a biopsychosocial model in caring for the older adult cancer patient. References 1. Cobb S. Social support as a moderator of life stress. Psychosom Med 1976; 38:300–14. 2. Hammer M. Cored and ‘extended’ social networks in relation to health and illness. Soc Sci Med 1983; 17:404–11. 3. Sollner W, Zschocke I, Zingg-Schir M et al. Interactive patterns of social support and individual coping strategies in melanoma patients and their correlations with adjustment to illness. Psychosomatics 1999; 40:239–50. 4. Ryan MC, Austin AG. Social supports and social networks in the aged. Image 1989; 21:176–80. 5. Ganz PA, Schag CC, Heinrich RL. The psychosocial impact of cancer on the elderly: a comparison with younger patients. J Am Geriatr Soc 1985; 33:429–35. 6. Cassileth BR, Lusk TB, Strouse DS et al. A comparative analysis of sk diagnostic groups. N Engl J Med 1984; 311:506–11. 7. Maisiak R, Gams R, Lee E, Jones B. The psychosocial support status of elderly cancer outpatients. Prog Clin Biol Res 1983; 120:395–403. 8. Roberts CS, Rosetti C, Cone D, Cavanagh D. The psychosocial impact of gynecologic cancer: a descriptive study. J Psychosoc Oncol 1992; 10:101–10. 9. Mor V, Allen S, Malin M. The psychosocial impact of cancer on older versus younger patients and their families. Cancer 1994; 74:2118–27. 10. McMillan SC. The relationship between age and intensity of cancer-related symptoms. Oncol Nurs Forum 1989; 16:237–241. 11. Edlund B, Sneed NV. Emotional responses to the diagnosis of cancer: Age-related comparisons. Oncol Nurs Forum 1989; 16:691–7. 12. Massie MJ, Holland JC. The older patient with cancer in special issues in psychological management of cancer. In: Handbook of Psyoncology (Holland JC, Rowland JH, eds). New York: Oxford University Press, 1990:444–52. 13. Raveis VH, Karus DG. Elderly cancer patients: correlates of depressive symptomatology. J Pysch Oncol 1999; 17:57–77. 14. Kane, RA. Psychological and social issues for older people with cancer. Cancer 1991; 68:2514–18. 15. Roberts CS, Cox CE, Reintgen D. The psychological impact of breast cancer on older women. Cancer Control 1994; 1:367–71. 16. Ell K. Social networks, social support and health status. Soc Serv Rev 1984; 58:133–45. 17. Wortman CB. Social support and the cancer patient: conceptual and methodological issues. Cancer 1984; 63:2339–60. 18. Wells NL, Balducci L. Geriatric oncology: medical and psychosocial perspectives. Cancer Pract 1997; 5:87–91. 19. Reuben DB. Geriatric assessment in oncology. Cancer 1997; 80: 1311–16. 20. Kantor DE, Houldin A. Breast cancer in older women: treatment, psychosocial effects, interventions, and outcomes. J Gerontol Nurs 1999; 25:19–25; quiz 54–5. 21. Turner-Cobb JM, Sephton SE, Koopman C et al. Social support and salivary cortisol in women with metastatic breast cancer. Psychosom Med 2000; 62:337–45. 22. Spiegel D, Sephton SE, Terr AI, Stites DP. Effects of psychosocial treatment in prolonging cancer survival may be mediated by neuroimmune pathways. Ann NY Acad Sci 1998; 840:674– 83. 23. Krongrad A, Lai H, Burke MA et al. Marriage and mortality in prostate cancer. J Urol 1996; 156:1696–70.

Comprehensive Geriatric Oncology

548

24. Ho SC. Health and social predictors of mortality in an elderly Chinese cohort. Am J Epidemiol 1991; 133:907–20. 25. Helsing KJ, Szklo M, Comstock GW. Factors associated with mortality after widowhood. Am J Public Health 1981; 71:802–9. 26. Giraldi T, Rodani MG, Cartei G, Grassi L. Psychosocial factors and breast cancer: a 6-year Italian follow-up study. Psychother Psychosom 1997; 66:229–36. 27. Vernon SW, Jackson GL. Social support, prognosis and adjustment to breast cancer. In: Aging, Stress and Health (Markides KS, Cooper CL, eds). New York: John Wiley, 1989:165–98. 28. Suarez L, Lloyd L, Weiss N et al. Effect of social networks on cancer screening behavior of older Mexican-American women. J Natl Cancer Inst 1994; 86:775–9. 29. Wagle A, Komorita NI, Lu ZJ. Social support and breast self-examination. Cancer Nurs 1997; 20:42–8. 30. Kang SH, Bloom JR. Social support and cancer screening among older Black Americans. J Natl Cancer Inst 1993:95:737–42. 31. Richardson JL, Mondrus GT, Deapen D, Mack TM. Future challenges in secondary prevention of breast cancer for women at high risk. Cancer 1994; 74:1474–81. 32. Berkanovic E. Seeking care for cancer relevant symptoms. J Chronic Dis 1982; 35:727–34. 33. Samet JM, Hunt WC, Lerchen ML, Goodwin, JS. Delay in seeking care for cancer symptoms: a population-based study of elderly New Mexicans. J Natl Cancer Inst 1988; 80:432–8. 34. Moritz DJ, Satariano WA. Factors predicting stage of breast cancer at diagnosis in middle aged and elderly women: the role of living arrangements. J Clin Epidemiol 1993; 46:443–54. 35. Goodwin JS, Hunt WC, Key CR, Samet JM. The effect of marital status on stage, treatment and survival of cancer patients. JAMA 1987; 258:3125–30. 36. Gotay CC, Wilson ME. Social support and cancer screening in African American, Hispanic, and Native American women. Cancer Pract 1998; 6:31–7. 37. Berkman B, Stolberg C, Calhoun J et al. Elderly cancer patients: factors predictive of risk for institutionalization. J Psychosoc Oncol 1983; 1:85–100. 38. Goodwin JS, Hunt WC, Samet JM. Determinants of cancer therapy in elderly patients. Cancer 1993; 72:594–601. 39. Goodwin JS, Hunt WC, Sarnet JM. A population-based study of functional status and social support networks of elderly patients newly diagnosed with cancer. Arch Intern Med 1991; 151:366–70. 40. Larson PJ, Lindsey AM, Dodd et al. Influence of age on problems experienced by patients with lung cancer undergoing radiation therapy. Oncol Nurs Forum 1993; 20:473–80. 41. Lindsey AM, Larson PJ, Dodd MJ et al. Comorbidity, nutritional intake, social support, weight, and functional status over time in older cancer patients receiving radiotherapy. Cancer Nurs 1994; 17: 113–24. 42. Mor V, Masterson-Allen S, Houts P, Siegel K. The changing needs of patients with cancer at home: a longitudinal view. Cancer 1992; 69:829–38. 43. Northouse LL. Social support in patients’ and husbands’ adjustment to breast cancer. Nurs Res 1988; 37:91–5. 44. Funch DP, Mettlin C. The role of support in relation to recovery from breast surgery. Soc Sci Med 1982; 16:91–8. 45. Lichtman RR, Taylor SE, Wood JV. Social support and marital adjustment after breast cancer. J Psychosoc Oncol 1987; 5:47–74. 46. Ell KO, Mantell JE, Hamovitch MB, Nishimoto RH. Social support, sense of control, and coping among patients with breast, lung, or colorectal cancer. J Psychosoc Oncol 1989; 7:63– 89. 47. Halstead MT, Fernsler, JI. Coping strategies of long-term cancer survivors. Cancer Nurs 1994:17:94–100. 48. Feher S, Maly RC. Coping with breast cancer in later life: the role of religious faith. Psychooncology 1999; 8:408–16.

Social support and the elderly cancer patient

549

49. Holland JC, Kash KM, Passik S et al. A brief spiritual beliefs inventory for use in quality of life research in life-threatening illness. Psychooncology 1998; 7:460–9. 50. Roberts CS, Cox CE, Shannon V, Wells N. A closer look at social support as moderator of stress in breast cancer. Health Soc Work 1994; 19:157–64. 51. Kessler RC, McLeod JD. Social support and mental health in community samples. In: Social Support and Health. San Diego: Academic Press, 1990:219–40. 52. Yancik R. Frame of reference: old age as the context for the prevention and treatment of cancer. In: Perspectives on Prevention and Treatment of Cancer in the Elderly. New York: Raven Press, 1983:5–17. 53. Yancik R, Ries LG. Caring for elderly cancer patients: quality assurance considerations. Cancer 1989:64:335–41. 54. Oberst MT, Thomas SE, Gass KA, Ward SE. Caregiving demands and appraisal of stress among family caregivers. Cancer Nurs 1989; 12: 209–15. 55. Kurtz ME, Given B, Kurtz JC, Given CW. The interaction of age, symptoms and survival status on physical and mental health of patients with cancer and their families. Cancer 1994:74:2071– 8. 56. Vachon M, Freeman K, Formo A et al. The final illness in cancer: the widow’s perspective. Can Med Assoc J 1977; 117:1151–3. 57. Given B, Stommel M, Collins C et al. Responses of elderly spouse caregivers. Res Nurs Health 1990; 13:77–85. 58. Grobe ME, Ahmann DL, Ilstrup DM. Needs assessment for advanced cancer patients and their families. Oncol Nurs Forum 1982; 9:26–30. 59. Ferrell BR, Ferrell BA, Ahn C, Tran K. Pain management for elderly patients with cancer at home. Cancer 1994; 74:2139–46. 60. Welch-McCaffrey D. Family issues in cancer care: current dilemmas and future directions. J Psychosoc Oncol 1988; 1:199–210. 61. Boyle DM. Realities to guide novel and necessary nursing care in geriatric oncology. Cancer Nurs 1994; 17:125–36. 62. Revenson TA, Wollman CA, Felton, BJ. Social supports as stress buffers for adult cancer patients. Psychosom Med 1983; 45:321–31. 63. Wortman CB, Dunkel-Schetter D. Interpersonal relationships and cancer: a theoretical analysis. J Soc Issues 1979; 35:120–55. 64. Koopman C, Hermanson K, Diamond S, Angell K, Spiegel D. Social support, life stress, pain and emotional adjustment to advanced breast cancer. Psychooncology 1998; 7:101–11. 65. Kane RA, Kane RL. Assessing the Elderly: A Practical Guide to Measurement. Lexington, MA: DC Heath, 1981. 66. Spiegel D, Bloom JR, Yalom I. Group support for patients with metastic cancer. Arch Gen Psych 1981; 38:527–33. 67. Spiegel D, Bloom JR, Krawmer HC, Gottheil E. Effect of psychosocial treatment on survival of patients with metastic breast cancer. Lancet 1989; ii:888–91. 68. Shrock D, Palmer RF, Taylor B. Effects of a psychosocial intervention on survival among patients with stage I breast and prostate cancer: a matched case-control study. Altern Ther Health Med 1999; 5:49–55. 69. Guidry JJ, Aday LA, Zhang D, Winn RJ. The role of informal and formal social support networks for patients with cancer. Cancer Pract 1997; 5:241–6. 70. Hermann JF. Psychosocial support: interventions for the physicians. Semin Oncol 1985; 12:466–71. 71. Hirano T, Uchida H, Hiruma S, Iizumi H, Oikawa K. Psychosocial support to improve quality of life (QOL) in home terminal carcinoma patients. Gan to kagaku ryoho 1996; 23:317–21. 72. Fridfinnsdottir EB. Icelandic women’s identifications of stressors and social support during the diagnostic phase of breast cancer. J Adv Nurs 1997; 25:526–31.

Comprehensive Geriatric Oncology

550

73. Roberts CS, Cox CE, Reintgen DR et al. Influence of physician communication on newly diagnosed breast patients’ psychological adjustment and decision making. Cancer 1994; 74:157–64. 74. Silliman RA, Dukes KA, Sullivan LM, Kaplan SH. Breast cancer care in older women: sources of information, social support, and emotional health outcomes. Cancer 1998; 83:706–11.

26 Prognostic evaluation of the older cancer patient Lazzaro Repetto, Antonella Venturino, Walter Gianni Introduction The incidence of all cancers increases with age, and cancer is a major cause of morbidity and mortality in the older population in the USA, as well as in Europe.1–3 Nevertheless, there are few clinical trials for this age group, and few patients are referred to existing trials. The limited attention paid to cancer in the elderly may, at least in part, be ascribed to the difficulty in the definition of biological age. Recently, with the progressive prolongation of mean life-expectancy and the awareness of the age-related increase of cancer risk, the need to stimulate research in older patients has been recognized. These studies should help to better understand the biological interactions of cancer and age, which include the clinical course, the etiology, the diagnosis, and the management of cancer in the elderly. The differences in the biological behavior of cancer, shorter life-expectancy, and higher vulnerability to stress highlight the need to define new prognostic factors and to plan different therapeutic strategies. In recent years, reliable progress has been made in oncology with the introduction into clinical practice of new, less toxic, antiblastic agents, new treatment schedules (i.e. weekly, continuous infusion) and better supportive therapies. This allows the extension of the scope of chemotherapy. In order to approach elderly cancer patients properly, we need to know the following: (i) how to evaluate functional, psychological, and physical status in the older person; (ii) which parameters are important and useful to be evaluated; (iii) whether standard and reproducible assessment instruments are available; (iv) whether their prognostic role is defined; and (v), whether there is evidence of their importance in therapeutic decisions. This chapter explores some results from trials specifically performed on older patients to answer these questions related to the influ- ence of age on the treatment and prognosis of the more frequent cancer types. Definition of the problem and prognostic assessment of elderly patients There are several reasons that can account for the limited amount of information on older cancer patients. First, there is the peculiar heterogeneity of the geriatric population. Second, there is a scarcity of clinical trials specifically designed for the aged, coupled with low participation in existing clinical trials owing to concerns about treatment

Comprehensive Geriatric Oncology

552

toxicity and lack of benefit from treatment, as well as economic, logistic, and social factors.4 Cancer survival rates among the elderly in Europe using the EUROCARE database show that survival decreases with increasing age, and standardized 5-year survival rates are significantly lower in European patients than in American patients for all cancer sites except the stomach, when the survival rates of 12 major cancers from the EUROCARE and the US National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) databases are compared.5 The available data suggest that the stage at diagnosis has a remarkable influence on survival, particularly among the elderly. Recent studies show a similar course of breast cancer for all ages, when corrected by stage and mortality for other causes (i.e. comorbidity).6 Therefore, all possible causes of delayed diagnosis such as reluctance to refer older people to specialistic care, comorbidity, and disability, appear to be considerable prognostic factors. On the other hand, older patients with cancer may be treated less aggressively, inadequately, or not at all.4,7–9 Inadequate and inappropriate care can take the form of undertreatment, mistreatment, or overtreatment, all of which can result in unfavorable outcomes. Cancer management in the elderly Currently available data show that every aspect of detection and treatment, including early detection and screening, through to surgery, adjuvant therapy, and therapy of metastases, is relatively inadequate in elderly patients. Cancer in the elderly is generally poorly treated. Geriatricians or family doctors do not refer elderly patients to medical oncologists. Furthermore, cancer risk is often not recognized by the elderly themselves, who think of cancer as a disease of the young or who attribute possible symptoms to other aging-related diseases. There is a lack of level I evidence about any type of cancer treatment in the elderly, and most evidence is of level II or III.10 The lack of sound, evidence-based information concerning the treatment of elderly patients with cancer negatively affects clinical practice.10 Cancer management in the elderly requires particular attention owing to the heterogeneity of the geriatric population.11 Is a different clinical approach to the older cancer patient needed? What objective criteria must be employed? The most important clinical problem is to select patients eligible for cancer treatment and to identify those cases in which less aggressive therapies are indicated owing to a high risk of treatment-related toxicity. Chronological age is not an adequate predictor of treatment-related complications. For example, the mortality of elective surgery does not increase with age: the main differences between young and older patients occur with emergency surgery.12 The safety of standard radiation therapy in older persons has been shown in several studies.13,14 On the other hand, age leads to a progressive decline in functional reserves of multiple organ systems, and this can have consequences for treating older persons with chemotherapy. The elderly, particularly the frail, may be at special risk for chemotherapy-related toxicity. Myelodepression, mucositis,

Prognostic evaluation of the older cancer patient

553

cardiomyopathy, and central and peripheral neurotoxicity appear more common and more severe in the older than the younger patient.15 In contrast, several studies of chemotherapy-induced toxicity failed to demonstrate a clear correlation between patient age and the incidence and severity of therapeutic complications.16–20 However, these studies have included older patients, eligible for clinical trials designed for younger patients, who are not representative of the general older population. The frail patient The term ‘frailty’ is used to describe combinations of aging, disease, and other factors that make some people vulnerable to stress.21 The frail patient may present special problems in cancer management. These persons have poor tolerance to stress and are at high risk of loss of independence and of more frequent and severe treatment-related toxicity. Since these patients require continuous and effective treatment of their symptoms, they appear to be candidates for palliative care. There is no broadly accepted definition or standard system for the classification of elderly people who are at risk for adverse health outcomes.22 Age 85 denotes the beginning of frailty, but is age a valid criteria to define frailty?22 Winograd criteria (age 85 and older; ADL (see below) dependent in at least one item; ≥3 comorbidities; ≥1 geriatric syndrome) are frequently used, but currently we have no universally adopted criteria.23 These criteria are useful, but probably too limited. In the definition of frailty, it is important to include those patients without any specific disease and disability whose general conditions suggest an increased vulnerability to stress. Fried et al24 have provided criteria that seem to better fulfill this need. They include loss of 10% or more of body weight over 1 year, low energy level, difficulty in initiating movements, slow movements, and decreased grip strength. Frailty is defined by three or more of these criteria. The claim that frailty is a distinct clinical condition is based on the observation that this condition appears irreversible, and the most helpful intervention is avoidance of further deterioration.25 Also, of special interest, frailty is associated with specific biochemical changes, including increased serum concentrations of interleukin6 and Ddimer.26 The definition of frailty is an important landmark in clinical oncology outlining a group of patients for whom aggressive interventions may be harmful. Although frailty is probably the best-defined stage of age in both clinical and biological terms, this definition needs further fine-tuning. Comorbidity In the elderly population, particular care is needed to maintain an adequate level of independence—a primary endpoint in this age group—to warrant a good quality of life and to control the side-effects of treatment. One of the essential goals of geriatric medicine is to maximize the elderly patient’s ability to perform the tasks of independent living. The continuous growth of the geriatric population, with the high incidence and

Comprehensive Geriatric Oncology

554

prevalence of comorbidity and disability, suggests that enhanced preventive, as well as rehabilitative, programs catering to the needs of older adults will be necessary and highly desirable. Prolongation of survival is not the only effective aim for older patients with cancer; palliative care and psychosocial support are also important in this age group. The increased, age-related, prevalence of comorbidities and functional impairment among elderly patients may enhance the risk of treatment-related complications, as well as the risk of mortality among cancer patients.27–35 Comorbidity may decrease the benefits of treatment and delay the detection of tumors, because of ‘symptom confusion’. Several studies evaluating the associations of functional impairment with comorbidity show an increased probability of disability with the number of comorbid conditions.36–45 The assessment of comorbidity needs further research in order to define not only the number of comorbidities, but also the grade of severity and its extent. With the aim of identifying a reliable and sensitive instrument to be employed among older cancer patients, Extermann et al46 compared, in a univariate analysis, the Charlson Comorbidity Scale and the Cumulative Illness Rating Scale-Geriatric (CIRS-G), and their association with functional status measured by Eastern Cooperative Oncology Group (ECOG) Performance Status (PS), Activities of Daily Living (ADL), and Instrumental Activities of Daily Living (IADL). Despite the large difference in sensitivity between the two scales, a consistent lack of association with functional status was reported. The authors concluded that comorbidity needs to be assessed independently of functional status. In the Italian Group for Geriatric Oncology (GIOGer) study,47 we evaluated in a multivariate analysis the association of comorbidity (measured using the Satariano Index) with functional status (measured by ADL and IADL) and with ECOG PS. We found a statistically significant association between comorbidity and ADL and IADL. Conversely, no association was found between PS and comorbidity. Our study indicated that assessment of comorbidity and functional status adds substantial information to PS index. Age alone frequently represents the main parameter for the choice of treatment. In a recent review of literature, in which the impact of some comorbidities (regardless of TNM stage) on 5-year survival rates was reported, Piccirillo and Feinstein48 concluded that concomitant diseases and symptoms provide fundamental information and should be incorporated in the clinical system of tumor classification to improve prognostic accuracy. Yancik et al,30 studying a large series of colorectal cancer patients, showed how the type and number of comorbid conditions significantly predicted 2-year mortality. Although disease stage at diagnosis was the strongest predictor of mortality, comorbidity affected both cancer management and survival duration. Despite such strong evidence, a standardized instrument for measuring comorbidities is not yet available. Reproducible comorbidity measurements represent an area of urgent research in geriatric oncology. Comprehensive Geriatric Assessment The frequent use in geriatric oncology of inadequate therapies results at least in part from lack of effective prognostic parameters. The prognostic value of PS, universally

Prognostic evaluation of the older cancer patient

555

employed in clinical oncology, appeared less meaningful for elderly cancer patients in a large study performed with the aim of identifying a comprehensive instrument assessing the status of health of older cancer patients.47 PS does not recognize some aspects of disability in elderly patients, in particular those identified by the ADL and IADL scales, and these may influence compliance with the clinical trials and/or therapeutic protocols.47 With aging, mental, psychological, and socio-economic status become more important, and should be included in diagnostic and therapeutic choices. The life-expectancy and the independence level of the individual patient should be considered in the clinical approach to elderly cancer patients. Several instruments have been proposed to monitor comorbidities and to investigate functional status, although none has been validated and widely accepted by the oncological community. A Comprehensive Geriatric Assessment (CGA) scale was developed by the GIOGer with the aim of avoiding arbitrary decisions on patient selection, favoring uniform treatment monitoring, and allowing a better comparison of oncological results.49 Currently, CGA appears to be a useful instrument to direct therapeutic choice in older cancer patients.50–56 In several studies, advantages in terms of survival and cost reduction for care of patients submitted to CGA have been noted. An association of ADL/IADL with lifeexpectancy has been suggested: a lack of independence in the ADL predicts increased immediate and 6-month mortality for hospitalized elderly patients. Therefore, functional status represents a reliable predictive factor for mortality.57–62 The clinical relevance of measuring functional status in elderly cancer patients remains little investigated. An adequate instrument is still to be implemented, and its usefulness is still controversial. Thus, studies are required to clarify whether a more accurate evaluation can be provided by CGA, which has proved useful in predicting mortality and disability in several clinical settings, in order to better tailor treatment plans at an individual level.52–54 Clinical studies in elderly cancer patients have shown the negative impact of comorbidity on prognosis, as well as on disability, but few of these studies have underlined the relevance of a full comorbidity assessment. Thus, in elderly cancer patients, the relevance of both functional status and/or comorbidity represents a largely underinvestigated area. Furthermore, a selection bias may exist of elderly cancer subjects addressed to cancer centers.32 The observation that comorbidity and disability as measured by CGA are, in the elderly, positively associated with cancer, and the knowledge of the prognostic role of CGA in the older patients, suggest the utilization of CGA in elderly cancer patients. Further studies are needed to assess whether CGA can properly address therapeutic decision-making and the risk of treatment-related toxicity, thus helping to achieve a wider consensus on the instruments to be adopted. CGA should thus be performed through large follow-up cooperative studies, to allow a better understanding of the indications and efficacy of chemotherapy for elderly cancer subjects. The importance of a comprehensive assessment of the global health status of elderly cancer patients by means of CGA should be underlined. Longitudinal studies are needed to clarify whether CGA may support therapeutic decisions tailored for each patient. The impact of CGA on the life-expectancy of elderly cancer patients needs to be investigated through longitudinal evaluations.

Comprehensive Geriatric Oncology

556

Elderly cancer patients represent a subgroup in which a similar multidimensional assessment could provide useful information about life-expectancy, treatment compliance, and risk of therapy-related toxicity.63,64 The potential benefits associated with CGA in oncology are: • providing a functional evaluation more effective than PS; • analyzing the functional changes due to cancer and cancer treatment; • estimating the life-expectancy of individual patients; • selecting more adequately those patients who are eligible for cancer treatment; • revealing unknown comorbid conditions; • identifying the ‘frail’ elderly; • employing a common language in clinical trials. While more studies are needed to further define the role of CGA in the management of cancer, it is clear from the present evidence that it is an useful instrument. The main concern relates to the time-expenditure involved, which may not be easily absorbed in a busy practice. Several important solutions may be tested: • the use of screening instruments to identify those patients in whom the geriatric assessment is likely to be abnormal—these may include personal interviews or functional assessments, such as rising from a chair; • strict cooperation between oncologist and geriatrician, with the geriatrician providing the oncologist with the result of the CGA and the oncologist determining the treatment course based on the CGA; • better compensation for the performance of the CGA.

Management of specific diseases in the elderly To illustrate the complexity of cancer management in the aged and the specific information necessary in this age group, we shall review the current knowledge related to four common solid neoplasms: breast, lung, prostate, and colorectal cancers. Breast cancer Age is the major risk factor for breast cancer in developed countries: more than half of all newly diagnosed women with breast cancer are 65 and older, and the majority of breast cancer deaths occur in this age group. Breast cancer represents a leading cause of morbidity and mortality in the elderly. Studies of breast cancer biology and age show that older women are more likely to have lower-grade, node-negative, estrogen receptor (ER)-positive tumors compared with younger women.65–67 Therefore, many physicians have long suspected that breast cancer affecting the elderly is relatively indolent, or less aggressive. As a result, doctors have been reluctant to treat breast cancer in the elderly as aggressively as they do in younger women. Also, they feared that since older women are more likely to have comorbid conditions, they would not be able to tolerate aggressive therapy. Contrary to this long-

Prognostic evaluation of the older cancer patient

557

held perception, breast cancer can be just as aggressive in elderly women as it is in younger women, according to a study presented at the American Society for Therapeutic Radiology and Oncology annual meeting in Boston in October 2000. The results concluded that treatment of the disease in women over 70 should not be approached differently than that of younger women, but rather treatment should be guided by physiological age and comorbidities. Breast cancer-specific 5-year survival rates in women aged 70–84 are not lower than those in younger women matched for tumor size and nodal status.68,69 Management of breast cancer in older women remains controversial. The inadequacy of prognostic assessment may account in part for lack of more precise information. Several trials have shown that older women with breast cancer are frequently undertreated, even when no comorbidities or other non-age-related factors are identified.70–73 Age has a strong influence on treatment modalities, and this is still more true in particular in the very elderly: these women are not offered the full range of options, according to the results of a study funded by the Agency for Healthcare Research and Quality (AHRQ) in the USA. The findings concerning both chemotherapy and radiation therapy remained valid even after adjusting for women’s treatment preferences, health status, and comorbidity, as Mandelblatt et al74 report. These authors acknowledge that there remains substantial scientific uncertainty as to the most appropriate treatment for older women. In terms of local control, surgery is curative for breast cancer in many cases, but is not always offered to the elderly. Elderly women with breast cancer can benefit from surgical treatment of their disease regardless of age.75 Age alone was not a contraindication to surgical therapy of breast cancer, and survival rates in those older than 70 were not significantly different from those in younger patients in retrospective analyses comparing patients younger and older than 75.76 There are a number of randomized studies showing that tamoxifen alone is not as effective as surgery plus tamoxifen; thus, elderly patients who are treated with tamoxifen alone are not being adequately treated.77–79 Breastconserving surgery can be used with the same indications as in younger women, and it may be preferred to radical surgery in older women who have other medical problems.80 Radiation therapy can also be administered as safely to elderly people as to younger, unless they are unable to attend hospital daily. Postoperative breast irradiation produces a significant reduction in locoregional cancer recurrence, and it is well tolerated by women over 65 compared with younger counterparts.81,82 There are no studies of axillary lymph node dissection or of sentinel node biopsies in elderly women. At present, it is recommended that an axillary lymph node dissection should be contemplated in tumors larger than 2 cm where the risk of positivity is very high.83 Since a 70-year-old patient still has a life-expectancy of about 15 years, discussion of adjuvant treatment in such a patient should be open to all possibilities. There are very few randomized studies, however, that have included women from this age group. Direct information on the value of adjuvant therapy in older women is limited, especially for chemotherapy. An updated analysis (Oxford, September 2000) of Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) data supports the major conclusions of previous analyses of the benefits of hormonal therapy and chemotherapy.65 However, few patients older than 70 have been included in randomized studies of chemotherapy, and they likely represent a healthy subset.84 The meta-analysis shows that tamoxifen significantly increases both relapse-free and overall survival also in women 70 and older

Comprehensive Geriatric Oncology

558

with early breast cancer and ER-positive tumors.85 In contrast, few data from randomized trials are available concerning the benefits of chemotherapy in this age group.86 It is difficult to perform studies in the elderly because they often have comorbidities and because the necessary follow-up may not always be feasible. Crivellari et al87 evaluated toxicity and effectiveness of the association of CMF (cyclophosphamide, methotrexate, and 5-flourouracil (5-FU)) with versus ≥65 years), in women with breast cancer and tamoxifen versus tamoxifen alone with respect to age (<65 positive nodes. More grade 3 toxicity among older women without apparent negative effects on quality of life has been shown. Furthermore, the association of CMF with tamoxifen, even if favorable in terms of 5-year disease-free survival, was less effective in groups of women older than 65. Analysis of received dose intensity shows that this is not related to the different doses administered. Comorbidity may play a major role in adjuvant treatment selection in order to define the life-expectancy and probable tolerability of treatment.88 The effect of comorbidity on treatment outcome has also been estimated using mathematical models. Extermann et al84 concluded that comorbidity should be considered in recommendations for adjuvant therapy. Clinical trials have not yet established the efficacy of adjuvant chemotherapy for locoregional disease in women over 70. Clinical studies evaluating its role in older women are currently being developed. For advanced disease in older women, hormonal therapy is clearly an effective and safe option.89,90 However, about 20% of all women of this age group will not have ERpositive tumors, and a higher percentage than that will not respond to hormones. Chemotherapy can provide the elderly with substantial palliation of disease-related symptoms.91,92 Chemotherapy may be less well tolerated owing to age-related reductions in functional reserves. However, elderly women without major medical complications experience equal benefit and no greater levels of toxicity than younger patients with advanced cancer.93 Despite its advantages, chemotherapy is offered significantly less often in women aged 75 or older, even after adjustments for other medical conditions have been made.94 Given the palliative aim of this treatment, drugs that are effective but not too toxic are needed. Vinorelbine is well tolerated in the elderly, and has similar activity to that seen in younger patients. Gemcitabine and capecitabine may be safely employed in older persons. Similarly, weekly schedules of anthracyclines or taxanes have been shown, in small phase II studies, to be feasible and effective. Larger studies are needed to elucidate the role of these agents in elderly breast cancer patients. In carefully selected patients, there is no increase in unexpected morbidity or mortality related to chemotherapy.95 Once again, the proper selection of patients seems to be the principal issue. A very interesting study conducted by the Cancer and Leukemia Group B (CALGB) showed that older women were as likely as younger women to accept and undergo clinical trials.96 In general, however, clinical trials were offered less frequently to older patients. This important study indicates that physician’s bias, more than patient’s unwillingness, is the main cause of the scarce enrollment of older individuals in clinical trials of cancer treatment.

Prognostic evaluation of the older cancer patient

559

Lung cancer Lung cancer occurs in 30–35% of cases in patients aged 70 or older.97,98 With increasing cessation of smoking and more prolonged survival of ex-smokers, one may expect an increasing proportion of lung cancer cases after the age of 70.99 The choice of chemotherapy is problematic in elderly patients, who are often both excluded from clinical trials and left without treatment in clinical practice. This is unfortunate, because these patients frequently present cancer-related symptoms that are not relieved by supportive care alone. Less aggressive approaches are needed in this age group. Vinorelbine as a single agent showed benefits in terms both of survival and of quality of life.100 On the basis of retrospective studies, another antimetabolite, gemcitabine, showed similar activity and toxicity in patients older than 65 compared with younger patients.101 Data from the Multicenter Italian Lung Cancer in the Elderly Study (MILES) showed that the association of gemcitabine with vinorelbine is well tolerated and outcomes are encouraging, but it does not appear to be superior to chemotherapy with a single agent.102 An ongoing Southwest Oncology Group (SWOG) study is evaluating the influence of PS on treatment outcomes of elderly patients. About 25–30% of small cell lung cancer (SCLC) occurs in elderly people. Many older patients remain undertreated and excluded from clinical trials. There are no guidelines for the treatment of lung cancer in the elderly; for this reason, prospective clinical trials have to be encouraged. In clinical practice, the therapeutic choice should take into consideration not only the stage of disease, but also the patient’s general condition (i.e. PS and CGA), lifeexpectancy, and presence of comorbidity. In SCLC, the association of chemotherapy with radiation therapy compared with radiation therapy alone showed a greater benefit in terms of mortality in younger than older patients.103 However, phase II studies of chemotherapy plus radiation therapy in the elderly provided encouraging results (with objective response rates (OR) of 71–90%).104 Chemotherapy should be considered as the treatment of choice for SCLC also in elderly people, even if there is no standard treatment.105 On the basis of data in the literature, CAV (cyclophosphamide, doxorubicin, and vincristine) and EP (etoposide and cisplatin) are the most common combinations. In particular, in one study performed in patients with limited-stage SCLC treated with alternating CAV/EP, the authors concluded that age did not represent an unfavorable prognostic factor and that moderately aggressive chemotherapy may be safely administered in elderly patients with good PS, although decreased or skipped doses are needed more often.106 In phase II studies in elderly patients with SCLC, oral etoposide as a single agent produced OR rates ranging from 53% to 71%.107 However, the same agent compared with polychemotherapy using CAV in a phase III study in patients with poor PS showed results that were clearly inferior to those of polychemotherapy in terms of both OR rate (45% versus 51%) and survival (p=0.03); therefore, the trial was stopped.108 The association of carboplatin plus etoposide in phase II studies in elderly patients provided good outcomes, with OR rates of up to 85%, but often with important myelotoxicity.109 Other studies of polychemotherapy including cisplatin have also reported interesting results.110

Comprehensive Geriatric Oncology

560

Radiation therapy may be considered in elderly patients with limited-stage SCLC obtaining a complete response after chemotherapy. Finally, the role of prophylactic cranial irradiation (PCI) seems to be independent of age.111 Prostate cancer Prostate cancer is a typical neoplasm of advanced age. After the age of 50, its incidence and mortality increase in a nearly exponential manner.112 Analogous to breast cancer, prostate cancer is a disease that exhibits a response to hormonal manipulation, radiation therapy, surgery and chemotherapy.113 Cancer localized at the gland may be treated with surgery or radiation therapy, while patients with lymph node metastases or disseminated disease are treated with hormonal therapy. Adjuvant chemotherapy strategies have been formulated, and are currently under-going testing; the role of adjuvant therapy for elderly patients with prostate cancer remains unclear.113 In older patients in whom surgery may be contraindicated by medical conditions, radiation therapy is an effective treatment, with outcomes in terms of survival similar to those reported with surgery.114 Since prostate cancer is a hormone-dependent disease, the treatment of choice for locally advanced and disseminated disease is hormonal therapy, essentially aimed either at inhibiting androgen secretion or at interfering with its action at the prostate level, or both, through androgen withdrawal. Chemotherapy has a marginal role to play in treating prostate cancer. Its use as palliative treatment in patients who are refractory to hormonal therapy needs further evaluation. The results obtained with this modality are disappointing.115,116 In a phase III randomized study, Tannock et al117 compared mitoxantrone plus prednisone versus prednisone alone, and showed an advantage for the combination therapy in terms of palliation and quality of life. There was no survival benefit, but because of good tolerability and effective palliation, this treatment should be considered in symptomatic older patients in clinical practice. Among the new drugs, moderate activity has been reported for vinorelbine, gemcitabine, and the taxanes.118–121 The role of chemotherapy in prostate carcinoma is evolving.122 With the development of more defined criteria for assessment and quality of life, it has become clear that anticancer effects occur in 20–60% of prostate cancers treated with chemotherapy.123 Colorectal cancer Almost 50% of deaths from colorectal cancer occur in patients older than 75, with the median age at diagnosis being around 68.4 years for rectal cancer and 70.5 years for colon cancer.124,125 The incidence of this disease increases steadily up to the eighth decade and is nearly similar in both sexes. Yet the optimal management of colorectal cancer in the elderly is controversial. Advanced age alone is not a reason to deny surgery. In reviewing data from 28 studies, including 34194 patients, Simmonds and colleagues126 found that elderly patients had an increased frequency of comorbid conditions, were more likely to present with later-stage disease and undergo emergency surgery, and were less likely to have curative surgery

Prognostic evaluation of the older cancer patient

561

than younger patients. They point out that cancer-specific survival after colorectal cancer surgery does not vary by age: at 2 and 5 years after surgery, they found that there was little difference in cancer-specific survival between older and younger patients. They concluded that although elderly people have higher rates of postoperative morbidity and mortality, the outcomes for selected elderly patients undergoing surgery for colorectal cancer, even in the oldest-old category (i.e. older than 85) can be good and many of these patients survive for 2 or more years after surgery. Only a few studies have explored the efficacy of adjuvant chemotherapy in stage II or III colon cancer in elderly patients. Sargent et al127 presented data from a meta-analysis of seven phase III randomized trials in the USA and Europe, comparing 5-FU plus leucovorin (LV) or 5-FU plus levamisole (LEV) with observation in 580 patients older than 70 out of 3351 patients with Dukes stage B2 or C colon cancers. They reported that, compared with younger patients, patients older than 70 did not have substantially greater side-effects from chemotherapy, and received similar benefits. The advantage of adjuvant therapy does not depend on age (analyses were performed in decade-based ranges). Greater toxicity in the older group was observed only for leukopenia with the 5-FU/LEV therapy. It was concluded that older patients benefit from 5-FU-based adjuvant therapy without a significant increase in toxicity compared with younger patients. The results, however, were derived from patients elegible for clinical trials, and hence they do not apply universally to the overall older population. These data seem to be in contrast with results from the updated analysis (Oxford, September 2000) of the EBCTCG, who failed to show benefits from the association of adjuvant chemotherapy in elderly breast cancer patients, according to biological differences of neoplasms in the elderly. The lifeexpectancy of a 70-year-old man is 10 years and that of a 70-year-old woman is 15 years. All patients older than 70 with colon cancer should be considered for adjuvant chemotherapy. However, the decision to treat should integrate assessment of organ reserves, comorbidity, functional status, and the endpoints of therapy.128 For the last four decades, 5-FU has been the mainstay for colorectal cancer chemotherapy; the 5-FU/LV regimen has become the standard schedule. In stage IV colorectal cancer, this regimen gives a 10–20% OR rate, with a median survival of 9 months. Many tumors become resistant to 5-FU; therefore, colorectal cancers have been considered less responsive to chemotherapy and, until now, there have been no available effective second-line therapies. New drugs, including irinotecan, oxaliplatin, and the oral fluoropyrimidines (capecitabine and tegafur/uracil (UFT)), have shown specific activity in this disease, and are currently under study. In metastatic colorectal cancer, oxaliplatin combined with 5-FU/LV improved the tumor regression rate and the time to tumor progression.129,130 There are no data related to phase I or II trials in elderly patients, but in trials including patients older than 75, a severe increase of toxicity was not observed in this age group with oxaliplatin. In particular, in a phase III study of 420 patients, among the 160 aged 65–75, only a significant increase in grade 3/4 diarrhea was reported.129 The use of irinotecan/5-FU/LV in stage IV colorectal cancer, compared with the standard regimen, resulted in superior response rates, a longer time to disease progression, and prolonged survival.131 Benefits in terms of OR and time to tumor progression were also observed in the group of older patients, but there was no analysis of toxicity by age in this study. The activity is similar to that of oxaliplatin.132 In the older persons’ age group, there are few data for the determination of a standard of care. Studies aimed at evaluating

Comprehensive Geriatric Oncology

562

toxicity, the activity of the new regimens, overall survival, possible prognostic factors, quality of life, and the prognostic relevance of CGA in elderly patients with colorectal cancer are needed. Conclusions The problem of cancer in the elderly needs further research in several areas, including the increased incidence of tumors in older age, the different biological and clinical factors, the under-representation of the elderly in clinical trials, and the need to improve current knowledge of the biology of aging, with the aim of defining an adequate selection of elderly patients, in order to not exclude older people only on the basis of chronological age from effective antineoplastic treatments and to offer them the same possibilities of care as are offered to younger patients. There is no chronological definition of the older patient, but two ages are crucial: 70 years increases the prevalence of age-related changes, while 85 years increases the prevalence of frailty. Yet, treatment results are inadequate not always because of the real presence of comorbidity or disability. Instruments suitable to provide proper evaluation of the biological ages of patients are needed. The CGA allows (i) estimation of functional reserves and life-expectancy; (ii) better knowledge of the individual course of aging; (iii) identification of the specific medical, social, and emotional needs of older individuals; and (iv) the provision of a common language to classify the older cancer patient in both retrospective and prospective studies and in everyday clinical communication. The physician who cares for the elderly patient with cancer should be able to answer the following questions: Will the patient die because of or with cancer? Is the patient able to tolerate the stress due to cancer treatment? Which benefits and risks may arise from treatment? Schematically, it is possible identify three groups of elderly patients: (i) the patient without comorbidity and disability; (ii) the frail patient; and (iii) all the other patients not included in the first two categories. In the first group, the patient may be eligible for any type of standard therapy; the patients in the second group are nearly always candidates for palliative care only; finally, for the remaining patients’ individualized approaches and specific clinical trials are needed. The results and the toxicity related to cancer treatment in the elderly may be improved not only by new agents and new supportive care, but also by proper selection of patients. Provision of suitable means to measure the level of ‘aging’ of each single person has priority. Functional status represents an important indicator of the general conditions of health. Therapeutic choice should be led by evaluation, on the one hand, of the conditions of the individual older patient, including age, comorbidity, functional status, CGA, and lifeexpectancy, and, on the other hand, of the course and the biological characteristics of the tumor, including the expected outcomes of treatment, in terms of toxicity, efficacy, and quality of life.

Prognostic evaluation of the older cancer patient

563

References 1. Busshouse S, Punyko J, Soler J et al. The Occurrence of Cancer in Minnesota, 1988–1996: Incidence, Mortality, Trends. Minneapolis: Minnesota Cancer Surveillance Systems, Minnesota Department of Health, August 1999. 2. Yancik R. Cancer burden in the aged. An epidemiologic and demographic overview. Cancer 1997; 80:1273–83. 3. Vercelli M, Quaglia A, Casella C et al, and the EUROCARE Working Group. Cancer in elderly patients: the population based indexes in Europe (incidence, mortality, survival and prevalence). Ann Oncol 1998; 9:55–6. 4. Kennedy BJ. Cancer research and the aging population. Oncol Issues 2000; 15:20–6. 5. Gatta G, Capocaccia R, Coleman MP et al. Toward a comparison of survival in American and European cancer patients. Cancer 2000; 89: 893–900. 6. Satariano WA, Ragland DR. The effect of comorbidity on 3-year survival of women with primary breast cancer. Ann Intern Med 1994; 120:104–10. 7. Goodwin JS, Hunt WC, Samet JM. Determinants of cancer therapy in elderly patients Cancer 1993; 72:594–601. 8. Goodwin JS, Samet JM, Key CR et al. Stage at diagnosis of cancer varies with the age of the patient. J Am Geriatr Soc 1986; 34:20–6. 9. Holmes FF, Heame E. Cancer stage-to-age relationship: implications for cancer screening in the elderly. J Am Geriatr Soc 1981; 29:55–7. 10. Monfardini S, Repetto L, Zagonel V et al (eds). Guidelines for the Management of Cancer in the Elderly. Crit Rev Oncol Hematol 1998; 27(2). 11. McKenna RJ. Clinical aspects of cancer in the elderly: treatment decisions, treatment choises, and follow up. Cancer 1994; 74: 2107–17. 12. Berger DH, Roslyn JJ. Cancer surgery in the elderly. Clin Geriatr Med 1997; 13:119–42. 13. Olmi P, Ausili-Cefaro G, Balzi M. Radiotherapy in the aged. Clin Geriatr Med 1997; 13:143– 68. 14. Zachariah B, Balducci L, Venkattaramanabalaji GV et al. Radiotherapy for cancer patients aged 80 and older: a study of effectiveness and side-effects. Int J Radiat Oncol Biol Phys 1997; 39:1125–9. 15. Balducci L. Prevention and treatment of cancer in the elderly. Oncol Issues 2000; 15:26–8. 16. Newcomb PA, Carbone PP. Cancer treatment and age: patient perspectives. J Natl Cancer Inst 1993; 85:1580–4. 17. Christman K, Muss HB, Case LD et al. Chemotherapy of metastatic breast cancer in the elderly: the Piedmont Oncology Association experience. JAMA 1992; 268:57–62. 18. Ibrahim N, Buzdar A, Frye D et al. Should age be a determinant factor in treating breast cancer patients with combination chemotherapy? Proc Am Soc Clin Oncol 1993; 12:68. 19. Giovanazzi-Bannon S, Rademaker A, Lai G et al. Treatment tolerance of elderly cancer patients entered onto phase II clinical trials: an Illinois Cancer Center study. J Clin Oncol 1994; 12:2447–52. 20. Gelman RS, Taylor SG 4th. Cyclophosphamide, methotrexate and 5-fluorouracil chemotherapy in women more than 65 years old with advanced breast cancer: the elimination of age trend in toxicity by using doses based on creatinine clearance. J Clin Oncol 1984; 2: 1404–13. 21. Rockwood K, Stadnyk K, MacKnight C et al. A brief clinical instrument to classify frailty in elderly people. Lancet 1999; 353:205–6. 22. Rockwood K, Fox RA, Stolee P et al. Frailty in elderly people: an evolving concept. Can Med Assoc J 1994; 150:489–95. 23. Winograd CH, Gerety MB, Chung M et al. Screening for frailty: criteria and predictors of outcomes. J Am Geriatr Soc 1991; 39: 778–84.

Comprehensive Geriatric Oncology

564

24. Fried LP, Tangen CM, Walston J et al. Frailty in older adults. Evidence for a phenotype. J Gerontol Med Sci 2001; 56A; M146–56. 25. Hamerman D. Toward an understanding of frailty. Ann Intern Med 1999, 130:945–50. 26. Cohen HJ, Pieper CF, Harris H. Markers of inflammation and coagulation predict decline in function and mortality in community dwelling elderly. Proc Am Geriatr Soc 2001; Abst A3. 27. Strawbridge WJ, Kaplan GA, Camacho T, Cohen RD. The dynamics of disability and functional change in an elderly cohort: results from the Alameda County Study. J Am Geriatr Soc 1992; 40:799–806. 28. Bergman L, Dekker G, Van Kerkhoff EHM et al. Influence of age and comorbidity on treatment choice and survival in elderly patients. Breast Cancer Res Treat 1991; 18:189–98. 29. Guralnik JM. Assessing the impact of comorbidity in the older population. Ann Epidemiol 1996; 6:376–80. 30. Yancik R, Wesley MN, Ries LAG et al. Comorbidity and age as predictors of risk for early mortality of male and female colon carcinoma patients. Cancer 1998; 82:2123–34. 31. Yancik R, Havlik RJ, Wesley MN et al. Cancer and comorbidity in older patients: a descriptive profile. Ann Epidemiol 1996; 6:399–412. 32. Repetto L, Venturino A, Vercelli M et al. Performance status and comorbidity in elderly cancer patients compared with young patients with neoplasia and elderly patients without neoplastic conditions. Cancer 1998; 82:760–5. 33. Extermann M, Balducci L, Lyman GH. Optimal duration of adjuvant tamoxifen treatment in elderly breast cancer patients: influence of age, comorbidities and various effectiveness hypotheses on life-expectancy and costs. Breast Dis 1996; 9:327–39. 34. Fried L, Bandeen Roche K, Kasper J, Guralnik J. Association of comorbidity with disability in older women: the women’s health and aging study. J Clin Epidemiol 1999; 52:22–37. 35. Coebergh JWW, Janssen-Heijnen MLG, Post PN, Razenberg PPA. Serious comorbidity among unselected cancer patients newly diagnosed in the southeastern part of The Netherlands in 1993–1996. J Clin Epidemiol 1999; 21:1–6. 36. Fried LP, Ettinger WH, Lind B et al. Physical disability in older adults: a physiological approach. J Clin Epidemiol 1994; 47:747–69. 37. Fried LP, Guralnik JM. Disability in older adults: evidence regarding significance, etiology, and risk. J Am Geriatr Soc 1997; 45:92–100. 38. Verbrugge LM, Lepkowski JM, Imanaka Y. Comorbidity and its impact on disability. Milbank Q 1989; 67:450–84. 39. Guralnik JM, LaCroix AZ, Everett DF, Kovar MG. Aging in the Eighties: The Prevalence of Comorbidity and its Association with Disability. Advance Data from Vital and Health Statistics, No. 170. Hyattsville, MD: National Center for Health Statistics, 1989. 40. Mor V, Murphy J, Masterson Allen S et al. Risk of functional decline among well elders. J Clin Epidemiol 1989; 42:895–904. 41. Fried LP. Older women: health status, knowledge, and behavior. In: Women’s Health: Commonwealth Fund Survey (Falik M, Scott Collins K, eds). Baltimore, MD: Johns Hopkins University Press, 1996:175–204. 42. Guralnik JM, LaCroix AZ, Abbott RD et al. Maintaining mobility in late life: demographic characteristics and chronic conditions. Am J Epidemiol 1993; 137:845–57. 43. Ettinger WH, Davis MA, Neuhaus JM, Mallon KP. Long-term physical functioning in persons with knee osteoarthritis from NHANES-1. Effects of comorbid medical conditions. J Clin Epidemiol 1994; 47: 809–15. 44. Campbell AJ, Busby WJ, Robertson MC et al. Disease, impairment, disability and social handicap: a community based study of people aged 70 years and over. Disabil Rehabil 1994; 16:72–9. 45. Almy TP. Comprehensive functional assessment for elderly patients. Ann Intern Med 1988; 109:70–2.

Prognostic evaluation of the older cancer patient

565

46. Extermann M, Overcash J, Lyman GH et al. Comorbidity and functional status are independent in older cancer patients. J Clin Oncol 1998; 16:1582–7. 47. Repetto L, Fratino L, Audisio RA et al. Comprehensive Geriatric Assessment adds information to Eastern Cooperative Group Performance Status in elderly cancer patients: an Italian Group for Geriatric Oncology study. J Clin Oncol 2002; 20:494–502. 48. Piccirillo JF, Feinstein AR. Clinical symptoms and comorbidity: significance for the prognostic classification of cancer. Cancer 1996; 77:834–42. 49. Monfardini S, Ferrucci L, Fratino L et al. Validation of a multidimensional scale for use in elderly cancer patients. Cancer 1996; 77: 395–401. 50. Beghe’ C, Bruce ER. Comprehensive Geriatric Assessment: diagnostic, therapeutic and prognostic value. Cancer Control 1994; 1:121–5. 51. Deyo R, Applegate WD, Kramer A et al. The future of Geriatric Assessment: report of a Consensus Conference sponsored by Department of Veterans Affairs National Institute of Aging, Robert Wood Johnson Foundation. J Am Geriatr Soc 1991; 39:1S–59S. 52. Stuck AE, Siu AL, Wieland GD et al. Comprehensive Geriatric Assessment: a meta-analysis of controlled trials. Lancet 1993; 342: 1032–6. 53. Bernabei R, Landi F, Gambassi G et al. Randomised trial of impact of model of integrated care and case management for older people living in the community. BMJ 1998; 316:1348–51. 54. National Institutes of Health Consensus Development Conference Statement. Geriatric assessment methods for clinical decision-making. J Am Geriatr Soc 1988; 36:342–7. 55. Rich MW, Beckham W, Wittenberg C et al. A multidisciplinary intervention to prevent readmission of elderly patients with congestive hearth failure. N Engl J Med 1995; 333:1190–5. 56. Rubenstein LZ, Rubenstein LV. Multidimensional geriatric assessment. In: Textbook of Geriatric Medicine (Brocklehurst JC, Tallis RC, Fillit HM, eds). New York: Churchill Livingstone, 1992:150–7. 57. Siu AL, Hays RD, Ouslander JG et al. Measuring functioning and health in the very old. J Gerontol Med Sci 1993; 48:M10–14. 58. Reuben DB, Wieland DL, Rubenstein LZ et al. Functional status assessment of older persons: concepts and implications. Facts Res Gerontol 1993; 7:231–40. 59. Cohen HJ. Geriatric principles of treatment and applied to medical oncology: an overview. Semin Oncol 1995; 22(Suppl):1–2. 60. Cohen HJ, Saltz CC, Samsa G et al. Predictors of two-year post hospitalization mortality among elderly veterans in a study evaluating a geriatric consultation team. J Am Geriatr Soc 1992; 40: 1231–5. 61. Inoyoue SK, Peduzzi PN, Robison JT et al. Importance of functional measures in predicting mortality among elder hospitalized patients. JAMA 1998; 279:1187–93. 62. Narain P, Rubenstein LZ, Wieland GD et al. Predictors of immediate and 6-month outcome in hospitalized elderly patients: the importance of functional status. J Am Geriatr Soc 1988; 36:775–83. 63. Monfardini S, Fratino L, Zagonel V et al. Elderly cancer patients undergoing chemotherapy or radiotherapy should be tested for their ability in drug self-administration, use of means of transportation and telephone. Proc Am Soc Clin Oncol 1996; 15:507. 64. Zagonel V, Fratino L, Ferrucci L et al. Therapeutic choice with regard to life expectancy and cost benefit analysis in cancer diagnosis and treatment. Crit Rev Oncol Hematol 1998; 27:121– 3. 65. Muss HB. Breast cancer in the elderly: the role of systemic adjuvant therapy. Educational Book Am Soc Clin Oncol 2001:106–110. 66. Diab SG, Elledge RM, Clark GM. Tumor characteristics and clinical outcome of elderly women with breast cancer. J Natl Cancer Inst 2000; 92:550–6. 67. Lyman GH, Lyman S, Balducci L et al. Age and the risk of breast cancer recurrence. Cancer Control 1996; 3:421–7.

Comprehensive Geriatric Oncology

566

68. Holli K, Isola J. Effect of age on the survival of breast cancer patients. Eur J Cancer 1997; 33:425–8. 69. Masetti R, Antinori A, Terribile D et al. Breast cancer in women 70 years of age and older. J Am Geriatr Soc 1996; 44:390–3. 70. August DA, Rea T, Sondak VK et al. Age-related differences in breast cancer treatment. Ann Surg Oncol 1994; 1:45–52. 71. Merchant TE, McCormick B, Yahalom J et al. The influence of older age on breast cancer treatment decisions and outcome. Int J Radiat Oncol Biol Phys 1996; 34:565–70. 72. Hillner BE, Penberthy L, Desch CE et al. Variation in staging and treatment of local and regional breast cancer in the elderly. Breast Cancer Res Treat 1996; 40:75–86. 73. Newschaffer CJ, Penberthy L, Desch CE et al. The effect of age and comorbidity in the treatment of elderly women with nonmetastatic breast cancer. Arch Intern Med 1996; 156:85– 90. 74. Mandelblatt JS, Hadley J, Kerner JF et al. Patterns of breast carcinoma treatment in older women: patient preference and clinical and physical influence. Cancer 2000; 89:561–73. 75. Amsterdam E, Birkenfeld S, Gilad A et al. Surgery of carcinoma of the breast in women over 70 years of age. J Surg Oncol 1987; 35: 180–3. 76. Herbsman H, Feldman J, Seldera J et al. Survival following breast cancer in the elderly. Cancer 1981; 47:2358–63. 77. Gazet JC, Markopoulos C, Ford HT et al. Prospective randomized trial of tamoxifen versus surgery in elderly patients with breast cancer. Lancet 1988; i: 679–81. 78. Robertson JFR, Todd JH, Ellis IO et al. Comparison of mastectomy with tamoxifen for treating elderly patients with operable breast cancer. BMJ 1988; 297:511–14. 79. Mustacchi G, Milani S, Pluchinotta A et al. Tamoxifen or surgery plus tamoxifen as primary treatment for elderly patients with operable breast cancer: a GRETA trial. Anticancer Res 1994; 14: 2197–200. 80. Dixon JM, Sainsbury JRC, Rodger A. Breast cancer: treatment of elderly patients and uncommon conditions. BMJ 1994; 309: 1292–5. 81. Cerrotta A, Lozza L, Kenda R et al. Current controversies in the therapeutic approach to early breast cancer in the elderly. RAYS 1997; 22(Suppl):66–8. 82. Wyckoff J, Greenberg H, Sanderson R et al. Breast irradiation in the older women: a toxicity study. J Am Geriatr Soc 1994; 42: 150–2. 83. Forrest APM, Fentiman IS. Breast cancer: principles of management. In: Cancer in the Elderly, Treatment and Research (Fentiman IS, Monfardini S, eds). Oxford: Oxford University Press, 1994: 61–77. 84. Extermann M, Balducci L, Lyman GH. What threshold for adjuvant therapy in older breast cancer patients? J Clin Oncol 2000; 18:1709–17. 85. Early Breast Cancer Trialist’s Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998; 351:1451–67. 86. Early Breast Cancer Trialist’s Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998; 352:930–42. 87. Crivellari D, Bonetti M, Castiglione-Gertsch M et al. Burdens and benefits of adjuvant cyclophosphamide, methotrexate, and fluorouracil and tamoxifen for elderly patients with breast cancer. The International Breast Cancer Study Group Trial VII. J Clin Oncol 2000; 18:1412–22. 88. Aapro M, Piccart M. Breast cancer. Crit Rev Oncol Hematol 1998; 27:135–7. 89. Repetto L, Venturino A, Comandini D et al, for the GIOGer. A loading dose of tamoxifen followed by a standard dose in frail older women with breast cancer is feasible and effective. J Am Geriatr Soc 2000; 48:346–7. 90. Venturino A, Comandini D, Granetto C et al, on behalf of the GIOGer. Formestane is feasible and effective in elderly breast cancer. patients with comorbidity and disability. Breast Cancer Res Treat 2000; 62:217–22.

Prognostic evaluation of the older cancer patient

567

91. de Valeriola D, Awada A, Roy JA et al. Breast cancer therapies in development. A review of their pharmacology and clinical potential. Drugs 1997; 54:385–413. 92. Christman K, Muss HB, Case LD et al. Chemotherapy of metastatic breast cancer in the elderly: the Piedmont Oncology Association experience. JAMA 1992; 268:57. 93. Cascinu S, Del Ferro E, Catalano G. Toxicity and therapeutic response to chemotherapy in patients aged 70 years and older with advanced cancer. Am J Clin Oncol 1996; 19:371–4. 94. Fetting JH, Comstock GW, Eby S et al. The effect of aging on the utilization of chemotherapy for metastatic breast cancer: a population-based study. Cancer Invest 1997; 15:199–203. 95. Muss H. Chemotherapy of breast cancer in the older patients. Semin Oncol 1995; 22:1417. 96. Kemeny M, Muss HB, Kornblith AB et al. Barriers to participation of older women with breast cancer in clinical trials. Proc Am Soc Clin Oncol 2000; 19:2371. 97. Silverberg E. Cancer statistics. CA Cancer J Clin 1988; 38:5. 98. Gridelli C, Perrone F, Monfardini S. Lung cancer in the elderly. Eur J Cancer 1997; 33:2313. 99. Halpern MT, Gillespie BW, Warner KE. Patterns of absolute risk of lung cancer mortality in former smokers. J Natl Cancer Inst 1993; 17:457–464. 100. The Elderly Lung Cancer Vinorelbine Italian Study Group. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small cell lung cancer. J Natl Cancer Inst 1999; 9: 66–72. 101. Shepherd FA, Abratt RP, Anderson H et al. Gemcitabine in the treatment of elderly patients with advanced non-small cell lung cancer. Semin Oncol 1997; 24:50–5. 102. Gridelli C, Perrone F, Gallo C et al. Chemotherapy for elderly patients with advanced nonsmall-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst 2003l 95:362–72. 103. Pignon JP, Arriagada R, Ihde DC et al. A meta-analysis of thoracic radiotherapy for small cell lung cancer. N Engl J Med 1992; 327: 1618–24. 104. Murray N. Abbreviated treatment for elderly, infirm, or non compliant patients with limitedstage small-cell lung cancer. J Clin Oncol 1998; 16:3323–8. 105. Shepherd FA, Amdemichael E, Evans WK et al. Treatment of small cell lung cancer in the elderly. J Am Geriatr Soc 1994; 70:64–70. 106. Siu LL, Shepherd FA, Murray N et al. Influence of age on the treatment of limited-stage small-cell lung cancer. J Clin Oncol 1996; 14: 821–8. 107. Carney DN, Grogan L, Smit EF et al. Single-agent oral etoposide for elderly small cell lung cancer patients. Semin Oncol 1990; 17 (1 Suppl 2):49–53. 108. Girling DJ et al. Comparison of oral etoposide and standard intravenous multidrug chemotherapy for small cell lung cancer: a stopped multicentre randomised trial. Medical Research Council Lung Cancer Working Party. Lancet 1996; 348:563–66. 109. Matsui K, Masuda N, Fukuoka M et al. Phase II trial of carboplatin plus oral etoposide for elderly patients with small cell lung cancer. Br J Cancer 1998; 77:1961–65. 110. Westeel V, Murray N, Gelmon K et al. New combination of the old drugs for elderly patients with small-cell lung cancer: a phase II study of the PAVE regimen. J Clin Oncol 1998; 16:1940–7. 111. Auperin A, Arriagada R, Pignon JP et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 1999; 341:476–84. 112. Vercelli M, Quaglia A, Morani E et al. Prostate cancer incidence and mortality trends among elderly and adult Europeans. Crit Rev Oncol Hematol 2000; 35:133–44. 113. Raghavan D. Adjuvant therapy for prostate cancer in the elderly patients. Educational Book Am Soc Clin Oncol 2001:116–23. 114. Hanks GE, Houlon AL, Schultheiss TE et al. Dose escalation with 3D conformal treatment: five-year outcomes, treatment optimizations, and future directions. Int J Radiat Oncol Biol Phys 1998; 41:491–500.

Comprehensive Geriatric Oncology

568

115. Vogelzang N. One hundred thirteen men with hormone-refractory prostate cancer died today. J Clin Oncol 1996; 14:1753–54. 116. Oh WK. Chemotherapy for patients with advanced prostate carcinoma. Cancer 2000; 88; 3015–21. 117. Tannock IF, Osoba D, Stocker MR et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative endpoints. J Clin Oncol 1996; 14:1756–64. 118. Field-Jones S, Koletsky A, Wilding G et al. Improvements in clinical benefit with vinorelbine in the treatment of hormone-refractory prostate cancer: a phase II trial. Ann Oncol 1999; 10:1307–10. 119. Morant R, Bernhard J, Mailbach R et al. Response and palliation in a phase II trial of gemcitabine in hormone-refractory metastatic prostate carcinoma. Swiss Group for Clinical Cancer Research (SAKK). Ann Oncol 2000; 11:183–8. 120. Trivedi C, Redman B, Flaherty LE et al. Weekly 1-hour infusion of paclitaxel. Clinical feasibility and efficacy in patients with hormone-refractaory prostate carcinoma. Cancer 2000; 89:431–6. 121. Berry W, Rorbaugh T. Phase II trial of single agent weekly Taxotere in symptomatic hormone-refractaory prostate cancer. Proc Am Soc Clin Oncol 1999; 18:335. 122. Raghavan D, Kocswara B, Javle M. Evolving strategies of cytotoxic chemotherapy for advanced prostate cancer. Eur J Cancer 1997; 33: 566–74. 123. Beer T, Raghavan D. Chemotherapy for hormone-refractory prostate cancer: beauty is in the eye of the beholder. Prostate 2000; 45:184–93. 124. Silverberg E, Boring CC, Squires TS. Cancer statistics. CA Cancer J Clin 1990; 40:9–26. 125. Young JL, Percy CL, Asire AJ (eds). Surveillance, Epidemiology, and End Results: Incidence and Mortality Data. Washington, DC: US Government Printing Office, 1981:66. 126. Colorectal Cancer Collaborative Group. Surgery for colorectal cancer in the elderly patients: a systematic review. Lancet 2000; 356:968–74. 127. Sargent D, Goldberg R, MacDonald J et al. Adjuvant chemotherapy for colon cancer is beneficial without significant increased toxicity in elderly patients: results from a 3351 pt metaanalysis. Proc Am Soc Clin Oncol 2000; 19:241a (Abst 933). 128. Bergsland EK. Study suggests little difference in resposne to adjuvant colorectal cancer therapy among those younger and older than 70 years: But is therapeutic method the key? Abst Hematol Oncol 2000; 3:3–4. 129. Giacchetti S, Perpoint B, Zidani R et al. Phase III multicenter randomized trial of oxaliplatin added to chrono-modulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 2000; 18:136–47. 130. de Gramont A, Figer A, Seymour M et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18:2938–47. 131. Saltz LB, Cox JV, Blanke C. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2000; 343: 905–14. 132. Mayer RJ. Moving beyond fluorouracil for colorectal cancer. N Engl J Med 2000; 343:963–4.

PART 5 Cancer prevention in the aged

27 Nutrition, cancer, and the aging process: A rationale for nutritional practice guidelines Nagi Kumar, Jeanne Hudson, Theresa Crocker, Diane Riccardi, Kathy Allen Introduction This chapter reviews the multifactorial etiology of malnutrition in the elderly cancer patient population as a consequence of the neoplastic disease and the effects of its treatment and as a consequence of aging. Although elsewhere in this volume other authors discuss these nutritional issues with specific reference to cancer treatment, tumor effects, and nutritional effects related to the site of malignancy, our goal here is to review the specific nutritional consequences of disease, treatment, and aging combined and to develop an ideal model for nutritional practice guidelines, including screening, assessment, nutritional intervention, reassessment, and follow-up criteria in the senior adult oncology patient. In the year 2000, there were an estimated 35 million people aged 65 or older in the USA, accounting for almost 13% of the total population. The number of older Americans has increased more than tenfold since 1900; in 2011, the ‘baby boom’ generation will begin to turn 65, and by 2030, it is projected that one in five people will be aged 65 or older. The size of the older population is projected to double over the next 30 years, growing to 70 million by 2030. Dramatic growth is also projected in the numbers of Americans aged 85 and older, from 4.3 million (1.6%) in 2000, to 19.4 million (4.8%) in 2050—placing a significantly greater number of people at risk for disease and disability.1 Mortality from cancer Among the diseases affecting the elderly, one that contributes a significant economic burden to the nation is cancer. About 77% of all cancers are diagnosed at age 55 or older. The estimated probability of developing invasive cancer over age 60 is 1 in 3 for men and 1 in 5 for women.2 It has been well documented that the second leading cause of death among the elderly is cancer, with individuals aged 65 and over accounting for 70% of cancer mortality in the USA. In addition, research has shown a consistent relationship between adverse nutritional effects of cancer in the elderly, which are compounded by effects of treatment regimens, and psychological effects, resulting in a profound loss of nutritional stores leading to malnutrition and affecting the outcome of malignant disease.

Comprehensive Geriatric Oncology

572

Prevalence and significance of malnutrition in the senior adult oncology patient Malnutrition can be defined as a nutritional deficit or altered nutritional status associated with an increased risk of adverse clinical events, such as morbidity and death.3 Nearly one out of three senior Americans may be at high risk for malnutrition, which amounts to almost 10 million Americans today.4 The prevalence of malnutrition in the free-living elderly is relatively low (5–10%) compared with hospitalized or institutionalized elderly,5 where it is estimated that 30–65% are malnourished. Malnutrition is an important predictor of morbidity and morality—even more so in the elderly than in younger adults5– 7 —which verifies previous reports that elderly patients with unintentional weight loss are at the highest risk for infection, depression, and death. Unplanned weight loss is also identified as a clinically significant independent predictor of morbidity and mortality in all cancer patients with malnutrition, consistently observed in over 50% of cancer patients at the time of diagnosis. Although it would be impossible to isolate the impact of malnutrition alone on poor disease outcome in an elderly cancer patient, it is reasonable to infer that a poor nutritional state is a comorbidity, and malnourished patients will respond to nutritional support. In addition, research indicates that the elderly in particular are at risk for marginal deficiency of vitamins and trace minerals.8 Chronic conditions may increase requirements of certain nutrients as a result of changes in absorptive and metabolic capacity. Research has demonstrated that failure to correct malnutrition delays recovery and prolongs hospital stay.9 It has also been shown that advanced malnutrition is much more difficult to treat in the elderly than in younger adults.10 Timing of nutritional screening and assessment and appropriateness and timeliness of nutritional support thus become critical. Nutritional challenges in neoplastic disease The growth of the population aged 65 and older has affected every aspect of our society, presenting challenges as well as opportunities to healthcare providers. With a booming growth in the elderly population, there is an urgency not to only identify and characterize the special healthcare needs of this population, but also to develop more effective nutritional management strategies to prevent or delay the onset of disease and disability among older persons and improve their quality of life. Contrary to previous beliefs, aging itself does not lead to malnutrition in the elderly. This is more so in the senior adult oncology patient. The etiology of malnutrition in the specific group of the elderly is multifactorial, and may be a consequence of the nutritional impact of neoplastic disease and treatment, as well as a result of the physiological and psychosocial changes that may occur throughout the aging process. These may include social problems such as depression, social deprivation, and loneliness, among many others.6 Cancer and cancer therapies contribute to several adverse changes in the nutritional status of the elderly. A clear understanding of the etiology of malnutrition in this population can provide the basis for assessing, planning, and implementing effective nutritional support, when indicated.

A rationale for nutritional practice guidelines

573

Etiology of malnutrition in cancer patients Tumor effects Several nutritional problems in the individual with cancer stem from tumor effects. Localized effects of various tumors may affect nutritional status. Tumors in the gastrointestinal tract, such as esophageal, gastric, and colon carcinomas, causing partial or complete obstruction in one or more sites,11 are more common in the adult oncology patient population, and contribute to malnutrition. Malabsorption due to impaired mucosal function has been observed, not only in gastrointestinal tumors, but also in generally malnourished patients.11 Enlarged tumors of the gastrointestinal tract, in addition to obstruction, can also cause delayed transit, impaired digestion, malabsorption, nausea, and vomiting. Central nervous system tumors that cause somnolence may affect attention, leading to decreased intake. Ovarian cancer, gastrointestinal tumors, and liver metastases may lead to ascites, which can cause early satiety and progressive proteincalorie malnutrition. In addition, metabolic alteration of carbohydrate, protein, and lipid metabolism may occur.12 Tumor cells have an increased requirement for glucose as an energy source, in addition to energy-inefficient cycling by deriving significant energy from metabolism of glucose to lactate (the Cori cycle) rather than from more complete oxidation of carbon dioxide and water.12,13 Altered protein metabolism has also been observed as a result of tumors, which may be a consequence of increased uptake of amino acids by tumor cells relative to normal cells, decreased protein synthesis, increased protein degradation, and protein losses through fistulae and gastrointestinal losses. A decrease in fat metabolism has been observed, in addition to fats being used for energy when carbohydrates are exhausted by increased expenditure.4–16 In addition, cancer cells produce peptides, oligonucleotides, and other metabolites that may be responsible for the genesis of anorexia and cachexia.12 Tumors also produce hormones, similar to those seen in paraneoplastic syndromes, which can alter the intake of nutrients, absorption, and metabolism.17 Effects of cancer therapies Surgery, chemotherapy, radiation therapy, and immunotherapy of cancer, and their sideeffects, may contribute significantly to progressive malnutrition. Many chemotherapeutic agents, in particular, act by influencing and killing rapidly proliferating tumor cells; however, they may also affect those normal cells that also happen to divide rapidly, and thus cause damage to tissues composed of such cells. Changes in taste and smell Ingability to taste (aguesia) and decreased taste acuity (hypoguesia)18 are common sideeffects of radiation to the head and neck and of certain types of chemotherapy or medication. Changes in smell and taste perception are associated with disease, with some antineoplastic agents, and with chemotherapy and/or radiation therapy to the neck and mouth area. Chemotherapy-induced learned taste aversions have been reported in both adults and children. Patients may also experience a heightened sense of smell that results

Comprehensive Geriatric Oncology

574

in sensitivity to food preparation odors. Part of the taste change may be due to changes in smell perceptions as well as in taste perceptions. Smell receptor cells and taste bud cells are rapidly proliferating cells, and are therefore prone to be affected by cancer chemotherapeutic agents. Loss of these cells leads to overall loss of taste sensitivity (K Bartoshuk, Yale University, personal communication). Cancer cachexia Anorexia or lack of appetite resulting in an involuntary decline in food intake is the most common problem for individuals with cancer, contributing to malnutrition and progressive inanition in malignancy.19 Patients with cancer often develop anorexia due to cancer cachexia. Although the cause is not completely understood, it is thought to result from overproduction of pro-inflammatory mediators called cytokines. Tumor necrosis factor (TNF), interleukin-6 (IL-6), and interferon-γ (IFN-γ) are believed to be among the more important mediators of the cachexia response.20–23 Some tumor-derived factors cause lipolysis and protein catabolism. Shibata et al24 have demonstrated that the production of IL-12 decreased significantly with advancing disease and was lowest in patients with distant metastases. Cytokines produced by the host in response to the presence of a tumor cause metabolic abnormalities, which result in decreased protein and lipid synthesis, increased lipolysis, and anorexia.25 Studies using rodent models of muscle wasting have indicated that accelerated protein degradation by the proteasome is the principal cause of muscle atrophy induced by cancer cachexia.26 The downstream involvement of a specific ATP-ubiquitin-proteasome proteolytic system of skeletal muscle may potentially provide sites for pharmacological interventions.27 The presence of these mediators can result in anorexia, hypermetabolism, and alterations in normal metabolic pathways. In simple starvation, the body readily adapts to calorie deficit by shifting to fatty acids as the major source of energy, thereby preserving lean body mass. In cancer cachexia, the body fails to make this adaptation. This results in malnutrition, disproportionate wasting of lean body mass, and loss of strength and functional status, leading to negative outcomes in the cancer patient.20–23,28 Human cancers in which muscle catabolism is present may require specific interventions. It has also been shown that advanced malnutrition is much more difficult to treat in the elderly than in younger adults,10 and the consequences of failure to correct malnutrition delay recovery and have a significant impact on functional dependence and quality of life. Multiple catabolic profiles exist in animal models of cancer-associated muscle wasting, as observed in cancer cachexia. Current research has identified low levels of contractile activity, nutritional status, and disease-associated mediators as contributors to different degrees of this atrophy.29 Lung cancer and antiandrogen therapies are associated with decreased testosterone levels, and may contribute to decreased lean body mass.29 Physical activity is the key contributor to the maintenance of skeletal muscle mass. Resistance exercise attenuates muscle wasting associated with a variety of catabolic conditions, possibly including cancer cachexia. Cancer-induced muscle wasting may occur even despite normal food intake.30 In addition, a decline in lean body mass and an increase in adipose tissue associated with the aging process and not due to any specific disease have been noted in both men and women from the age of 40.31 After the age of 70, a decline in lean body mass as well as body fat has been associated with a decline in

A rationale for nutritional practice guidelines

575

body mass. Aging is inversely associated with total appendicular skeletal muscle mass in older men (aged 50–85), and this effect persists after standing height, physical activity, and dietary protein intake per kilogram of body weight have been taken into account.29 Similar changes have been observed in women. There also seems to be a redistribution of body fat from the lower body to the central and intraabdominal region.72 This redistribution has been associated with increased risk of diabetes, hypertension, breast and endometrial cancers, and coronary artery disease, and more recently with poor prognosis of breast cancer.33 Research has continued to show that several diseases associated with aging can be positively affected by an active lifestyle. Musculoskeletal, endocrine, and cardiopulmonary changes that occur with aging and chronic illness show a decline in progression with regular physical activity. Exercise training has been shown to benefit in improving gait velocity, range of motion, and endurance, and consequently functional capacity, in the elderly. More recent studies have demonstrated the significant benefits to the musculoskeletal system with resistance training, improving functional and overall activity level in the elderly.30,34,35 Mucositis Mucositis, or inflammation of the mouth lining, ranging from dryness to ulcers, is observed in patients receiving radiation to the head and neck. Mucositis is usually due to the necrotic and inflammatory effect of radiation on oral mucosa. In chemotherapy, the mucositis is usually due to the chemotherapy itself and its effect on highly proliferating cells, and may be in association with a low white blood cell count.36 Dry mouth (xerostomia) Xerostomia is a condition where saliva production is decreased, and saliva becomes thicker, resulting in a dry mouth. This can interfere with chewing, swallowing, speech, and oral hygiene. It is an uncomfortable sensation, and a major complaint that often persists for prolonged periods, although it varies from patient to patient. Xerostomia during cancer treatment can be caused by radiation therapy to the head and neck area affecting the salivary glands. Exposure of the major salivary glands to the field of ionizing radiation induces fibrosis, fatty degeneration, glandular (acinar) atrophy, and cellular necrosis within glands, causing xerostomia. The higher the dose of radiation, the worse is the prognosis for xerostomia. Nausea and vomiting Nausea is an unpleasant sensation—a feeling of queasiness, often culminating in vomiting. Anticipatory nausea is the psychological pattern in which stimuli other than chemotherapy or radiation can trigger symptoms of nausea/vomiting. There are a number of antinausea medications available, which have led to good control of nausea and vomiting. Nausea is a frequent side-effect of cancer therapy, such as chemotherapy and radiation. It can also be due to the tumor itself or can be brought on by obstruction of the intestine or irritation of the gastrointestinal tract. Vomiting may follow nausea, and can be brought on by treatment or food odors. Anticipatory nausea is quite a common

Comprehensive Geriatric Oncology

576

occurrence, with patients experiencing some nausea/vomiting due to their anxiety about the cancer and its treatment. Pain Pain is a well-documented symptom in cancer patients. It is critical to evaluate pain according to its intensity, quality, and frequency. Intense pain can decrease appetite, contributing to poor nutritional status. Thus, pain management becomes critical in the cancer patient. Constipation Constipation in cancer patients may be medicationinduced (by chemotherapy or pain medication), due to metabolic abnormalities such as hypothyroidism or hypercalcemia, or due to lack of exercise or a diet low in fiber. Constipation can also occur in diseases of the upper gastrointestinal tract or the large bowel that result in decreased peristalsis or in outlet obstruction.33,38 Diarrhea Diarrhea is observed in cancer patients as a consequence of both the disease and its treatment. Osmotic diarrhea is caused by the presence of osmotically active solutes that are poorly absorbed in the intestinal tract, including those accompanying dumping syndrome and in lactase deficiency. Secretory diarrhea may be caused by some chemotherapeutic drugs, exotoxins, viruses, or increased intestinal hormone secretion. Exudative diarrhea is always associated with mucosal damage, and may occur with radiation enteritis. Limited mucosal contact diarrhea results from inadequate mixing of chyme and exposure to the intestinal epithelium, and occurs following extensive bowel resection.39,40 Dysphagia Dysphagia is a condition resulting in a disturbance in the normal transfer of food from the oral cavity to the stomach.41 Symptoms include difficulty in swallowing resulting from abnormalities in any one of the normal phases of swallowing: the oral phase (voluntary), the pharyngeal phase (beginning of swallowing reflex), or the esophageal phase, which may result in aspiration. Dysphagia or difficulty in swallowing may be a result of surgery to the mouth and throat, radiation therapy, or generalized weakness. The severity of swallowing problems may vary depending on the type of surgery and whether the patient has undergone radiation treatment. There may be only temporary discomfort due to pain and swelling or more severe problems requiring supplementation by tube feeding until the ability to swallow is restored. Early satiety or a feeling of fullness after eating a small amount of food can occur after surgery, chemotherapy, and radiation, resulting from consumption of small amounts of food for a long period of time, causing inadequate intake of calories, protein, and other nutrients.

A rationale for nutritional practice guidelines

577

Nutritional challenges in the elderly as a biological consequence of aging A variety of physiological, psychological, behavioral, and socioeconomic changes impact the intake and nutritional status of the elderly. Loss of lean body mass As discussed above in the section on cancer cachexia, there is a decline in lean body mass and an increase in adipose tissue with aging in both men and women,31 and a decrease in total appendicular skeletal muscle mass.29 Together with these changes, there appears to be a redistribution of body fat from the lower body to the central and intraabdominal region,32 which has been associated with an increased risk of certain diseases (both malignant and non-malignant—see above). Gastrointestinal tract function In the absence of disease, little change in gastrointestinal function occurs because of aging, and the function of the gastrointestinal tract is relatively well preserved.42 Some problems such as reduced salivary flow and feeling of dryness have been associated with alterations in taste as well as difficulty with chewing and swallowing.43 The stomach does undergo some changes with advancing age. Most notable is the development of hypochlorhydria associated with atrophy of the stomach. The prevalence of atrophic gastritis varies depending on the population, and generally occurs with an autoimmune condition, such as pernicious anemia. Decreased intrinsic factor will result in vitamin B12 malabsorption and deficiency if not identified and treated. Lack of gastric acid production may result in bacterial overgrowth syndrome with symptoms such as abdominal discomfort, nausea, diarrhea, and weight loss.42 Although rare, malabsorption may occur if gastric acid production is decreased or lost. Optimal absorption of nutrients with pHdependant uptake mechanisms may also be affected. Gastric motility may be affected with aging. This usually results in a slowing of the liquid emptying of the stomach, although solid emptying seems to be preserved. Small-intestinal transit seems to be intact, although small-intestinal overgrowth is a common cause of malabsorption in this population. This influences the absorption of some micronutrients, including iron, folate, calcium, and vitamins B12 and K.42 Physiological changes Aging is associated with physiological changes that affect energy balance, including a decreased basal metabolic rate. A decrease in neuropeptide Y and a decreased responsiveness to opioid-induced feeding drive may affect appetite. In undernourished elderly individuals, an increased secretion of postprandial cholecystokinin may result in early or decreased satiety.44

Comprehensive Geriatric Oncology

578

Sensory losses Sensory perception-related losses may contribute to age-related malnutrition by affecting food selection and consumption.45 It has been demonstrated that sensory perception can modulate nutritional status—specifically during the transition from fasting to refeeding. Gradual loss of taste and smell perception seems to be part of the aging process. There have been some reports that taste perception is less affected than smell perception.43 Individuals may begin to experience chemosensory changes by the age of 60, with more significant losses after the age of 70. It is estimated that half of the elderly population experience olfactory dysfunction. Chemosensory loss may include ageusia, hypogeusia, dysgeusia, anosmia, hyposmia, and dysmosia. Losses not only result from anatomic changes occurring with normal aging but also due to certain diseases, pharmacological interventions, and various treatments,44 such as surgery, chemotherapy, and radiation therapy. These sensory losses can affect nutritional status, since poor appetite has been associated with a loss of sensory perception.46 Decreases in the sense of smell and taste may lead to decreased intake, resulting in inadequate nutrition as well as reduced quality of life. This group may be at higher risk of developing a poor nutritional status— especially troublesome is the group who are already sick.44 Dentition has also been suggested to influence taste perception, so older adults with inadequate dentition may experience further problems.43 Neurological function Nutritional deficiencies in older adults have been found to be associated with cognitive deficits. Dementia has been commonly associated with weight loss, and it has been suggested that greater alterations in taste and smell are experienced by persons with dementia. Energy utilization may be increased by pacing or wandering, although most weight loss has been associated with a failure to eat in this population.32 Failure of the ability to smell seems to be particularly acute in those with Alzheimer’s disease, and this group may also experience decreased appetite.44 This may further compound other problems previously discussed. Immunocompetence Aging has been associated with an increased susceptibility to nutritional deficiencies and a progressive reduction in immune competence, with both humoral and cellular components being affected.47 A decrease in immune response, a high rate of formation of free radicals, and a decreased antioxidant capacity have been associated with aging. A decrease in immune response as well as increased lipid peroxidation are associated with cardiovascular disease, cancer, and an increased incidence of infection.48 The function of the immune system is influenced by nutritional status, and the adverse effect of severe malnutrition on cell-mediated immunity is well recognized. A number of essential micronutrients play a significant role in metabolic pathways and cell functions related to immunocompetance, and so deficiencies due to inadequate intake or malabsorption may further complicate matters.47

A rationale for nutritional practice guidelines

579

Prolonged chronic illness There is a strong association between nutrition and many degenerative diseases common in the elderly.31 Diseases may alter appetite or result in malabsorption or increased metabolism.32 The side-effects of drugs necessary for the treatment of chronic conditions have also been shown to be a major contributor to weight loss in the elderly. Weight loss results from decreased appetite, malabsorption, increased metabolism, or the combined effect of anorexia and increased metabolism. Therapeutic diets for chronic disease management have also been associated with the development of protein-energy malnutrition in older persons.32 Pressure ulcers Several factors related to host and environment contribute to pressure ulcer formation. A number of host (i.e. patient) factors are critical to pressure ulcer formation: old age; nutritional compromise; impaired circulation; chronic disease (including diarrhea); surgery; dependence on artificial ventilation; and amputation with limited or no ambulation. Environmental factors are also important: moisture; incontinence; and the bed-ridden patient who is not evaluated for risk of pressure ulcers, who is not turned on a scheduled frequency, or who does not receive pressure-free devices (air mattress, heel pads, etc.) to prevent bedsore formation. Currently, there are no clinical trials to provide evidence pointing towards the course of pressure ulcer initiation and progression in the elderly contributed by a single factor, such as malnutrition. Prospective and crosssectional studies have demonstrated some association between the development of pressure ulcers and malnutrition, specifically low albumin levels.49 Patients with serious pressure ulcers generally have low prealbumin and albumin levels. It has been reported that impaired wound healing occurs at an early stage of protein depletion and that maintenance of normal food intake is important for healing, although most patients with pressure ulcers have an inadequate intake.50 Although timely adequate nutritional supplementation, in addition to alleviating host and environmental factors, is logically appropriate for a better chance at preventing pressure sores, clinical trials have yet to prove that nutritional support alone is sufficient. Specifically in the elderly patient, if underlying host factors such as malignancy and other comorbidities are irreversible, then aggressive treatments, including nutritional intervention using enteral or parenteral routes, may carry more risks than benefits. Psychological Depression is often undetected in older adults, especially those with chronic illness or conditions, and can affect self-care and compliance with treatments, including medication and food intake.51 Depression may be a primary diagnosis or a complication of a physical illness, and has been found to be a major cause of weight loss in older persons in both community and institutional settings. Fortunately, depression is also one of the most treatable causes of anorexia and weight loss.32 Substance abuse is another factor that may affect nutritional status if undetected and therefore untreated.

Comprehensive Geriatric Oncology

580

Physical limitations Limitations in the activities of daily living have been identified as a cause of weight loss in older adults. Two percent of those aged 65–84 require assistance with feeding, and after the age of 85 this increases to 7%.32 A loss of postural and locomotive muscle mass has been observed within 7 days of bed rest, continuing for at least 35 days with no apparent tendency to plateau, suggesting that there is no long-term mechanism to control muscle mass.29 Chronic diseases or their treatment may also affect the physical ability to chew and swallow foods. Poor dentition related to gum disease or to missing or poorly fitting dentures can also be a problem.52 In addition, since chronic diseases pose difficulties for the elderly in carrying out activities of daily living, this may increase the requirements for certain nutrients owing to changes in absorptive and metabolic capacity.8 Free radicals and oxidative stress have been identified as critical factors in the biology of aging and many of the age-related degenerative diseases. Living situation/social support Many factors contribute to the increased vulnerability to malnutrition experienced by the elderly. Individuals who live alone have been shown to be at risk of having a poor food intake.31 Social deprivation or isolation also increases risk, and has been associated with weight loss.52 Social networks play a role in the maintenance of adequate food intake, and socialization results in increased food intake during a meal.53 Lack of adequate finances and lack of knowledge about nutrition have also been identified as risk factors for malnutrition in this population.31 Guidelines for nutritional support of the senior adult oncology patient Identifying the individual effects of acute illness and malnutrition on elderly patient outcome and the timing and appropriateness of nutritional support of this population continue to challenge health professionals. Determining the exact degree of malnutrition in this population has consistently been difficult because it depends on the sensitivity and specificity of the parameters used for nutritional assessment and because of the lack of universal agreement on the validity of these parameters11—more specifically in this population. It may thus be ideal to evaluate a combination of several parameters, individually demonstrated to be important contributors to malnutrition, affecting disease outcome in the adult oncology patient. Nutritional assessment is the interpretation of information obtained from dietary, biochemical, anthropometric, and clinical evaluation. The aim of nutritional assessment is (i) to define the type and severity of malnutrition and (ii) to plan, implement, and monitor nutritional support. First, the emphasis is on nutritional screening to estimate nutritional status. After the potentially high-risk group is identified, the goal must be to address risks to nutritional status more definitively. Next, it is critical to prevent or treat problems that have been identified. Without reassessment or follow-up, it is useless to screen and assess the patient.54 In addition, a vital component of nutritional support includes patient and family education.

A rationale for nutritional practice guidelines

581

The first step in nutritional assessment is the initial nutritional screening. Nutritional screening can identify patients at risk for malnutrition in order to implement preemptive, preventive, and early interventional care in the hope of avoiding the morbidity, mortality, and quality of life effects of malnutrition.55 The goal of nutritional screening is to discover characteristics or risk factors known to be associated with dietary nutritional problems and to identify individuals who are potentially at risk for malnutrition, so that this can be dealt with early and so that treatment plans can be modified if necessary. Screening tools are used to screen and triage those individuals or populations at greatest nutritional risk. Such tools may be simple or complex.56 Several screening forms are available, but some are dependent upon specific biomarkers that may not be routinely tested (e.g. body mass index, weight, anthropometric measurements, diet history, fluid intake, medication review, and finances). Currently the most commonly used screening forms include the Nutrition Screening Initiative, the Subjective Global Assessment, and the Mini Nutritional Assessment. Although several screening forms exist, including the Initial Nutritional Screening Form (Appendix 27.1) used at the H Lee Moffitt Cancer Center, Tampa, Florida, the basic aim of all of these instruments is to obtain objective data, both biological and social, that influence nutritional status. Nutritional assessment itself is the next step, and is a comprehensive process of identifying individual and populations at nutritional risk and of planning, implementing, and evaluating a course of action. It may include identification of current nutritional status and nutritional requirements. It may include systematic collection of data, classification of the degree of malnutrition, and institution of appropriate treatment and intervention techniques. The nutritional status of the patient is determined, clinically relevant malnutrition is defined, and changes in nutritional status during nutritional support are monitored.54,57 Several models of nutritional assessment criteria have been used and reported in the research literature. To increase the accuracy of diagnosis of malnutrition, several methods should be used, rather than a single criterion such as body weight or height. All assessment parameters include components of a Comprehensive Nutrition Assessment as described in Appendix 27.2, which include anthropometric, biochemical, functional, social, clinical, and dietary markers. A Nutrition Intervention Algorithm is given in Appendix 27.3. Nutritional assessment of the cancer patient Medical history Information regarding the patient’s past diagnoses, surgery, treatment, and physical manifestations of disease or nutrient deficit are essential to the assessment of nutritional status and the development of a plan for nutrition therapy. Evaluation of the patient’s functional status and barriers to obtaining adequate nutrients are also necessary. Information to be evaluated in the review of medical history should include the following: • diagnosis and stage of disease; • presence of complications such as infection or sepsis;

Comprehensive Geriatric Oncology

582

• time since diagnosis and start of treatment; • present and past antineoplastic therapy; • prior surgery, especially gastrointestinal; • current medication; • concurrent medical problems, such as diabetes and inflammatory bowel disease; • usual and current diet; • toxicities from treatment, including mucositis, nausea, vomiting, diarrhea, steatorrhea, constipation, and recent unintentional weight loss; • potential drug-nutrient interactions. Social history Social risk factors can also be identified at this time, including smoking history, alcohol or drug use, socioeconomic status, and social support system. Information on religious, cultural, and lifestyle influences that impact nutritional intake is essential. Functional markers Physical examination should include evaluation of functional status such as the ability to chew and swallow, dental or oral problems causing odynophagia or dysphagia, signs of muscle wasting or anasarca, presence of edema, presence of skin or mouth lesions, and ability to perform instrumental activities of daily living (IADL) such as cooking, shopping, and self-feeding. It is critical to assess activities of daily living (ADL), physical activity, exercise, sleep, and ability to work and perform other functional roles. These markers can assessed using standard validated instruments such as the Eastern Cooperative Oncology Group (ECOG) or Karnofsky functional scales. Dietary markers Nutrition history A vital component in the assessment of a patient’s nutritional status is a detailed diet history and the collection of information regarding the patient's eating behavior. This is extremely important in order to identify factors that may result in diminished nutrient intake. The following information should be obtained: • habitual diet and any change in diet pattern; • frequency of meals or snacks; • quantity of food at meals; • self-imposed food restrictions; • ability to chew or swallow; • specific intolerance of texture or type of food; • presence of mechanical obstruction; • poor dentition or pain with swallowing; • recent or prolonged food or smell aversions; • taste changes;

A rationale for nutritional practice guidelines

583

• early satiety; • nausea; • vomiting; • appetite loss; • food allergies or intolerance; • use of complementary nutritional therapies; • vitamin/mineral use. Questions should be open-ended to allow for accurate recall of diet history. The patient should also be asked about cultural, religious, or ethnic differences, which may impact on eating habits or food choices. Information regarding level of physical activity is also important in determining nutrient requirements. After a diet history has been obtained, current nutrient intake should be compared with predicted requirements to determine the adequacy of intake and any need for intervention. Clinical markers Anthropometrics Standard nutritional assessment methods that are commonly used for hospitalized patients can be used for cancer patients as well; however, it is important to realize how cancer therapy or the disease itself (in addition to physiological changes that are specific to aging) can

Table 27.1 Unintentional weight loss as percentage of usual body weight (UBW) • 1% loss of UBW in 1 week • 5% loss of UBW in 1 month • 7.5% loss of UBW in 3 months • 10% loss of UBW in 6 months • >15% loss of UBW = severe depletion

greatly affect the validity and interpretation of these parameters. Anthropometry is the measurement of the physical dimensions and composition of the body, such as height, weight, body density, percentage of body fat, and fat-free mass.58 Body weight and weight history are essential components of the initial nutritional assessment due to the significant impact of weight loss and underweight on morbidity and mortality. Current weight is only useful as an indicator of nutritional risk or depletion if it is evaluated in comparison with the patient’s usual weight:

Comprehensive Geriatric Oncology

584

Weight loss must also be assessed in relation to its duration and whether it is unintentional or intended weight loss. Unintentional weight loss can be expressed as a percentage of usual body weight (Table 27.1). Current weight that is 20% below ideal body weight is also an indication of nutritional risk.54 In most cases, measurement of body weight and information regarding recent weight loss are important indicators of the presence of malnutrition upon initial screening and assessment; however, weight loss has serious limitations as an outcome measure or monitoring tool. The weight of cancer patients is frequently influenced by hydration status or the presence of edema and ascites. Total weight gain or loss does not provide information regarding the composition of the weight change and does not identify protein malnutrition. For these reasons, weight and weight change must be assessed in combination with other parameters. The most widely accepted method of estimating body composition changes is the use of standardized equipment, and procedures for measuring triceps skin fold and midarm muscle circumference. These values are then compared with a table of standard measurements based on a reference group of healthy subjects. There is still controversy regarding the validity of these measurements as part of the initial baseline assessment due to influences of inactivity and the disease process on muscle mass and difficulty in obtaining accurate results in the presence of edema or obesity.59 However, there is general agreement that these measurements can be useful for serial evaluation during a long course of therapy to identify large changes in body fat and lean body mass. Assessment of protein status is critical in the identification and treatment of proteincalorie malnutrition. Measurements of body composition combined with physical assessment for signs of obvious muscle wasting may help to identify significant losses in somatic protein stores; however, a more objec- tive and sensitive measure of protein nutriture is the biochemical assessment of visceral protein stores. Biochemical parameters Traditional biochemical indices of visceral protein status include serum albumin, transferrin, prealbumin, retinolbinding protein, total lymphocyte count, and delayed cutaneous hypersensitivity. The appropriate laboratory tests should be selected based on their half-life or sensitivity to change, their availability within the facility, and the degree to which they are influenced by the disease process or treatment. Albumin Serum albumin is the most commonly used and readily available biochemical parameter used to assess protein status; however, it may not be a reliable indicator in the cancer population. Its relatively long half-life (14–20 days) makes it slow to respond to dietary interventions, and its concentration is influenced by hydration status. In addition, its rate

A rationale for nutritional practice guidelines

585

of synthesis can be altered by liver involvement and renal dysfunction. Sepsis and surgery have also been shown to decrease albumin levels, regard- less of overall nutritional status. Transferrin Serum transferrin is also synthesized in the liver, and therefore is influenced by liver dysfunction, metastases, or the toxic effects of chemotherapy; however, owing to its shorter half-life (8–9 days), it is more sensitive to short-term changes in nutrient intake. The limitation of using transferrin as an indicator of nutritional status in cancer patients is that serum levels will decrease in chronic infections, acute catabolic states, surgery, and with renal impairment.58 Prealbumin Prealbumin, also known as transthyretin and thyroxinebinding prealbumin, is also synthesized in the liver, but has a very short half-life (2–3 days), making it a much more sensitive indicator of protein status. However, as with albumin and transferrin, caution must be used when interpreting results, owing to its sensitivity to other metabolic abnormalities. Prealbumin levels may be reduced with hepatic dysfunction, acute catabolic stress, sepsis, surgery, trauma, or severe enteritis or ulcers, which may result from cancer treatment or progression of disease versus inadequate intake.58 Total lymphocyte count and delayed cutaneous hypersensitivity Abnormalities in immune function have been associated with malnutrition. Those most frequently used in hospitalized patients are measures of total lymphocyte count and delayed cutaneous hypersensitivity reaction.60 While this information may be useful in the initial evaluation of the newly diagnosed patient with a solid tumor, the application of these parameters during treatment is limited owing to the immunosuppressive effects of steroids and many chemotherapy agents. Also, some hematological malignancies are known to cause depression of bone marrow function, resulting in leukopenia. Behavioral markers Information on current nutritional intake, knowledge of therapy or plan of care, and compliance with nutritional recommendations are characteristics indicative of compliance behavior, and may be important to assess in the cancer patient. Determining nutrient requirements Energy Energy requirements generally decrease with age owing to a decline in the basal metabolic rate and physical activity. The basal metabolic rate (BMR) or basal energy

Comprehensive Geriatric Oncology

586

expenditure (BEE) represents the actual measure of energy expenditure in the resting and fasting state. In healthy adults, this accounts for 65–75% of total energy expenditure. It is well accepted that many malignancies exert a metabolic effect on the host; however, the difficulty lies in predicting the degree to which the metabolic rate is affected, owing to the great variability in individual response as well as the type of cancer and combination of therapies. Studies have measured the BEE in a variety of cancer patients. Cancer patients with pancreatic tumors, liver carcinomas, and other solid tumors have been observed to be hypermetabolic;60–62 however, other studies have not demonstrated a similar pattern in cancers of the lung and colon, esophageal cancers, and metastatic liver cancer.63–65 Although others have demonstrated no differences in BMR between cancer patients and controls, the decrease

Table 27.2 Calculating energy requirements65 BEE needs: For females: 65.5(9.6 x wt in kg)+(1.7×ht in cm)−(4.7×age) For males 66.5(13.7×wt in kg)+(5×ht in cm)−(6.8×age) For weight maintenance needs: BEE×1.15 For weight anabolism needs: BEE×1.5 For protein needs: Divide BEE by 2.2×IBW in kg For protein maintenance: Multiply BEE by 1.4×IBW in kg For protein anabolism: Multiply BEE by 1.5×IBW in kg Percentage of usual body weight: Divide actual wt by usual wt and multiply by 100% BMI=weight (Ib) divided by height (inches) squared, multiplied by 705 Consult BMI classification table BEE, basal energy expenditure; IBW, ideal body weight; BMI, body mass index.

in energy expenditure that is normally seen in starvation and weight loss in healthy men and women could not be demonstrated in weight-losing gastric or colorectal cancer patients.65 The best and most accurate way to determine calorie expenditure is by measuring metabolic rate via direct or indirect calorimetry under a variety of conditions. However, these methods are limited by the expense and availability of the necessary equipment and the added inconvenience in performing additional diagnostic testing on the already stressed and anxious patient. Another simpler method for calculating expected metabolic rate is with a formula developed by Harris and Benedict66 (Table 27.2). This equation used in combination with accepted activity and stress factors is widely used for calculating BEE in hospitalized patients. This method takes into account the patient’s gender, height, weight, and age—factors that are known to influence metabolic rate. The accuracy of this equation has been verified in validation studies comparing actual measurements and predicted values of healthy individuals, with a mean difference of only 4%.67 The calculations of predicted total energy expenditure (TEE) are derived using the Harris—Benedict equation multiplied by an activity factor or a stress factor (Table 27.3).

A rationale for nutritional practice guidelines

587

These factors are based on data collected by Long et al,68 measuring the metabolic response to injury and illness. In order to estimate energy requirements, it is critical to obtain information regarding the patient’s nutritional status and treatment, together with any additional metabolic stresses as identified in the nutritional assessment. To determine calorie needs in the absence of

Table 27.3 Activity and stress factors for calculating total energy expenditurea Activity factors Bedrest

1.2

Low activity

1.3

Moderate activity

1.5–1.75

Highly active

2.0

Injury factors Minor surgery

1.1

Major surgery

1.3

Mild infection

1.2

Moderate infection

1.2–1.4

Sepsis

1.4–1.8

Skeletal trauma

1.2–1.4

Skeletal or head trauma (treated with steroids)

1.6–1.8

a

Frorn: Long CL The energy and protein requirements of the critically ill patient. In: Nutritional Assessment (Wright RA, Heysmsfield SB, eds). Boston: Blackwell Science, 1984.

surgery or infection, as is often the case with cancer patients, a factor of 1.15×BEE can be used for weight maintenance or 1.5×BEE for repletion and anabolism3 Because these calculations are estimates and are not based on actual measurement of calorie expenditure, the best indicator of adequacy is the patient’s response to the nutrition regimen. Monitoring of patient’s progress and adjustments of calorie goals as needed are essential parts of the nutrition care plan. Protein Injury and illness are known to produce marked losses of protein, as indicated by increases in urinary nitrogen excretion.67 Acceleration of protein turnover and derangements in protein metabolism have also been seen in cancer patients.11 In contrast to simple starvation, where the body attempts to spare protein, the opposite is true under conditions of metabolic stress, such as the cancer process itself or when it is combined with antineoplastic therapy. The most accurate method of determining protein

Comprehensive Geriatric Oncology

588

requirements in a hypermetabolic patient is based on urinary nitrogen loss; however, this is impractical in most settings owing to the labor intensity involved in collecting 24-hour urine specimens and fecal specimens for total nitrogen output in addition to accurately calculating protein intake. The only setting in which this might be feasible is in critical care. According to the Food and Nutrition Board of the National Research Council, the protein requirement for healthy adults is 0.8 g/kg/day. Protein requirements are typically determined based on the patient’s ideal body weight (IBW), calculated using either the Metropolitan Height-Weight Tables or another frequently used method due to Hamwi:69 IBW (females)=100 Ib+5 Ib for each inch above 5 ft IBW (males)=106 Ib+6 Ib for each inch above 5 ft A desired weight range can then be created allowing for ±10% for frame size.58 The estimated protein requirement can then be determined based on the degree of protein depletion and the metabolic stress factors. For the well-nourished mildly stressed individual, the protein needs may only be 0.8–1.0 g/kg IBW; however, with mild to moderate depletion combined with metabolic stress, 1.5–2.0 g protein/kg IBW may be required to achieve positive nitrogen balance and protein repletion. Another method of estimating protein requirements is by calculating the ratio of nitrogen to non-protein calories. It is recommended to provide 1 g nitrogen (protein in grams divided by 6.25) per 120–150 non-protein calories for anabolism in the moderately to severely malnourished or stressed patient.67,70 As with estimating calorie requirements, the best indicator of whether protein needs are being met is with monitoring and reassessment for weight gain and nitrogen retention in the malnourished patient and weight maintenance and nitrogen equilibrium in the well-nourished patient.71 There are no recommended dietary allowances for lipids and carbohydrates. However, the recommendation to restrict fats to 30% of total calories is prudent in this population. In addition, lactose intolerance may be frequently observed in this population as a result of diminished lactase secretion. Dairy products with active culture or lactase-treated products must be recommended to prevent gastrointestinal symptoms and ensure adequate calcium intake. Although calorie needs diminish in this population, the need for vitamins and minerals is increased. It has been observed that the elderly consume less than two-thirds of the recommended daily amounts of several nutrients.72 Hydration Water accounts for over 50% of body weight in older individuals. This reflects a decline of over 10% due to progressive loss of lean body mass. Daily fluid replacement is essential, specifically in chronically or acutely ill elderly who are on diuretics, laxatives, or other therapeutic regimens for cancer treatment. In addition, dehydration is commonly observed in the elderly since they have reduced thirst sensation and diminished water conservation by the kidneys. Nutrition-related symptoms as a result of cancer treatment, such as diarrhea, inability to swallow liquids, and fever, may also increase requirements contributing to clinical dehydration. Recurrent urinary tract infections have been

A rationale for nutritional practice guidelines

589

documented in hospitalized elderly women. A minimum schedule of 30–35 ml fluid/kg of body weight or a minimum 1500 ml is recommended. Nutrition care plan After screening and comprehensive assessment of nutritional status and nutritional risk, appropriate intervention can be initiated. The nutrition care plan should be problemfocused, identifying specific nutrition-related symptoms or educational needs. Table 27.4 addresses common nutritional symptoms that are associated with cancer diagnosis and therapy and that may be interfering with proper alimentation, together with suggestions for intervention. The plan of care should also include appropriate follow-up to reassess the effectiveness of intervention and modify the plan as needed. Outcome measures or goals should be clearly defined and measurable. Expected outcome may be functional, behavioral, or clinical, depending on the type of intervention.53,73,74 Low nutritional risk For patients who have no nutritional symptoms and have been determined to be in good nutritional status upon initial assessment, general information regarding the importance of maintenance of nutritional status and specific education regarding how to obtain or maintain optimal nutrient intake may be provided. Potential nutritional risk Patients who have symptoms affecting their food intake but no clinical symptoms of malnutrition should receive specific education regarding recommended intervention, potential side-effects of treatment, and their management. These patients who are at nutritional risk despite the absence of clinical protein-calorie malnutrition will require careful monitoring and follow-up to identify any need for intervention for preservation of nutritional status. High nutritional risk or malnutrition Patients who at baseline are identified as being at high nutritional risk or are diagnosed with protein-calorie malnutrition should receive specific intervention and education with the goal of repletion, preferably prior to initiation of treatment, although often this is not practical in the acute care setting. For the patient at high nutritional risk, serial assessments should be performed, including re-evaluation of the patient’s tolerance of oral intake, anthropometric measures, biochemical parameters, and

Table 27.4 Nutritional symptoms and treatment Symptom Definition/description Etiology

Suggested nutritional intervention

Pharmacology

Comprehensive Geriatric Oncology

Dysguesia, Altered taste perception aguesia, (dysguesia); inability to dysosmia taste, decrease in taste acuity (aguesia); alteration in sense of smell (dysosmia)

Chemotherapeutic agents that affect rapidly dividing cells may also damage taste buds and smell receptors. Many patients also report a ‘bad’ taste or metallic taste associated with certain agents. Heightened sense of smell with associated food aversions has also frequently been reported with patients receiving chemotherapy. While dietary modifications and interventions should be individualized, common taste and smell alterations that tend to occur during many types of chemotherapy include aversion to sweets, meats, and strong odors

590

None • Patients should avoid being in the same room where the food is being prepared, to avoid strong odors • Plastic utensils may reduce metallic taste • Flavoring food with herbs, vinegar, lemon juice, mustard, catsup/ketchup, onions, garlic, or mint may increase intensity for those with decreased taste acuity • Foods eaten cold or at room temperature may be better tolerated for those with taste and smell sensitivity • Marinating meats may improve tolerance • Include other protein sources, such as poultry, peanut butter, eggs, nuts, and beans • Rinsing the mouth, drinking club soda, or brushing the tongue before meals may help to remove bad taste

A rationale for nutritional practice guidelines

Mucositis/ stomatitis

Soreness or inflammation of the mucous membrane of the mouth or throat. This can range from dryness to open ulcers

591

Radiation to the • Soft, bland foods • Diphenhydramine head and neck hydrochloride are usually better may cause elixir (alcoholtolerated. Choose necrosis and/or free) calorie/proteininflammation of dense foods such the oral mucosa. as custard, eggs, Certain casseroles, cream chemotherapeutic soups, agents may also milkshakes, and cause ice cream inflammation and ulceration due to • Chloroseptic spray the cytotoxic effect on rapidly • Dental salve dividing cells (Oral Balance or Orabase) • Highcalorie/highprotein liquid supplements may also be used (e.g. Ensure Plus, Boost Plus, Sustacal Plus, or Carnation Instant Breakfast Drink) mixed with whole milk • Viscous lidocaine • ‘Magic Mouthwash’ (2% lidocaine 2400 ml, Maalox oral supension 2400 ml, diphenhydramine hydrochloride powder 12 g) • Moisten foods with butter, gravy, oil, cream, or mildly seasoned sauces • Avoid tart acidic foods, such as tomato products, citrus, and pickled foods

Comprehensive Geriatric Oncology

592

• Avoid highly spiced foods if there are open sores • Avoid alcohol or alcoholcontaining medications • Adjust food temperature as tolerated. Cold or roomtemperature foods are generally better tolerated • Use a straw when possible to bypass sores around the lips and gums • Diligent oral Xerostomia Dry mouth or a condition Xerostomia in hygiene is where saliva production oncology patients imperative is is usually a result of radiation • Rinse mouth therapy to the frequently with mild saline solution decreased and saliva becomes thicker. This can interfere with chewing, swallowing, speech, and oral health

head and neck area. • Avoid commercial alcoholcontaining The salivary glands mouthwashes, may become tobacco, and inflamed, fibrotic, alcoholic beverages or atrophic. Cellular necrosis may also • Drink water or occur within the other liquid glands themselves. throughout the day This condition may for a total of 8-2 persist even after cups per day treatment has ceased • Increase use of foods and beverages containing citric acid (e.g. lemons, lemon juice, lemonade, grapefruit juice, or orange juice)

• Pilocarpine hydrochloride as solution or tablets

(Salagen) or cevimeline (Evoxac) may be helpful in stimulating saliva production

• Synthetic saliva substitutes (e.g. Salivert, Biotene, MouthKote, and Glandosane) may also be helpful

A rationale for nutritional practice guidelines

593

• Sucking on lemon drops, sugarless chewing gum, or tart candy may increase secretions • Soft wet, foods are better tolerated. Avoid rough, dry foods Early satiety

Feeling of fullness after eating a small amount of food

May have physical • Eat small frequent • Appetite stimulants meals and snacks etiology due to may be used (e.g. every few hours surgical resection of cannabinoids, part of the instead of 2 or 3 megestrol acetate, gastrointestinal large meals per day cyproheptadine) tract, tumor burden • Keep snacks impinging on visible, convenient, stomach capacity, or and handy ascites. May also be a side- • Meals and snacks effect of should have a high chemotherapy or nutrient density radiation therapy. (e.g. nuts, potato Patients often report chips/crisps, peanut early satiety in butter, whole milk association with loss products, cream of appetite or nausea soups versus brothtype soups, granola/muesli, and dried fruit) • Avoid carbonated beverages and highfiber/low-calorie foods • Limit intake of water or caloriefree beverages with meals, but save them for after or between meals and snacks

Nausea and Unpleasant vomiting sensation or feeling of queasiness, often resulting in vomiting.

Nausea alone or with vomiting is a frequent sideeffect of cancer therapy such as chemotherapy (or

• Take antiemetics as • Medications such directed to prevent as ondansetron, nausea or vomiting, granisetron, since it is easier to prochlorperazine, prevent than to try dexamethasone, to treat and lorazepam are

Comprehensive Geriatric Oncology

Anticipatory nausea is the psychological pattern in which a negative association is formed with an event such as chemotherapy, radiation, or a hospital visit in which nausea or vomiting has previously occured

occasionally radiation if it involves the gastrointestinal tract). These symptoms can also occur owing to the disease itself (e.g. brain tumors), obstruction of the alimentary tract, or medications such as narcotics or antibiotics. Nausea or vomiting may be triggered by food odors or anxiety related to treatment, as in the case of anticipatory vomiting.

594

• Eat small regular meals to avoid having an empty stomach • Avoid strongly flavored foods immediately after chemotherapy to prevent potential food aversions • Food choices should be individualized according to tolerance and preferences • Metoclopramide and dimenhydrinate are also used on occasion. • If odors trigger nausea, have someone else do the food preparation and stay out of the area until mealtime • Cold or roomtemperature foods may be better tolerated, since they tend to have less of an odor • Foods that are typically well tolerated: canned fruits or fruit juices, salty snacks (e.g. potato chips/crisps), bland starchy foods (e.g. mashed potatoes), macaroni and cheese, rice, cream of wheat cereal, grits, or oatmeal. Puddings custard

very effective for preventing and controlling nausea and vomiting in most patients

A rationale for nutritional practice guidelines

595

and ice cream are also usually well tolerated, unless lactose intolerance is a problem • Foods that are typically not well tolerated: meats, strongly flavored or spicy foods, carbonated cola drinks, coffee, fried or greasy foods, tomato products • If vomiting is present, maintenance of hydration and electrolytes is a priority. Small amounts of clear liquids should be consumed regularly throughout the day, starting with 1 teaspoon every 10 min, gradually increasing as tolerated to 1 tablespoon every 20 min as tolerated, then 2 tablespoons every 30 min for total of 8–10 cups/day Anorexia

Loss of appetite resulting in involuntary decline in food intake

Anorexia is common • High-calorie/high- • Appetite protein meals and stimulants may be among cancer snacks are essential helpful (e.g. patients, and owing to limited cannabinoids, sometimes occurs intake megestrol acetate even prior to the and sometimes diagnosis of cancer. corticosteroids It may be due to the • Meals and snacks should be such as tumor itself causing consumed at dexamathasone) overproduction of regularly scheduled cytokines that times rather than interfere in the relying on appetite normal metabolic or hunger cues pathways. Anorexia may also occur as a • Favorite foods

Comprehensive Geriatric Oncology

result of cancer treatment, depression, pain, or anxiety

596

should be consumed as often as possible, and food choices should not be restricted • If high-fat or fried foods are being avoided for other health reasons, these should be reintroduced to the diet until appetite and intake improves

• If depression is present, antidepressants without an appetitesuppressant effect may also be helpful

• Sugar-sweetened foods should be consumed if tolerated, to increase calorie intake without increasing food volume • Keep snacks visible, convenient, and handy Lactose Loss of or intolerance decrease in production of enzyme (lactase) necessary to properly digest lactose. The incomplete digestion of this milk sugar results in bacterial fermentation in the gut, which then

• The lactase Lactose intolerance • Avoid or limit lactose-containing may occur as a result enzyme (Lactaid foods (e.g. milk, of a prolonged and DairyEase) ice cream, cottage period of time in can be used prior cheese, milk which dairy products to consumption of puddings, custard, are not consumed. lactose-containing cream, milkshakes, This may be due to foods to aid in hot chocolate food restriction for digestion and mixes, instant diagnostic testing, minimize breakfast drinks) postsurgical diet symptoms modification, or • Cheese is usually limited well tolerated, especially if aged and eaten in small amounts. Yogurt and

A rationale for nutritional practice guidelines

causes gastrointestinal symptoms (e.g. abdominal bloating, cramping diarrhea, and nausea)

597

buttermilk may intake due to loss of be tolerated in appetite. Radiation some therapy to the individuals with abdominal area or mild lactose chemotherapuetic drugs intolerance with gastointestinal toxicity may also lead to • Products that lactose intolerance. have been 100% Lactose intolerance lactose-reduced occurs with varying (e.g. Lactaid degrees of severity. and DairyEase) Most individuals can are also very still tolerate the small well tolerated amounts of lactose and should be found in prepared used in place or products or cheeses. regular milk or Lactase deficiency is dairy products usually transient in this population, unless it • Soy milk and was pre-existing soy-based beverages can be used as a milk substitute; however, they should be calciumfortified • Calciumfortified orange juice can also be used as an alternative calcium source • Rice milk and rice-based beverages can be used, but are usually lacking in protein and calcium

Diarrhea

Change in normal bowel habits characterized by the frequent f

Diarrhea may be due to inflammation of the intestinal mucosa as a result of chemotherapy or radiation therapy. It l

• The primary treatment for diarrhea is maintenance of fluids and l t l t A

Pharmacological therapy depends on etiology: • antimotility agents

Comprehensive Geriatric Oncology

passage of may also occur as a loose, fluid, result of viral or unformed stools bacterial infection or as a result of lactose intolerance or bowel resection

598

electrolytes. An • antisecretory intake of 6–8 agents cups per day of liquid is recommended to prevent dehydration • The liquid may include diluted fruit juices, electrolyte replacement beverages, water, or decaffeinated tea. Caffeinated beverages should be avoided • Foods high in bran or insoluble fiber such as whole wheat or brown rice should be avoided • High-fat or greasy foods should be limited • Foods containing fructose, sorbitol, xylitol, hydrolyzed food starch, or oestra may increase stool output • High-fiber foods such as fruits and vegetables with their skins on may also increase stool output

• lactase • Lactinex • antibiotics • psyllium powder

A rationale for nutritional practice guidelines

599

• If lactose intolerance is present, limit use of dairy products Constipation Change in normal bowel habits characterized by a decrease in frequency and/or difficult passage of hard dry stools

Constipation can occur • Eat meals at regular times as a result of each day chemotherapeutic drugs or drugs used to control • Maintain intake symptoms (e.g. of nonantiemetics, caffeinated antihistamines, and pain beverages at 8– medications). It may 10 cups per day also be a result of lack of activity due to fatigue • Increase intake or a decrease in food of high-fiber intake and low-fiber foods (e.g. bran food choices and wholegrain breads and cereals, beans, and dried or fresh fruits)

• Bulk laxative (e.g. methylcellulose or psyllium) with several glasses of water

• Stool softeners or cathartics may be necessary if constipation is due to narcotics (e.g.

• If a high-calorie, high-protein, as a result of altered food tolerance and taste alterations

liquid supplement is being used, choose one that contains fiber

senna, docusate sodium, bisacodyl, casanthranol, • Use warm prune or magnesium juice or dried prunes citrate) daily • One cup of a caffeinated beverage each day can act as a stimulant without contributing to dehydration

Dysphagia A condition resulting in a disturbance in the normal transfer of food from the oral cavity to the stomach. Symptoms include difficulty or pain on swallowing (odynophagia), choking or aspiration

Dysphagia may be due to surgery to the mouth, throat, or esophagus, radiation therapy to the head and neck area, mucositis due to chemotherapy, or obstruction due to the tumor. It may also be

• Tolerance of None consistency and food texture should be determined by swallowing studies and confirmed with an evaluation by a speech pathologist to determine the risk for aspiration

Comprehensive Geriatric Oncology

during swallowing, and inability to pass food through the esophagus due to obstruction.

due to a cerebral vascular accident or surgery to the brain. Difficulty or pain on swallowing may be short-or long-term, requiring feeding by nasogastric or gastrostomy tube

600

• In general, thin liquids and foods that fall apart or are in small pieces should be avoided (e.g. rice, small pasta, corn, or peas, dry cottage cheese, and ground or chopped meats). Also avoid foods with a fibrous or stringy consistency • Foods with a thick or pasty consistency (e.g. puddings, pureed foods, and casseroles) and thick liquids (e.g. thick creamed soups) are usually better tolerated. Thin liquids may also be thickened with a commercial thickening agent • A blenderized diet consisting of all the various food groups or supplementation with a commercially prepared highcalorie/high-protein formula may be necessary to meet macro- and micronutrient needs • Sit as upright as possible while eating or drinking • If the alimentary tract is obstructed, a semisolid or liquid diet may be necessary until the obstruction is alleviated

A rationale for nutritional practice guidelines

601

compliance with recommendations, as well as psychological and situational barriers to compliance. Patients’ responses to cytotoxic therapy and their prognosis will also impact on the nutrition care plan and intervention strategies. Ongoing communication among all members of the healthcare team, including the attending physician, social worker, speech therapist, physical therapist, dietitian, and nursing staff, and the patient’s family or caregiver, is essen tial in developing and implementing the best possible care plan for the patient. An integral part of the nutrition care plan is the establishment of short- and longterm goals. Nutritional repletion should be the long-term goal for malnourished cancer patients who present for cancer therapy.70 Short-term goals, such as behavioral or functional goals, may need to be established in order to achieve this repletion. Choosing a method of nutritional support Once nutritional needs have been assessed according to metabolic needs and stress expenditure, the best mode of nutritional delivery must be determined. Determinants for options of supportive nutrition in cancer patients include the presence or absence of functional gastrointestinal tract, treatment plans (surgery/hormonal/radiation/chemotherapy/biological response modifier therapy) degree of baseline deficit, quality of life and prognosis, and cost-effectiveness/utility.75 The choice of nutritional support is dependent on the degree of function of the gastrointestinal tract, access, patient comfort and motivation, type of therapy, anticipated disease course, duration of therapy, and anticipated toxicities.76 The availability of caregivers, the patient’s performance status, and financial resources should also be considered. The preferred method of nutritional intervention—the least expensive and least invasive—is a standard or modified diet plus oral supplementation.77 However, if a patient is unable to consume sufficient protein and calories for longer than 7–10 days with continued decline in nutritional status (albumin <3.4 and weight loss), alternate means of support via enteral support or total parenteral nutrition (TPN) may be indicated. Enteral support Enteral nutrition involves the non-volitional delivery of nutrients by tube into the gastrointestinal tract. Patients who cannot, should not, or will not eat adequately and in whom the benefits of improved nutrition outweigh the risk and have a functional gastrointestinal tract are candidates for enteral tube feedings.78 Enteral feeding provided through a tube, catheter, or stoma delivers nutrients distal to the oral cavity. The chosen route for enteral feeding depends on the patient’s clinical status, risk for aspiration, and anticipated duration of tube feeding. Short-term feeding (<3–4 weeks) is usually administered via a nasogastric, nasoduodenal, or nasojejunal tube. The nasoduodenal and nasojejunal (postpyloric) routes are preferable to the nasogastric route if the patient is at risk for aspiration. A decision to perform a tube enterostomy (esophagostomy, gastrostomy or jejunostomy) is usually made for long-term feeding (>3–4 weeks). In this case, jejunostomy is the preferred approach when the patient is at risk for aspiration, or is unable to consume adequate calories owing to uncontrolled nausea or vomiting. Enteral support via nasogastric tube, gastrostomy tube or jejunostomy tube is preferred over TPN because of preservation of gut integrity, a lower risk of infection, maintenance

Comprehensive Geriatric Oncology

602

of immune function, and lower cost.79 Enteral nutrition is indicated in hypermetabolic states (burns, trauma, or infection), when there is an inability to ingest food normally (dysphagia), in cases of malnutrition or risk for becoming malnourished, and when there is impairment of digestion and/or absorption.80 Enteral nutrition formulations for the cancer patient are essentially the same as for mild to moderately ill patients without cancer; however, there is some evidence that those containing glutamine may help to restore and maintain function of the small-bowel mucosa.70,81 More than 80 different enteral formulas are available for delivery via tube feedings, with new formulations being developed on a continuous basis. Standard formulas and criteria for selection are reviewed by Copeland and Ellis70 and Bloch.82 Although enteral nutrition is generally considered safe, gastrointestinal, metabolic, and respiratory complications have been documented.80 Inappropriate formula advancement or feeding interruptions may result in underfeeding. Gastrointestinal intolerance is often due to improper methods of feeding, such as bolus delivery into the small intestine. The most common problems associated with enteral feedings can be minimized or prevented through proper formula preparation and equipment selection, controlled administration, and monitoring. A reduced incidence of metabolic abnormalities and other improved outcomes of enteral nutrition have been demonstrated when patients are managed by an interdisciplinary team.83,84 Therefore, proper techniques of delivery are of great importance for optimal nutrient utilization and patient comfort. Total pareneteral nutrition The benefit of administering TPN as means of support or for repletion of nutritional status remains controversial owing to the lack of documentation of a favorable impact of TPN on response to therapy or survival.85–87 The decision to use TPN as an adjunct to therapy remains a matter of clinical judgment; however, malnourished patients unable to tolerate enteral feedings with a clear response or potential response to antineoplastic treatment are usually considered candidates for parenteral support.86,88 Although the parenteral formulation for the adult population is the same as that for other adults, consideration must be given to special problems and challenges identified in the elderly, such as organ failure, circulatory disorders, effects of other therapies, and tumor effects. Ethical issues The decision to use enteral tube feeding or TPN for patients with advanced incurable disease requires careful consideration of the goals of such support.77 It is difficult to justify expensive, aggressive, and sometimes invasive methods of nutritional support in patients who are not receiving curative antineoplastic therapy. As stated by Goldstein and Fuller,81 ‘decisions regarding initiation and withdrawal of life-sustaining artificial nutrition and hydration are complex and sometimes agonizing to make’. Conditions for which artificial feeding is refused or considered inappropriate include end-stage disease, advanced dementia, and a persistent vegetative state. The use of such support should be viewed as a palliative measure in these patients mainly to support hydration and a means of delivering necessary medications if needed. Some patients desire no support whatsoever, even in the form of intravenous hydration. The decision to deliver basic

A rationale for nutritional practice guidelines

603

support should be discussed with the family in terms of stage of cancer and prognosis, anticipated consequences of not receiving hydration or nutrition, any risks involved in administering support, and cost. In many patients, the provision of enteral support via a nasogastric or gastrostomy tube can provide a better quality of life by restoring some degree of strength and energy and allowing patients to eat for enjoyment rather than feeling pressured to eat for repletion of nutritional status or to sustain life. Ultimately, the choice for nutritional support in the end-stage cancer patient must lie with the family and caregivers, who should be given as much information as possible from the healthcare team. This is particularly important with the elderly cancer patient, where one must consider prognosis and life-expectancy. Physical fitness In addition to nutritional assessment and implementation of nutritional support, based on research into loss of lean body mass and lack of physical activity, it may be only logical to integrate a physical fitness assessment and plan for a physical fitness regimen. Research has continued to show that several diseases associated with aging can be positively affected by an active lifestyle. Musculoskeletal, endocrine, and cardiopulmonary changes that occur with aging and chronic illness show a decline in progression with regular physical activity. Exercise training has been shown to benefit in improving gait velocity, range of motion, and endurance, and consequently functional capacity, in the elderly. More recent studies have demonstrated the significant benefits to the musculoskeletal system with resistance training, improving functional and overall activity level in the elderly.30,34,35 After initial evaluation by a physical therapist, a planned daily physical fitness schedule, including aerobic exercise such as walking, aqua aerobics, or armchair aerobics in addition to resistance training, is highly recommended to decrease progression of biological aging and functional capacity (see Appendix 27.4) Nutritional support: pharmacological approaches Several approaches to nutritional support of the elderly cancer patient can be supported by pharmacological approaches that are used to treat adult cancer patients for specific symptoms. Although there is no empirical evidence demonstrating the efficacy of these agents in the elderly population, this can be considered as a logical approach, as demonstrated by our patients at the H Lee Moffitt Cancer Center. The most widely used are pharmacological interventions to treat cancer anorexia and cancer cachexia, which can range from management of pain and depression to treatment of nutritional symptoms such as nausea or anorexia. Early satiety and anorexia can be treated with appetite stimulants such as corticosteroids, orexigenic agents (e.g. megestrol acetate), cannabinoids, and more recently antidepressants. Currently, there are no clinical trials demonstrating the effectiveness of these agents in improving nutritional status in the elderly cancer patient population. Several nutritional symptoms are currently treated by the clinical teams using nutritional modifications supported by pharmacological agents. Although there are no specific combination therapies that have proven efficacy in senior adult oncology patients, the following regimens have been found to be effective in our institution. Treatment of diarrhea can include MCT oils, psyllium preparations, lactase-

Comprehensive Geriatric Oncology

604

containing preparations, antidiarrheal agents as indicated (intestinal transit inhibitors, proabsorptive agents, antisecretory agents, and intraluminal agents), and fluid and electrolytes. Therapies supporting treatment for constipation may include bulk-producing agents (methylcellulose and psyllium preparations), irritants/stimulants (senna, bisacodyl, and castor oil), lubricants (mineral oil), and surfactants/stool softeners (docusate sodium), with stimulants (casanthranol), as indicated. Antiemetics, such as prochlorperazine, lorazepam, diphenhydramine, dexamethasone, dimenhydrinate, droperidol, metoclopramide, ondansetron, and granistron, have been found to be effective in the treatment of treatment-related nausea and vomiting. Nutritional support of mucositis is supported by supplementing the tolerated oral intake with commercial nutritional supplements—Ensure, Boost, or Scandi-shake. Several mouthwashes, lozenges to eliminate pain temporarily or to reduce pain during food intake, and means of keeping the oral cavity clean are critical: diphenhydramine elixir, lozenges (Cepocal), Chloroseptic Spray, dental salve (Orabase or Oral Balance, with or without Kenalog—which covers mouth sores while they are healing), anesthetic jelly (viscous lidocaine), and mouthwash formula (viscous lidocaine 2%, 2400 ml); chlorhexidine oral rinse may help gum inflammation and bleeding, but contains alcohol and may ‘sting’. Treatment of dry mouth can be supported with pilocarpine hydrochloride (as a solution or tablets) or cevimeline, synthetic saliva solutions or saliva substitute lubricants, or guaifenesin. Alternative nutritional therapies in cancer treatment and prevention Complementary/integrative therapies are therapies provided as an adjunct to mainstream medicine, intended to provide symptom control, to enhance quality of life, and/or empower clients. Alternative therapies are therapies that are independent of surgery, radiation, and chemotherapy. Most alternative and complementary nutritional therapies can be classified under the following categories: folk remedies, diets, metabolic therapies, biological products, drugs/agents/nutritional supplements, and diagnostic tests. Currently, a large volume of data in the medical literature is available demonstrating the role of several nutrients in cancer prevention and treatment, based on epidemiological, laboratory, and animal studies. This evidence in the medical literature is limited to animal studies and the efficacy of some nutrients in various normal and cancer cell lines. Results of randomized clinical trials demonstrating the efficacy of nutrients in the prevention and treatment of cancers in human populations are ongoing and pending. However, a significant number of the elderly use these therapies for prevention of and during treatment for cancer. In a study of 820 cancer patients on active treatment, receiving chemotherapy or radiation therapy, 29.1% reported the use of complementary/integrative nutritional therapies, not prescribed by their physician. Demographic data indicate that Caucasians and patients over the age of 60 were predominant users of complementary/integrative therapies during treatment. It has become imperative for the health professional to develop a greater awareness of the alternative and complementary nutritional therapies that their elderly patients are using during therapy and to examine the potential interactions that these therapies may have with traditional cancer treatments. In addition, it is important for practitioners to identify patients who are vulnerable, and to support patients to allow them to make informed, safe, and appropriate choices. In an

A rationale for nutritional practice guidelines

605

effort to identify the subgroup of patients who might be using unconventional treatments concurrently with conventional ones, it is critical to screen patients for use of complementary therapies during physician, nursing, or dietetic screening of the patient. Clinical screening, in addition, must evaluate patient supplement intake against known and potential adverse interactions with the cancer therapy protocol being implemented. Both the patient and the medical team need to be aware of the potential interaction. For nutrient-based compounds such as vitamins, a great deal rests on the results of empirical research that clearly demonstrates the usefulness of the compounds at supplemental doses.89 Reassessment and follow-up nutritional care Although early initial screening and a comprehensive assessment are the first steps in determining the nutritional status of the elderly cancer patient prior to developing nutritional support, all this would be remiss if a systematic reassessment were not planned based on specific criteria. Nutritional reassessment is indicated when a patient’s intake indicates deficiency compared with assessed requirements, when a patient exhibits nutritional symptoms (e.g. nausea, vomiting, or diarrhea) or is on serial treatment regimens that have been shown to increase nutritional risk, when changes in medications or treatment regimens impact nutritional status or plan of care, or when a patient needs monitoring of nutritional status during nutritional support. Reassessment/re-evaluation for monitoring and evaluation of nutritional therapy must include monitoring of clinical, functional, dietary, and behavioral outcomes that have been identified by the comprehensive nutritional assessment. It is logical to believe that active nutritional support following the catabolic phase of acute illness and extending during the rehabilitative period may be beneficial in improving nutritional intake, status, and/or outcome.90 If the patient is discharged to a assisted living or skilled nursing facility, it is critical for the nutrition support team to communicate with the team at the facility with regard to the patient’s nutritional needs. If the patient is discharged to their home, it is important to evaluate the need for community nutrition program assistance, such as food procurement, preparation, meals-on-wheels, food banks, commodity food sources, or hospice organizations. Summary Conventional medical treatment of cancer, although demonstratedly effective in treating some cancers and prolonging life, continues to induce significant side-effects that affect the quality of life of the cancer patient—more so in the senior adult cancer patient population. This has been one of the reasons why the senior adult oncology patient seeks alternative therapies and complementary therapies to treat their disease, most of which are innocuous but may raise concerns regarding safety. The medical team has the burden of responsibility in their hands. First, they must establish the most effective, timely nutritional therapy (using the appropriate route of administration for the patient) whose benefits will outweigh the risks and that will lead to prolonged survival and quality of

Comprehensive Geriatric Oncology

606

life. Second, and most importantly, it is critical for the medical team to fully inform the patient and family of the scientific evidence and the prevailing standards of practice, and solicit their participation in the decision-making process. In the case of a mentally incapacitated patient, surrogates must make the decision on behalf of the patient. In addition, in striving to contain healthcare costs, it is critical for the medical team to avoid discriminating against the critically ill and the elderly, and to avoid making decisions based on economic value to society. The ultimate decision must be in the best interest of the patient, and must be made by the individual, informed patient. Acknowledgement We acknowledge Jayne Wellner for providing us with assistance in the preparation of this manuscript. References 1. Statistics, 2002. Baltimore: National Institute of Health/Institute on Aging, 2002. 2. Cancer Facts and Figures. Atlanta: American Cancer Society, 2002. 3. Dempsey DT, Mullen JL. Macronutrient requirements in the malnourished cancer patient. Cancer 1985; 55:290–4. 4. United States Department of Health and Human Services, Statistics (USDHHS), March 4, 2002. 5. Vallas B, Lauque S, Andrieu S et al. Nutrition assessment in the elderly. Curr Opin Clin Nutr Metab Care 2001; 4:5–8. 6. Pirlich M, Lochs H. Nutrition in the elderly. Best Pract Res Clin Gastroenterol 2001; 15:869–84. 7. Huffman GB. Evaluating and treating unintentional weight loss in the elderly. Am Fam Physician 2002; 65:640–50. 8. Meydani M. Nutrition interventions in aging and age-associated disease. Ann NY Acad Sci 2001; 928:226–35. 9. Zawada ET Jr. Malnutrition in the elderly. Is it simply a matter of not eating enough? Postgrad Med J 1996; 100:207–8, 211–14, 220–2. 10. Nourhashemi F, Andrieu S, Rauzy O et al. Nutritional support and aging in preoperative nutrition. Curr Opin Clin Nutr Metab Care 1999; 2:87–92. 11. Shike M, Brennan M. Nutritional support. In: Cancer: Principles and Practice of Oncology, 3rd edn (DeVita VT, Hellman S, Rosenberg SA, eds). Philadelphia: JB Lippincott, 1989:2029–44. 12. Tisdale MJ. Cancer cachexia. Anti-Cancer Drugs 1993; 4:115–25. 13. DeWys WD. Nutritional care of the cancer patient. JAMA 1980; 244: 374–6. 14. Goodlad GA, Clark CM. Protein metabolism in the tumour-bearing host. Acta Chir Scand Suppl 1980; 498:137–40. 15. Axelrod L, Costa G. The contribution of fat loss to weight loss in cancer. Nutrition Cancer 1980; 2:81–3. 16. Waterhouse C. Oxidation and metabolic interconversion in malignant cachexia. Cancer Treat Rep 1981; 65(Suppl 5):61–6. 17. Smith SA. Theories and intervention of nutritional deficit in neoplastic disease. Oncol Nurs Forum 1982; 9:43–6. 18. Abbott Hess M. Taste: the neglected nutritional factor. J Am Dietet Assoc 1997; 97:S205. 19. Nutrition, Cancer Information, Health Professionals. Atlanta: National Cancer Institute, 2002. 20. Tisdale MJ. Protein loss in cancer cachexia. Science 200; 289:2293–4.

A rationale for nutritional practice guidelines

607

21. Tisdale MJ. Metabolic abnormalities in cachexia and anorexia. Nutrition 2000; 16:1013–14. 22. Barber MD, Ross JA, Fearon KC. Disordered metabolic response with cancer and its management. World J Surg 2000; 24:681–9. 23. Marian M. Cancer cachexia: prevalence, mechanisms, and interventions. Support Line 1998; 20:3–12. 24. Shibata M, Nezu T, Kanou H et al. Decreased production of IL-12 and tupr 2 immune responses are marked in cachexic patients with colorectal and gastric cancer. J Clin Gastroenterol 2002; 34:416–20. 25. Bruera E, Sweeney C. Cachexia and asthenia in cancer patients. Lancet Oncol 2000; 1:138–47. 26. Jagoe RT, Goldberg AL. Curr Opin Clin Nutr Metab Care 2001; 4: 183–90. 27. Watchorn TM, Waddell I, Ross JA. Proteolysis-inducing factor differentially influences transcriptional regulation in endothelial subtypes. Am J Physiol Endocrinol Metab 2002; 282:E763–9. 28. Cox A, McCallum PD. Medical nutrition therapy in palliative care. In: The Clinical Guide to Oncology Nutrition (McCallum PD, Polisena CG, eds). Chicago: The American Dietetic Association, 2000: 143–9. 29. Baracos VE. Management of muscle wasting in cancer-associated cachexia. Cancer 2001; 92(Suppl):1669–77. 30. al-Majid S, McCarthy DO. Cancer-induced fatigue and skeletal muscle wasting: the role of exercise. Biol Res Nurs 2001; 2:186–97. 31. Wadhwa A, Sabharwal M, Sharma S. Nutritional status of the elderly. Indian J Med Res 1997; 106:340–8. 32. Morley JE. Anorexia of aging: physiologic and pathologic. Am J Clin Nutr 1997; 66:769–73. 33. Kumar NB, Cantor A, Allen K, Cox CE. Android obesity at diagnosis and breast carcinoma survival. Cancer 2000; 88:2751–7. 34. Dimeo FC. Effects of exercise on cancer-related fatigue. Cancer 2001; 92(6 Suppl):1689. 35. Baracos VE. Management of muscle wasting in cancer-associated cachexia: understanding gained from experimental studies. Cancer 2001; 92(6 Suppl):1669–77. 36. Wilkes JD. Prevention and treatment of oral mucositis following cancer chemotherapy. Semin Oncol 1998; 25:538–91. 37. Mahan KL, Escott-Stump S. Krauses Food, Nutrition and Diet Therapy, 10th edn. Philadelphia: WB Saunders, 2000:649–65. 38. Wilson JA. Constipation in the elderly. Clin Geriatr Med 1999; 15: 499–510. 39. Wright PS. Thomas SL. Constipation and diarrhea: the neglected symptoms. Semin Oncol Nurs 1995; 11:289–97. 40. Browning SM. Constipation, diarrhea, and irritable bowel syndrome. Primary Care Clin Office Pract 1999; 26:113–39. 41. Bloch AS. Nutritional management of patients with dysphagia. Oncology (Huntingt) 1993; 7(11 Suppl):127–37. 42. Saltzman JR, Russell RM. The aging gut: nutritional issues. Gastroenterol Clin North Am 1998; 27:309–24. 43. de Jong N, Mulder I, de Graaf C, van Staveren WA. Impaired sensory functioning in elders: the relation with its potential determinants and nutritional intake. J Gerontol Biol Sci 1999; 54A:B324–31. 44. Marcus E-L, Berry EM. Refusal to eat in the elderly. Nutr Rev 1998; 56:163–71. 45. Mulligan C, Moreau K, Brandolini M et al. Alternations of sensory perceptions sin healthy elderly subjects during fasting and refeeding, a pilot study. Gerontology 2002; 48:39–43. 46. Mathey M-FAM, Siebelink E, de Graaf C, van Staveren WA. Flavor enhancement of food improves dietary intake and nutritional status of elderly nursing home residents. J Gerontol 2001; 56:M200–M5. 47. Buzina-Suboticanec K, Buzina R, Stavljenic A et al. Aging, nutritional status and immune response. Int J Vitam Nutr Res 1998; 58:133–41.

Comprehensive Geriatric Oncology

608

48. Fortes C, Forastiere F, Farchi S et al. Diet and overall survival in a cohort of very elderly people. Epidemiology 2000; 11:440–5. 49. Anthony D, Reynolds T, Russell L. An investigation into the use of serum albumin in pressure sore prediction. J Adv Nurs 2000; 32; 359–65. 50. Guenter P, Malyszek R, Bliss DZ et al. Survey of nutritional status in newly hospitalized patients with stage III or stage IV pressure ulcers. Adv Skin Wound Care 2000; 13:164–8. 51. A Physician’s Guide to Nutrition in Chronic Disease Management for Older Adults. Washington, DC: Nutrition Screening Initiative, 2000. 52. Quinn C. The Nutritional Screening Initiative: meeting the nutritional needs of elders. Orthoped Nurs 1997; 16:13–24. 53. Ottery FD. Rethinking nutritional support of the cancer patient: the new field of nutritional oncology. Semin Oncol 1994; 21:770–8. 54. Dwyer IT. An assessment lexicon: assessment of dietary trends, physical activity patterns and nutritional status in the elderly. J Nutr Health Aging 2001; 5:108–12. 55. American Dietetic Association. Nutritional assessment of adults. In: Manual of Clinical Dietetics. Chicago: ADA, 1996. 56. Council on Practice. Quality Management Committee. ADA’s definitions for Nutritional Screening and Assessment. J Am Dietet Assoc 1994; 94:838. 57. Bozetti F. Nutritional Assessment from the perspective of a clinician. J Parenter Enter Nutr 1987; 11:1155–21. 58. Lee RD, Nieman DC. Nutritional Assessment, 2nd edn. St Louis, MO: Mosby Year Book, 1996. 59. Frisancho AR. Anthropometric Standardsfor the Assessment of Growth and Nutritional Status. Ann Arbor: University of Michigan Press, 1990. 60. Falconer JS, Fearon KC, Plester CE et al. Cytokines, the acute-phase response, and resting energy expenditure in cachectic patients with pancreatic cancer. Ann Surg 1994; 219:325–31. 61. Hyltander A, Korner U, Lundholm KG. Evaluation of mechanisms behind elevated energy in cancer patients with solid tumours. Eur J Clin Invest 1993; 23:46–52. 62. Merli M, Riggio O, Servi R et al. Increased energy expenditure in cirrhotic patients with hepatocellular carcinoma. Nutrition 1992; 8: 321–5. 63. Nixon DW, Kutner M, Heymsfield S et al. Resting energy expenditure in lung and colon cancer. Metab Clin Exp 1988; 37:1059–64. 64. Thomson SR, Hirshberg A, Haffejee AA, Huizinga WK. Resting metabolic rate of esophageal carcinoma patients: a model for energy expenditure measurement in a homogenous cancer population. J Parenter Enter Nutr 1990; 14:119–21. 65. Fredrix EW, Soeters PB, Rouflart MJ et al. Resting energy expenditure in patients with newly detected gastric and colorectal cancers. Am J Clin Nutr 1991; 53:1318–22. 66. Harris JA, Benedict FG. Biometric Studies of Basal Metabolism in Man. Washington, DC: Carnegie Institute, 1919. 67. Long CL. Nutritional assessment of the critically ill patient. In: Nutritional Assessment (Wright RA, Heymsfield SB, eds). Boston: Blackwell Science, 1984. 68. Long CL, Schaffel N, Geiger JW et al. Metabolic response to injury and illness: estimation of energy and protein needs from indirect calorimetry and nitrogen balance. J Parenter Enter Nutr 1979; 3: 452–6. 69. Hamwi GJ. Therapy: changing dietary concepts. In: Diabetes Mellitus: Diagnosis and Treatment (Danowski TS, ed). New York: American Diabetes Association, 1964. 70. Copeland EM, Ellis LM. Nutritional management in patients with head and neck malignancies. In: Management of Head and Neck Cancer: A Multidisciplinary Approach, 2nd edn (Million RR, Cassisi NJ, Eds). Philadelphia: JB Lippincott, 1994. 71. Buzby KM. Overview: screening, assessment and monitoring. In: Nutrition Management of the Cancer Patient (Bloch AS, ed). Rockville, MD: Aspen, 1990. 72. Blumberg J. Nutritional needs of seniors. J Am Coll Nutr 1997; 16: 517–23.

A rationale for nutritional practice guidelines

609

73. Gallagher-Allred CR, Voss AC, Finn SC, McCamish MA. Malnutrition and clinical outcomes. J Am Dietet Assoc 1996; 96:361–6. 74. Laviano A, Renvyle T, Yang ZJ. From laboratory to bedside: new strategies in the treatment of malnutriton cancer patients. Nutrition 1996; 12:112–22. 75. Ottery FD. Supportive nutrition to prevent cachexia and improve quality of life. Semin Oncol 1995; 22(2 Suppl 3):98–111. 76. Robuck JT, Fleetwood JB. Nutrition support of the patient with cancer. Focus Crit Care 1992; 19:129–30, 132–4, 136–8. 77. Mercandante S. Nutrition in cancer patients. Support Care Cancer 1996; 4:10–20. 78. ASPEN Board of Directors. Defmitions of terms used in ASPEN guidelines and standards. J Parenter Enter Nutr 1995; 19:1–2. 79. Berg RD. Bacterial translocation from the gastrointestinal tract. J Med 1992; 23:217–44. 80. ASPEN Board of Directors. Guidelines for use of parenteral and enteral nutrition in adult and pediatric patients. J Parenter Enter Nutr 2002; 26(Suppl):1SA–138SA. 81. Goldstein MK, Fuller JD. Intensity of treatment in malnutrition. The ethical considerations. Primary Care Clin Office Pract 1994; 21: 191–206. 82. Bloch AS. Nutritional management of patients with dysphagia. Oncology 1993; 7(Suppl):127– 37. 83. Brown RO, Carlson SD, Cowan GSM et al. Enteral nutritional support management in a university teaching hospital: team versus non-team. J Parenter Enter Nutr 1987; 11:52–6. 84. Hassell IT, Games AD, Shaffer B et al. Nutrition support team management of enterally fed patients in a community hospital is cost-beneficial. J Am Dietet Assoc 1994; 94:993–8. 85. Heys SD, Park KG, Garlick PJ, Ermin O. Nutrition and malignant disease: implications for surgical practice. Br J Surg 1992; 79:614–23. 86. Shike M. Nutrition therapy for the cancer patient. Hematol Oncol Clin North Am 1996; 10:221– 34. 87. Shils M. Nutrition needs of cancer patients. In: Nutrition Management of the Cancer Patient (Bloch AS, ed). Rockville, MD: Aspen, 1990. 88. Daly J, Shinkwin M. Nutrition and the cancer patient. In: American Cancer Society Textbook of Clinical Oncology, 2nd edn (Murphy G, Lawrence W, Lenhard R, eds). Atlanta: American Cancer Society, 1995:580–96. 89. Kumar NB, Moyers S, Allen KA et al. Alternative and complementary/integrative nutrition therapies for cancer prevention and treatment. Moffitt Cancer Network (Electronic), H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, February 2000. 90. Gabriballa, SE. Malnutrition in hospitalized elderly patients: When does it matter? Clin Nutr 2001; 20:487–91.

Comprehensive Geriatric Oncology

Appendix 27.1

610

A rationale for nutritional practice guidelines

Appendix 27.2A

611

Comprehensive Geriatric Oncology

Appendix 27.2B

612

A rationale for nutritional practice guidelines

Appendix 27.2C

613

Comprehensive Geriatric Oncology

Appendix 27.2D

614

A rationale for nutritional practice guidelines

Appendix 27.3

615

Comprehensive Geriatric Oncology

Appendix 27.4

616

A rationale for nutritional practice guidelines

617

28 Chemoprevention of cancer in the older person Lodovico Balducci, Claudia Beghe’ Introduction Chemoprevention of cancer involves the administration of substances capable of stopping or reversing carcinogenesis. This cancer control strategy is of special interest to older individuals: • both to cancer and to cancer treatment. Cancer is the It may eliminate the morbidity and mortality related second most common cause of death1,2 and disability3,4 for persons aged 65 and older (see Chapter 4 of this volume5). Likewise, the risk of treatmentrelated complications increases with the age of the cancer patient.6,7 • It is more practical than elimination of environmental carcinogens that in older individuals may already have caused permanent damage.8 • It is more appealing than secondary prevention (early diagnosis), which involves invasive procedures for the diagnosis and management of early cancer.9 • It may find the most appropriate target in the aged, because many molecular changes of aging reproduce molecular carcinogenesis (see Chapter 8 of this volume10). Thanks to this age-carcinogenesis interaction, it is not far-fetched to assume that cancer chemoprevention may also delay or reverse molecular aging (see Chapter 8). • According to a number of studies11 (see Chapter 26 of this volume12), cancer affects prevalently elderly individuals in good health, who are more likely to die of cancer than of other comorbid conditions. Thus, chemoprevention may save lives. Chemoprevention may also have significant drawbacks in older individuals: • The benefits of cancer prevention may be reduced in persons with limited lifeexpectancy. • The treatment itself may be associated with substantial morbidity. • Chemoprevention may prove too costly a form of cancer control. In this chapter, we shall examine the potential benefits and risks of chemoprevention of common cancers in the older aged person, after reviewing general principles of chemoprevention and the molecular interactions of cancer and age.

Chemoprevention of cancer in the older person

619

Chemoprevention Chemoprevention and carcinogenesis Two aspects of carcinogenesis support the use of chemoprevention:13 • The evolutionary aspect—carcinogenesis is a time-consuming process that develops through an ordained succession of stages. • The ‘field’ effect—the effects of carcinogenesis encompass all cells of the same field, rather than a single cell. This field effect accounts for the development of multiple malignancies in the same organ. Carcinogenesis evolves through multiple stages, whose number varies for different neoplasms.8 Each stage may be effected by different carcinogens and involves the activation of oncogenes or the suppression of antiproliferative genes (antioncogenes/tumor suppressor genes). These stages have been well-defined for cancer of the large bowel (Figure 28.1).14 The evolutionary nature of carcinogenesis has proved susceptible to multiple interventions: • It offers plenty of time for intervention, since the evolution from normal cell to cancer may require 5–10 years. • It offers multiple targets for prevention, since each stage of carcinogenesis is a checkpoint for the entire process. • It offers multiple opportunities to assess the process at both clinical and molecular levels. Several precancerous states are recognizable for common cancers

Figure 28.1 Molecular development of colon cancer.

Comprehensive Geriatric Oncology

620

(Table 28.1). 15–22 These lesions may be used for two purposes: to recognize persons at high risk of cancer and to monitor the effects of the preventive intervention. For example, the cyclooxygenase-2 (COX-2) inhibitor celecoxib causes regression of adenomatous polyps of the colon in patients with familial adenomatous polyps (FAP),18 and for this reason is considered a potential chemopreventive agent for colon cancer. Likewise, the preventive activity of tamoxifen might have been inferred from its ability to block the progression of ductal carcinoma in situ (DCIS) to invasive breast cancer.21,22 The study of molecular markers of carcinogenesis allows the practitioner to determine the effectiveness of chemoprevention. Disappearance of the molecular abnormalities would support the eradication of the cell clone evolving toward malignant transformation, while persistence of the abnormality would indicate a temporary effect

Table 28.1 Example ofs preneoplastic lesions that may be used as surrogate endpoints for chemoprevention •

Skin cancer: Actinic keratosis

•

Oropharyngeal cancer: Leukoplakia

•

Breast cancer: Atypical hyperplasia Ductal carcinoma in situ (DCIS) Lobular carcinoma in situ (LCIS)

•

Colorectal cancer: Adenomatous polyps

•

Prostate cancer: Prostate intraepithelial neoplasia (PIN)

•

Cervical cancer: Cervical intraepithelial neoplasia

n the malignant phenotype that may delay but is unlikely to prevent the development of cancer. For example, it was found that treatment with cis-retinoic acid may eliminate some of the p53 mutant clones, but fails to reverse loss of heterozygosity (LOH) at chromosome 9p in early oropharyngeal lesions.23 This observation is consistent with the clinical finding that eventually cancer develops despite the continuous administration of this agent, since the transformed cellular clone becomes resistant to cis-retinoic acid. The ‘field effect’ offers two important opportunities for chemoprevention:

Chemoprevention of cancer in the older person

621

• Recognition of subjects at increased risk of cancer: in general, after diagnosis of epithelial cancer, a person is susceptible to more cancer of the same type. This effect has already been exploited in clinical trials, including prevention of second oropharyngeal tumors and second lung cancers with retinoids.13,23,24 In addition, the chemopreventive action of the selective estrogen receptor modulator (SERM) tamoxifen was first hinted at by a reduction of incidence of contralateral breast cancer in women given adjuvant tamoxifen.25 • Prevention of multiple cancers with a single intervention. Chemopreventive agents Different substances with different mechanisms of action can effect chemoprevention (Figure 28.2). Substances with chemopreventive potential and their possible mechanism(s) are listed in Table 28.2. An old construct considered three basic stages in carcinogenesis: initiation, promotion, and progression.8 Although modified according to new molecular insights, this construct is still helpful, as a frame of reference, to understand the mechanisms of chemoprevention. Initiation involves the formation of DNA adducts that are highly electrophilic, and is effected by substances (mutagens) activated by the cytochrome P450 enzymatic system, and detoxified by type II liver reactions.26 The best-

Figure 28.2 Sites of action of chemopreventive agents. Table 28.2 Chemopreventive agents and their mechanisms of action Mechanism of action

Agent

Inhibition of carcinogen activation

Inhibition of cytochrome P450 enzymes • Isothiocyanates (cruciferous vegetables) • Diallyl sulfide (garlic)

Comprehensive Geriatric Oncology

622

• Flavonoids, isoflavonoids, coumarins (different plants) Inhibition of electrophilic groups derived from carcinogen activation • 2-Mercaptoethanol • Riboflavin • Ellagic acid and other plant phenols • Epigallocatechin-3-gallate (EGCG) (green tea) Enhanced carcinogen detoxification

Inducers of glutathione-S-transferases (GSTs) • Diallyl sulfide and S-allylcysteine (garlic) • Isothiocyanantes (cruciferous vegetables) • Oltipraz (antischistosomal drug) • N-Acetylcysteine (synthetic) Inducers of quinone transfemse • Resveratrol (grape and other fruits)

Enhancers of DNAdamage repair

• Calorie restriction • Selenium • Epigallocatechin gallate

Inhibitors of induced cell Reactive oxygen species (ROS) scavengers proliferation • Antioxidants (acorbic acid, α-tocopherol, selenium, polyphenolic compounds from green tea, spices, and vegetables) • Calorie restriction Antiprolifemtive and differentiating agents • Retinoids • Dimethylfluoroornithine (DMFO) • Hormonal agents (selective estrogen receptor modulators (SERMs), aromatase inhibitors, androgen deprivation) Prostaglandin synthesis inhibitors • Cyclooxygenase (COX)-1 and -2 inhibitors • Corticosteroids Inducers of apoptosis

• Retinoids • Hormonal agents • COX-1 and -2 inhibitors

Chemoprevention of cancer in the older person

623

established enzymes in these reactions are the glutathioneS-transferases (GSTs); other enzymes of interest include diphosphate-glucuronosyl transferase, quinone reductase, and epoxide hydrolase27 Some of the electrophilic intermediaries of mutagen activation may themselves have mutagenic activity. Thus, mutagen metabolism presents at least three targets to chemoprevention: inhibition of activation, inhibition of metabolic by-products, and enhancement of detoxification. Clearly, substances that inhibit P450 and those that induce phase II enzymes may lessen the activity of mutagens and prevent mutation. For example, it has been conclusively demonstrated in animal models that isothiocyanates interfere with the activation of tobacco-derived nitrosamines28–31and that diallyl sulfide inhibits P450 2E1 responsible for activation of several nitrosamines and dimethylhydrazine.32,33 Likewise, oltipraz34 and N-acetylcysteine,28 which induce GSTs, are powerful inhibitors of experimental carcinogenesis in the colon, lung, and bladder. Initiation involves the formation of DNA adducts, and is the crossroad of chemical, radiation-induced, and light-induced carcinogenesis.35 In contrast to what was believed in the past,8 initiation may be reversed by a number of DNA-repair enzymes, including methyltransferase, base-excision repair (BER) and nucleotide-excision repair (NER) enzymes.36 As these mechanisms have been discovered only recently, knowledge about modulation of repairing enzymes is limited. There is evidence that selenium, calorie restriction, and epigallocatechin gallate may facilitate this process.35 Promotion involves the activation of oncogenes and the suppression of antiproliferative genes (anti-oncogenes/ tumor suppressor genes). The net result of these changes is increased and limitless proliferation of the transformed cells. It is important to remember that promotion under-goes a number of endogenous influences, which may include reactive oxygen species (ROS), generated as by-products of cellular metabolism,35 hormones, growth factors,37 and eicosenoids.38 The growth factors so far identified include transforming growth factor α (TGF-α), insulin-like growth factor I (IGF-I), basic fibroblast growth factor (bFGF), and hepatocyte growth factor (HGF). With the exception of TGF-α, which derives from autocrine secretion by the tumor cell itself, the other growth factors derive from paracrine production by the tumor stroma.35–37 The production of IGF-I is under control of growth hormone (GH) in normal tissues. It is not clear whether GH affects the tumor stroma. The concentration of receptors for these growth factors is increased on the surface of transformed cells with respect to normal cells. Chemoprevention may inhibit the stimulation of receptors by growth factors, reduce the synthesis of receptors, and interfere with signal transduction from the receptor to the nucleus. The latter is the best understood mechanism of chemoprevention at this stage.39 Of special interest, the concentration of COX-2, an inducible enzyme is increased many-fold in transformed cells,40–41 because selective inhibitors of this enzyme are available and may be used for chemoprevention. The majority of the efforts of chemoprevention have been focused on these late carcinogenetic stages, and have involved the following: • Scavenging of ROS by antioxidants, including atocopherol, selenium, and ascorbic acid, and by calorie restriction.35 Calorie restriction is of particular interest, since it appears both to reduce the production of ROS and to enhance endogenous antioxidant activities. • Blockage of cell proliferation and enhancement of differentiation and apoptosis, through modulation of steroid receptors, which are ligand-activated nuclear

Comprehensive Geriatric Oncology

624

transcription factors.42 In some cases, including the receptors for steroid hormones, chemoprevention is achieved by inhibition of nuclear transcription, while in the case of retinoids, it is achieved by activation of nuclear transcription. • Inhibition of polyamine synthesis, an essential ingredient of cell proliferation, by competitive inhibition of the rate-limiting enzyme ornithine decarboxylase, with dimethylfluoroornithine (DMFO).43 • Inhibition of eicosanoid formation, by non-steroidal anti-inflammatory drugs (NSAIDs).18,40,44 The boundaries between tumor promotion and progression are not clear. Tumor progression involves the acquisition of a proliferative advantage for the clone of transformed cells, through increased proliferation and reduced apoptosis. A critical factor in many cancers appears to be mutation of the p53 gene, whose product is key to repair of DNA damage and to apoptosis of mutated cells.45 In addition, p53 maintains genomic stability. Induction of apoptosis appears to be the most reasonable strategy for chemoprevention of tumor progression. As already mentioned, this construct of carcinogenesis, which is based on the twostage induction of skin cancer in mice, with 7, 12-dimethylbenzanthracene (DMBA) as mutagen and 12-O-tetradecanoylphorbol-13-acetate (TPA) as promoter, should be reexamined in the light of the knowledge accumulated during the last half-century. Important new insights include the following: • Carcinogenesis involves the serial and sequential accumulation of genomic damage. Although mechanisms may differ, the molecular end-results of initiation, promotion, and progression are similar. • Some of the so-called promoters (late-stage carcinogens) may need metabolic activation not unlike mutagens. These include the organic peroxides. The metabolism of these agents may become another target for chemoprevention.37 • Many carcinogens may act at different carcinogenic stages; likewise, many chemopreventive agents may also prevent different carcinogenic stages. With these limitations in mind, the model still presents a useful frame of reference for the study of chemoprevention. Three groups of substances were proven to prevent cancer in humans: hormonal agents, retinoids, and NSAIDs. Of the hormonal agents, the best studied have been the selective estrogen receptor modulators (SERMs), in particular tamoxifen21 and raloxifene.46–48 Both agents compete with estrogens for estrogen receptors (ERs).42 The ERs are complex molecules that contain transcriptional factors, and DNA-, ligand-, and cofactorbinding domains.49 In the absence of SERMs, estrogens activate nuclear transcription by binding to the ERs and allowing the translocation of these elements into the nucleus, where they dimerize and bind estrogenresponse elements (EREs).49 When this process is interrupted, the neoplastic cell undergoes differentiation and apoptosis. Two forms of ER, α and β, have been identified.50,51 The ratio between these two forms and the distribution of isomers of ERβ are different in normal and neoplastic breast tissue. Tamoxifen preferentially inhibits ERβ and raloxifene ERα, which may account for the different antineoplastic and estrogen-like activities of these two agents. Another potential mechanism of action of SERMs includes suppression of the secretion of IGF-I and stimulation of the release of transforming growth factor β (TGF-β).52 Other hormonal

Chemoprevention of cancer in the older person

625

agents that may be used for chemoprevention of breast cancer include the aromatase inhibitors,53 which eliminate the production of estrogen in postmenopausal women. Of the aromatase inhibitors available in the USA, anastrozole and letrozole have nonsteroidal structures, whereas exemestane is steroidal and one of its metabolites has a mild androgenic effects. These differences may be important in terms both of activity and of complications. One may expect that estrogen deprivation may lead to an unfavorable lipid profile and osteoporosis. Letrozole was found to increase the serum concentration of cholesterol and apoprotein B and to induce an unfavorable high-density/low-density lipoprotein (HDL/LDL) ratio;54 opposite changes were observed with exemestane.55 Likewise, in experimental animals, letrozole induces osteopenia,56 while exemestane may promote accrual of new bone.55 The use of hormonal treatment has also been proposed for the prevention of prostate cancer.57,58 The agents under consideration include the α-reductase inhibitor fmasteride and androgen antagonists.57,58 Retinoids are synthetic and natural vitamin A derivatives capable of reversing the growth of preneoplastic lesions and preventing second primary cancers in the upper airways.23 The mechanisms of action of retinoids include differentiation and apoptosis of preneoplastic cells, immunologic enhancement, and angiogenesis inhibition.59,60 Retinoid activity depends on the interaction with retinoid receptors, of which two broad categories exist.60 The retinoic acid receptors (RARs) form only heterodimers, and only with retinoid X receptors (RXRs). RXRs may form both homodimers and heterodimers, and these may involve either RARs or a host of other steroid hormone receptors. According to the affinity for either receptor, the biologic action of the retinoid may vary. Natural compounds are less selective than synthetic compounds. Of special interest, bexarotene is RXR-specific.61 4-N-(4-hydroxyphenyl)retinamide (4-HPR, fenretinide) occupies a unique position among the retinoids in that it induces apoptosis of transformed cells in vitro, although it does not bind to any of the retinoid receptors.62 Fenretinide is largely devoid of the hepatic and cutaneous toxicities of the other retinoids. Whereas all NSAIDs may have cancer-preventive activity, the development of specific COX-2 inhibitors has simplified the execution of clinical trials, especially in older individuals, thanks to an improved tolerability profile. Unlike COX-1, which is a structural enzyme, present in all normal tissues, COX-2 is induced in pathologic conditions, such as infection or neoplasia.43 Selective inhibition of this enzyme results in chemopreventive and antiphlogistic activity, without increased toxicity on normal tissues. Clinical studies of chemoprevention Clinical studies of chemoprevention, in vitro cell cultures, and experimental carcinogenesis represent useful models for screening substances with chemopreventive activity. Transgenic mice with predispositions to certain types of cancer may prove particularly useful for this purpose.35 The conduction of clinical trials of chemoprevention presents challenges that have been well defined over the years:63 • Adequate sample size, to minimize the risk of type II (β) error. Given that the risk of cancer is relatively small in the general population, it may take several thousand individuals to detect the effectiveness of the intervention. For example, in the National

Comprehensive Geriatric Oncology

626

Surgical Adjuvant Breast and Bowel Project’s Breast Cancer Prevention Trial (BCPT: NSABP-P1), it took more than 13000 women to establish that tamoxifen reduced the risk of new breast cancer by 50%.21 Two smaller European trials,64,65 with less than 3000 subjects in one and less than 5000 in the other, failed to demonstrate a significant reduction in breast cancer, probably owing to inadequate sample size. Likewise, most of the trials in cervical cancer did not enroll adequate numbers of patients to establish the effectiveness of the intervention.19 • Toxicity of the chemopreventive agent. This issue is of special interest to older individuals, who are more subject to adverse drug reactions.66 Benner et al24 concluded that the toxicity of cis-retinoic acid, even at low doses, was too high to justify routine use of this agent for the chemoprevention of second oropharyngeal cancer. The BCPT showed that tamoxifen was associated with a threefold increased risk of endometrial cancer and an almost twofold increased risk of cerebrovascular accidents.21 Additionally, the quality of life of women enrolled in the BCPT was compromised by hot flushes, depression, and sexual dysfunction.67 Although the absolute risk of lifethreatening complications was low, many physicians are understandably reluctant to prescribe a medication that does not have proven survival benefits, may cause lifethreatening complications, and compromises a person’s quality of life.42 • Cost is also a serious consideration. Whereas Western societies have been reluctant to cap the cost of therapeutic interventions, there is general agreement that preventive interventions should not exceed a certain cost. Even outside the medical field, society consistently makes cost-related decisions when it comes to prevention of injury and death. For example, deaths related to railway crossings would be completely eliminated by subways; however, the cost of this provision appears excessive for the small number of lives saved. In medicine, in general, a cost of $50000–60000 per year of life saved, which is the cost of screening mammography in the general population aged 50–70,68 is considered the upper limit that the society is willing to pay for cancer prevention. Two chemoprevention strategies address to some extent all three concerns: • Enrollment in the studies being limited to people at increased risk of disease, who are more likely to benefit from the intervention. • Use of intermediary endpoints as surrogate outcomes.69,70 Whereas the golden standard of effectiveness is a decreased incidence of new tumors, surrogate endpoints may be helpful to predict which agents have more chance to succeed (phase Ilb trials).13 The ability of an agent to reverse preneoplastic lesions (Table 28.1) may be used to screen the chemopreventive potential of different substances. The ability of cis-retinoic acid to prevent second head and neck tumors was predictable when Hong et al16 proved that it reversed oral leukoplakia. In 1990, the same authors demonstrated that it prevented second head and neck neoplasms.71 Phase Ilb trials are appealing because they require a relative short time and a smaller number of patients. This elegant approach is not flawless, however: premalignant lesions in the cervix (cervical intraepithelial neoplasia, CIN) may undergo spontaneous regression in as many as 60% of cases,19 and although retinoids may cause regression of premalignant squamous metaplasia of the bronchus,13,72 clinical trials showed that they may even hasten progression to lung cancer. Finally, it is important to remember that the genetic

Chemoprevention of cancer in the older person

627

alterations may not be reversed, despite reversal of an abnormal phenotype.73 For example, LOH at chromosome 9p persisted in the oropharyngeal mucosa, despite regression of leukoplakia.23 Thus, it is important to correlate regression of phenotypic lesions with regression or lack thereof of genomic markers. Interactions of aging and carcinogenesis The association of cancer and aging2,3,43 may be accounted for by four, non-mutually exclusive hypotheses: 1. Time-length of carcinogenesis: as carcinogenesis is a time-consuming process, the likelihood of developing cancer is directly related to the number of years that a person has lived (see Chapter 8 of this volume10). 2. Some molecular changes of aging parallel those of carcinogenesis, so that the older person is primed to late-stage carcinogens. Both experimental and clinical data support this hypothesis: • DNA adducts, chromosomal translocations and point mutations, and DNA hypermethylathion are almost universal in aging cells in vitro. These changes are similar to those occurring during carcinogenesis75–77 (see Chapter 8). It is reasonable to expect aging cells to be primed to environmental carcinogens • Older rodents are more likely than young rodents to develop tumors of the skin, the liver, the central nervous system, and the lymphatic system, when exposed to a number of late-stage carcinogens78–81 (see Chapter 8). This effect is tissue-specific. • The incidences of some human neoplasms, including prostate and non-melanoma skin cancer, increase logarithmically with the age of the population. These findings suggest that aging cells express enhanced susceptibility to late-stage carcinogens15,82 (see Chapter 55 of this volume83). • In the Italian city of Trieste, exposure to the same dose of environmental carcinogen was more likely to cause cancer in older than in younger individuals.84 • For completeness, not all molecular changes of aging mimic carcinogenesis. For example, cellular aging is associated with decreased length of telomeres and increased expression of the p16 tumor suppressor gene, which encodes cyclindependent kinase 4 (CDK4), while cancer is associated with opposite changes.85–86 3. There may be an association between the genes of senescence and those involved in neoplasia. The aging of the population has been associated with increased incidence of certain malignancies (non-Hodgkin lymphomas and malignant brain tumors) in persons over 60. Franceschi and co-workers in Italy (C Franceschi, personal communication, Second Conference of the Society of Biogerontology, St Petersburg, Russia, August 2000) showed that the prevalence of homozygosity of certain genes was increased among centenarians, and suggested that this homozygosity was somehow related to longevity. Homozygosity may also represent a risk factor for cancer. 4. A number of environmental changes may favor development of cancer in the aged87,88 (see Chapter 13 of this volume89). Of special interest are the following:

Comprehensive Geriatric Oncology

628

• Proliferative senescence, which involves loss of apoptosis and production by the senescent cells of tumor growth factors (heregulin) and enzymes that favor tumor metastasis (metalloproteinases).87 • Immunesenescence, which may favor the development of new tumors in the older tumor host88,90 (see Chapter 13). Some age-related environmental changes, including decreased angiogenesis and decreased secretion of growth hormone, may also inhibit tumor development.76,91–93 Clearly, age is a risk factor for most cancers, at least up to age 85, due to interactions of molecular changes of aging with carcinogenesis. From the risk standpoint, the older person appears to be the ideal candidate for cancer chemoprevention. In the following sections, we shall examine the effectiveness of chemoprevention of common cancers in older individuals. The early clinical trials of chemoprevention have provided important lessons to be incorporated into future clinical trials. Breast cancer Risk assessment As the risk of breast cancer increases with age and two-thirds of breast cancer occur after age 55, age is the single most important risk factor for breast cancer (see Chapter 51 of this volume94). The Gail model, which incorporates age, family and reproductive history, and presence or absence of atypical breast hyperplasia in the assessment of the risk of breast cancer, is commonly used in the USA.95 It is important to remember that some of the established risk factors were not included in this model, including bone density,96,97 circulating concentration of free estradiol,98 and breast density.99 Despite some concerns,100 early detection of breast cancer with serial mammography68 and physical examination of the breast101 have reduced breast cancer mortality for women aged 50–70 by 20–30%. The results of chemoprevention should be compared with these established interventions. Clinical trials of chemoprevention Several lines of evidence suggest that elimination of estrogenic effect might prevent breast cancer. • Experimental data showed that long-term treatment of rodents with tamoxifen prevented the development of chemically induced breast cancer.52 More recently, Di Salle and co-workers showed that exemestane was more effective that raloxifene, but less effective than ovariectomy, in reducing the incidence of DMBA-induced tumors in rodents (E Di Salle, personal communication, Pharmacia Consultant Conference of Chemoprevention, New Orleans, January 12, 2002). • The Oxford meta-analysis of adjuvant treatment of breast cancer showed that adjuvant treatment with tamoxifen was associated with a 39% reduction in the incidence of contralateral breast cancer with respect to control patients.25 The reduction in incidence of breast cancer was related to the duration of treatment and concerned only

Chemoprevention of cancer in the older person

629

hormone receptor-rich tumors. The results of the Multiple Outcome Raloxifene Evaluation (MORE),47,102as well as a meta-analysis of different raloxifene trials for the prevention of osteoporosis,46 showed that the use of this SERM was associated with a decline of approximately 70% in hormone receptor-rich breast cancer. As prevention of breast cancer was not a primary or secondary objective of these trials, women had not been randomized to raloxifene or placebo according to breast cancer risk—yet the size of the effect is difficult to ascribe to chance alone. • The NSABP-B24 study explored the reduction in incidence of ipsilateral invasive breast cancer in women treated with partial mastectomy and radiation therapy for DCIS.22 At 5 years, there were reductions in ipsilateral invasive breast cancer of 43% and of noninvasive breast cancer of 30%; there was also a reduction of 30% in contralateral breast cancers; • The results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) study were reported at the end of 2001.103 This international trial involving more than 9000 patients studied the effects of anastrozole (Arimidex), tamoxifen, and the combination of the two agents as adjuvant treatment of hormone receptor-rich breast cancer in postmenopausal women. After 4 years, anastrozole was associated with a 17% reduction in recurrences and an almost 70% reduction in contralateral breast cancer. Of interest, the combination of the two agents was not more effective than tamoxifen alone, indicating some degree of antagonism. • Tan-Chiu et al20 reported that tamoxifen reduced the incidence of benign breast lesions, including epithelial hyperplasia and cysts of the breast. • Decensi et al104 showed that tamoxifen at low doses in healthy women produced a reduction in the concentration of IGF-I and an increased concentration of IGF-Ibinding protein. The combination of these events should oppose the growth of breast cancer. Three randomized controlled trials explored the possibility of reducing the incidence of breast cancer with tamoxifen. The BCPT (NSABP-P1 trial) enrolled 13300 women randomized to tamoxifen or placebo treatment.21 Eligibility criteria included a risk of 1.67% or more to develop breast cancer in 5 years, according to the Gail model, and absence of contraindication to treatment. All women aged 60 and older were eligible in terms of breast cancer risk. After a mean follow-up of 48 months, there was a 45% reduction in the risk of invasive breast cancer and a 50% reduction in the risk of non-invasive breast cancer for tamoxifen. The reduction in invasive breast cancer was limited to hormone receptor-rich tumors. Of interest, tamoxifen-treated women experienced a 19% reduction in overall mortality and a 50% reduction in breast cancer deaths. These differences, however, are not significant, owing to the small number of deaths during the course of this study, which involved mainly healthy individuals. The greatest risk reduction was obtained for patients at highest risk (Gail model 5.01% or more at 5 years). For example, individuals with atypical hyperplasia experienced an overall 86% reduction in the risk of breast cancer. Another beneficial effect of tamoxifen was a non-significant 19% reduction in bone fractures. The complications of treatment were of concern: they included a relative risk of 2.53 (95% confidence interval (CI) 1.35–4.97) in endometrial cancer, 3.01 (95% CI 1.15– 9.27) for pulmonary embolism, and 1.14 (95% CI 1.01–1.29) for cataracts. The incidence of stroke was also increased in the tamoxifen group, but was somehow balanced by an

Comprehensive Geriatric Oncology

630

increased risk of transient ischemic attacks (TIAs) among the controls. The risk of complications increased with age, and was statistically significant only for women aged 50 and older. In addition, women treated with tamoxifen reported increased risk of hot flushes and sexual dysfunction and overall compromised quality of life, though only a minority (~15%) interrupted the treatment because of symptoms. The UK Royal Marsden trial was designed as a pilot study for the International Breast Cancer Intervention Study (IBIS), which is still ongoing.64 Analysis of the data in 2471 women after 70 months failed to show any benefits for tamoxifen. Seemingly, the power of the study was inadequate. In addition, the women enrolled in the study were younger than the American women and had a stronger family history of breast cancer. The Italian study enrolled approximately 5000 women,65 48% of whom had undergone oophorectomy. The study was closed prematurely, and had a dropout rate of 26%. Inadequate number, poor treatment compliance, and relative low breast cancer risk may have led to a negative trial. It is difficult to argue with the results of the BCPT given the large participation and the quality of the data. In our opinion, the question is not whether SERMs and especially tamoxifen do prevent breast cancer, but rather when this preventive intervention is indicated. Lingering questions about chemoprevention of breast cancer The main questions concern who is a candidate for chemoprevention and what is the best agent for this purpose. Gail et al105 performed a decision analysis, based on the BCPT, to establish the threshold risk of breast cancer above which chemoprevention with tamoxifen would have been beneficial. Not unexpectedly, the threshold increased with age, and for women aged 70 corresponded to a 7% risk of breast cancer in 5 years. These conclusions should be tempered by two considerations. First, the Gail analysis was not based on utility; that is, it did not take into account the derangement in quality of life caused by tamoxifen, which probably would have rendered the threshold even higher. Second, it did not take into account that tamoxifen might cause some cognitive defects, especially in older women. This concern was not addressed by the BCPT, but Paganini-Hill et al106 showed that women taking tamoxifen had a twofold increased incidence of memory disorders. Chlebowski et al107 employed magnetic resonance spectroscopy of the brain after administration of myoinositol to establish the effects of hormone replacement therapy (HRT) and tamoxifen on cognitive function. When compared with controls not taking either agent, HRT was associated with better and tamoxifen with worse function. Of interest, Yaffe et al48 reported that raloxifene might have improved the cognitive function of women aged 70 and older. The results of the raloxifene osteoporosis prevention trials and of the ATAC studies suggest alternative forms of chemoprevention. The Study of Tamoxifen and Raloxifene (STAR, NSABP-2) trial is ongoing. Opened in 1997, STAR has the goal of enrolling 22000 patients. The primary objective is a reduction in invasive breast cancer, and secondary goals include reductions in non-invasive breast cancer, risk of endometrial cancer and cerebrovascular events, preservation of bone density, and slowing of the rate

Chemoprevention of cancer in the older person

631

of cognitive decline.42,108 STAR represents the most exhaustive attempt to balance the benefits and risk of chemoprevention with SERMs.. At the same time, the IBIS-2 trial is exploring the effects of anastrozole, tamoxifen, and placebo in women at increased risk of breast cancer established on the basis of age and presence of lobular carcinoma in situ (LCIS), atypical hyperplasia, or increased breast density. Patients with DCIS will be eligible for the study, but will not be assigned to placebo. This study will provide the definitive comparison of SERMs and aromatase inhibitors in terms both of effectiveness and of toxicity. This comparison is essential, because the long-term effects of anastrozole, both in breast cancer prevention and on bone and cognition, are unknown. Another important question concerns which aromatase inhibitor may be best suited for chemoprevention. In our opinion, exemestane deserves special attention, because, thanks to its mild androgenic effects, it may prevent osteoporosis and cognitive decline, and cause less disruption of quality of life. Other chemoprevention strategies under investigation include the use of other SERMs,42 of phytoestrogens,109 and of COX-2 inhibitors. COX-2 inhibitors may be synergistic with aromatase inhibitors because they interfere with the synthesis of prostaglandin E2 (PGE2), which is essential to the induction of aromatase. In rodents, the combination of celecoxib and exemestane was more effective than either agent in preventing development and inhibiting growth of DMBA-induced breast cancer.110 In conclusion: • Chemoprevention of breast cancer with tamoxifen is feasible, but the potential toxicity of this agent makes its use problematic in older individuals. At present, chemoprevention should be implemented only in persons at high risk of developing breast cancer (≥7% in 5 years for a 70-year-old woman), who express serious concerns about breast cancer and do not present contraindications to SERMs. • A number of promising chemoprevention strategies are emerging, including the use of third-generation SERMs, of aromatase inhibitors, and of COX-2 inhibitors, either alone or in combination. • Important endpoints of ongoing clinical trials should include quality of life, breast cancer-related mortality, rate of osteoporosis, cognitive decline, and cerebrovascular and cardiovascular complications.

Prostate cancer Prostate cancer is the most common neoplasm and the second most common cause of cancer death in men over 65111 both in the USA and in Western Europe. Not surprisingly, chemoprevention of prostate cancer has been intensively explored in recent years. In the case of prostate cancer, the benefits of early detection are controversial,112–114 and chemoprevention may provide a valid, less toxic alternative form of cancer control. Risk factors The best-established risk factor for prostate cancer is a family history of the disease,115 which accounts for 50% of cancers before age 50, but is of limited interest for the older

Comprehensive Geriatric Oncology

632

man. Criteria for the diagnosis of familial prostate cancer include one of the following: cancer in two first-degree relatives, cancer in three subsequent generations of the same family, and cancer before age 50 in one first-degree and two second-degree relatives. Another risk factor includes consistently elevated concentration of serum testosterone and of IGF-I, as established by the serial examination of banked serum in the Physicians’ Health Study.116 Dietary risk factors may include inadequate intake of phytoestrogens (soya),117 lycopenes (tomato),118,119 and selenium.120 The best established preneoplastic lesion is prostatic intraepithelial neoplasia (PIN).121,122 The histologic evolution of this lesion from dysplasia to high-grade PIN (HGPIN) is associated with phenotypic and genotypic changes that are also typical of prostate cancer. It has been well established that cancer will develop within PIN. Of special interest for the adoption of HGPIN as a surrogate endpoint of chemoprevention is the sensitivity of this lesion to androgen deprivation.123 After radical prostatectomy, the prevalence of HGPIN was much lower for patients who had undergone androgen deprivation preoperatively.124 A major obstacle to the use of this lesion as an endpoint of chemoprevention is the fact that it can only be diagnosed by transurethral resection of the prostate (TURP) or biopsy.121 Both serum concentration of prostate-specific antigen (PSA) and prostate ultrasound proved unreliable for diagnosis. Chemoprevention of prostate cancer Several lines of evidence support androgen deprivation as chemoprevention: • In experimental animals, castration is associated with a negligible incidence of prostate cancer.82 • The incidence of prostate cancer is negligible among eunuchs. • High lifelong production of testosterone is associated with an increased incidence of prostate cancer.116 • Androgen deprivation causes regression of HGPIN.124 Of course, long-term androgen deprivation is a drastic measure involving substantial changes in a person’s lifestyle and health. In addition to loss of libido, androgen deprivation may cause osteoporosis, depression, fatigue, and debilitating hot flushes.125 Another important concern is the risk that early hormonal manipulations may induce hormone-refractory prostate cancer, which is very aggressive and poorly responsive to any form of treatment.57,58,126 Unfortunately, this possibility can be ruled out only by prolonged follow-up of each individual. In the last decade or so, a great deal of effort has been spent in studying ways to deprive the prostate of androgens without systemic androgen deprivation.57 A large phase III clinical trial for men at average risk of prostate cancer studied 18000 individuals.127 Men aged 50 and older with normal serum PSA levels and absence of urinary symptoms were randomized to receive finasteride or placebo. An inhibitor of 5-α-reductase, finasteride prevents transformation of testosterone into the more active dihydrotestosterone. Finasteride was chosen because of its favorable toxicity profile. The most important aim of this study was to determine whether chemo-prevention trials are feasible in prostate cancer.57 The main problem with the study is the fact that finasteride did not show any activity against prostate cancer or against HGPIN, probably because of

Chemoprevention of cancer in the older person

633

the androgenic effect of testosterone.128 The final results of this study were reported in 2003, and showed that while individuals treated with finasteride had a lower incidence of prostate cancer, they presented a higher incidence of high-grade prostate cancer.129 On the basis of this evidence, finasteride cannot be considered at present for the chemoprevention of prostate cancer. Androgen antagonists130 and SERMs131 prevent the growth of prostate cancer in the experimental model. These compounds are attractive because they may spare sexual function and, in the case of SERMs, bone integrity. As in the case of finasteride, however, their action may be overwhelmed by compensatory overproduction of testosterone, and selection of hormone-refractory tumor cells may represent a problem. Low-dose estrogen132 represents another alternative that surprisingly has not yet been explored. In low doses (equivalent to 1mg of diethylstilbestrol (DES) daily), estrogen may cause effective androgen deprivation of the prostate by increasing the serum concentration of sex hormone-binding globulin, prevent osteoporosis, preserve some degree of libido, and avoid hot flushes. In addition, this form of treatment is much less expensive than finasteride and androgen antagonists. The risk of thromboembolic complications is probably minimal for physically active men without a history of thromboembolism. Several forms of non-hormonal chemoprevention are being explored.57 Of these, two deserve special mention. The use of COX-2 inhibitors is intriguing, since they may be synergistic with hormonal manipulations.133 The Selenium and Vitamin E Cancer Prevention Trial (SELECT) involves 32400 men and will take 12 years to complete.134 The rationale of this trial is the finding of the ATBC (α-Tocopherol, β-Carotene) cancer prevention trial,135 directed at chemoprevention of lung cancer, that α-tocopherol was associated with a reduced incidence of prostate cancer. Summary of chemoprevention of prostate cancer Prostate cancer is a major cause of morbidity and mortality in older men, and its prevention is highly desirable. Clearly, androgen deprivation is the most promising strategy. Before this strategy can be implemented, a number of important issues need to be addressed: • avoidance of long-term effects of androgen deprivation; • proof that androgen deprivation does not result in a higher incidence of hormonerefractory prostate cancer; • identification of individuals who are at risk of suffering from prostate cancer complications during their lifetime; • assessment of cost-effectiveness. Although HGPIN proved to be a reliable lesion to follow as a surrogate endpoint, the need for invasive procedures to make this diagnosis limits its usefulness; furthermore, this lesion cannot be used to address the concern of hormone-refractoriness. At present, no form of chemoprevention of prostate cancer has proved efficacious.

Comprehensive Geriatric Oncology

634

Colorectal cancer Colorectal cancer is the second most common cause of cancer death in the Western world. The incidence of this cancer increases with age.136 While chemoprevention of colorectal cancer is highly desirable, secondary prevention through early diagnosis has already proved effective in reducing cancer deaths.137–139 The benefits and cost of chemoprevention and of secondary prevention need then to be compared. There is evidence that NSAIDs may prevent colorectal cancer, including the following: • The concentration of prostaglandin is higher in many malignant tissues than in normal tissues.40,41 • Sulindac and the COX-2 inhibitor celecoxib prevent colorectal cancer in experimental animals after carcinogen exposure.40 • In two retrospective studies, regular aspirin intake was associated with a reduced risk of death from colorectal cancer;119,140 furthermore, aspirin reduced the number and size of polyps in patients with familial polyposis of the colon.40 • Celecoxib reduced the number and size of polyps in patients with familial polyposis in a randomized placebo-controlled study.18 The drug was approved by the US Food and Drug Administration (FDA) for the management of this condition. While a relationship between clinical use of NSAIDs and reduced risk of colon cancer appears likely, the clinical application of this finding is questionable: • Low doses of aspirin, as recommended for the prevention of coronary artery disease, may be ineffective in the prevention of colorectal cancer; higher doses may be associated with excessive risk of bleeding and gastrointestinal and renal complications; • There is no definitive proof that COX-2 inhibitors prevents colon cancer, and the longterm complications of these compounds are also unknown. They may include increased risk of coronary artery disease.141 Seemingly, only randomized controlled studies will be able to establish the risks and benefits of NSAIDs in the prevention of colorectal cancer. Of special interest are retrospective analyses suggesting that HRT may prevent colorectal cancer in post-menopausal women. Summary of the recommendations for chemoprevention of colorectal cancer While it is clear that NSAIDs and possibly HRT may lead to chemoprevention of colorectal cancer, no clinical recommendations may be derived from existing evidence.

Chemoprevention of cancer in the older person

635

Lung cancer Risk assessment Lung cancer is currently the most common cause of cancer deaths in men and the second most common in women.136 During the last two decades or so, the age at diagnosis of lung cancer has become more and more advanced, probably as a result of more and more people quitting smoking.141 Smoking cessation may have resulted in: • a decline in mortality from cardiovascular diseases; • delayed development of lung cancer; • development of a more indolent neoplasm. Thus, lung cancer in the USA has become more and more a disease of the aged. Although the majority of patients are smokers, it is important to remember that it may also be caused by passive exposure to cigarette smoke, asbestos, arsenic,142 and even cyclic amines in the diet.143,144 Genetic predisposition to lung cancer has been well established, and generally involves defective repair of mutagen-induced DNA damage,145–147 enhanced mutagen sensitivity,148 and increased activity of hepatic phase I and reduced activity of hepatic phase II enzymes.144 Molecular epidemiology of lung cancer suggests carcinogenic check-points amenable to chemoprevention. Early detection of lung cancer is still in the experimental phase.149 Spiral computed tomography (CT) proved superior to standard chest radiography in detecting early lung cancer.150 An ongoing randomized controlled trial is exploring whether serial screening with spiral CT leads to reduced cancer-related mortality.151 Thus, chemoprevention has a real opportunity to make a difference in the history of lung cancer in older individuals. Clinical trials of chemoprevention Several important points emerge from examination of the randomized clinical trials exploring chemoprevention of lung cancer (Table 28.3): • These trials are feasible, in several different sets: as phase Ilb trials, using surrogate endpoints, and as phase III trials exploring prevention of primary and secondary lung cancer. Individuals aged 65 and older were involved in all of the trials, so age does not appear as an obstacle to enrollment and participation. • None of the substances tested so far seems to have a substantial chemopreventive effect. • Of special concern, β-carotene seemed to increase the incidence and mortality of lung cancer in the ATBC trial135 and the CARET study (which was closed prematurely when the ATBC results emerged).157 The harmful effect of p-carotene appears to be limited to heavy smokers, and Wang et al161 have provided an experimental background for this effect. In ferret lungs, the combination of smoke and heavy doses of β-carotene suppresses the expression of RARp and enhances that of activator protein 1. Both changes tend to increase the development and growth of cancer. Along

Comprehensive Geriatric Oncology

636

the same lines, the Lung Intergroup Trial, conducted by the MD Anderson Cancer Center Community Clinical Oncology Research Data Base,160 showed that isotretinoin increased both the risk of second primary tumors and cancer recurrence among current smokers, while it might have been beneficial to never-smokers and ex-smokers. It is clear that chemoprevention studies of lung cancer are feasible and should exclude current smokers, given the unknown interaction between smoking and chemopreventive agents. They should be focused on patients at risk, especially former smokers. The ability to perform serial bronchoscopies and examination of sputum cytology allows the study of an emerging host of molecular markers, including RARs, hypermethylation, p53 abnormalities, telomerase, ras abnormalities, and LOH.13 Other cancers Head and neck cancer Although of limited interest to older individuals, chemoprevention of cancer of the upper airways deserve special mention, because it represents a paradigm for chemoprevention in at least three areas:23

Table 28.3 Randomized clinical trials of chemoprevention of lung cancer Study

Endpoint

Agent(s)

No. of patients

Results

Heimburger et al (1988)152

Reversal of metaplasia

Vitamin B12 plus folate

73

Negative

Arnold et al (1992)153

Reverse cytology

Etretinate

150

Negative

Lee et al (1994)154

Prevention of metaplasia

Isotretinoin

87

negative

Kurie et al (2000)155

Prevention of metaplasia

Fenretinide

68

Negative

Mclarty et al (1995)156

Sputum atypia in asbestos workers

β-Carotene and vitamin A

755

Negative

Phase IIb

Phase III: smokers ATBC (αTocopherol, βCarotene)135

Prevention of lung α-Tocopherol and cancer in smokers β-carotene

29133

β-Carotene was harmful; α-tocopherol may decrease the incidence of prostate cancer

β-Carotene and

Prevention of lung β-Carotene and

18324

Increased incidence of

Chemoprevention of cancer in the older person

Retinol Efficacy Trial (CARET) (Omenn)157

cancer in smokers and asbestos workers

retinol

637

and mortality from lung cancer

Phase III: previous history of lung cancer Pastorino et al (1993)158

Prevention of Retinyl palmitate second lung cancer

EUROSCAN (2000) Prevention of (van Zandijk et al)159 second lung or head and neck cancer Lippman et al (2001)160

307

N-Acetylcysteine, 2592 retinyl palmitate

Prevention of Isotretinoin second lung cancer

1166

Negative Negative

Negative

• demonstration that the use of surrogate endpoints (reversal of premalignant leukoplakia) may predict chemopreventive activity;16 • demonstration that the development of second primary tumors is a valid endpoint for chemoprevention;24 • demonstration of the discrepancy between genotypic and phenotypic changes in premalignant lesions following chemoprevention: LOH at chromosome 9p persisted in the oropharyngeal mucosa, despite regression of leukoplakia.73 Other important findings of these studies included higher activity of cis-retinoic acid than β-carotene in leukoplakia,162 chronic toxicity of cis-retinoic acid even in low doses,23 and development of resistance to cis-retinoic acid.24 Bladder cancer Currently, two strategies are being studied for the chemoprevention of bladder cancer: use of fenretinide and of COX-2 inhibitors in patients with early-stage disease. In the experimental system, fenretinide offset bladder carcinogenesis; celecoxib appears to be synergistic with bacille Calmette-Guérin (BCG) in patients with carcinoma in situ. 163 Conclusions Chemoprevention of cancer is clearly a promising strategy for cancer control in the older person. The discovery of intermediate markers of carcinogenesis and the development of safer agents targeted at specific molecular abnormalities should render research into chemoprevention highly fruitful in the near future. The possibility that chemoprevention of cancer may at the same time delay molecular aging is also of special interest. Currently, only tamoxifen has been proven beyond doubt to be capable of preventing a cancer (breast cancer). The use of this compound in older women is limited by the risk of complications, and should not be instituted unless the risk of breast cancer is 7% or higher at 5 years.

Comprehensive Geriatric Oncology

638

References 1. Berlin A. The conquest of cancer. Cancer Invest 1995; 13:540–50. 2. Yancik R, Ries LAG. Aging and cancer in America: demographic and epidemiologic perspectives. Hematol Oncol Clin North Am 2000; 14: 17–24. 3. Fried LP, Bandeen-Roche K, Kasper JD et al. Association of comorbidity with disability in older women: the women’s health and aging study. J Clin Epidemiol 1999; 52:27–37. 4. Barnabei R, Gambassi G, Lapana K et al. Management of pain in elderly patients with cancer. SAGE study group. Systematic assessment of geriatric drug use via epidemiology. JAMA 1998; 17: 1877–82 5. Yancik RM, Ries LAG. Cancer in older persons: magnitude of the problem and efforts to advance the aging/cancer research interface. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004: 38– 46. 6. Balducci L, Extermann M. A practical approach to the older patient with cancer. Curr Prob Cancer 2001; 25:1–76. 7. Repetto L, Balducci L. A case for geriatric oncology. Lancet Oncol 2002; 3:289–97. 8. Sugimura T. Multistep carcinogenesis: a 1992 perspective. Science 1992; 258:603–7. 9. Balducci, Beghe’ C. Prevention of cancer in the older person. Clin Geriatr Med 2002; 18:505– 28. 10. Anisimov VN. Age as a risk factor in multistage carcinogenesis. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004: 75–101. 11. Diab SG, Elledge RM, Clark GM. Tumor characteristics and clinical outcome of elderly women with breast cancer. J Natl Cancer Inst 2000; 92:550–6. 12. Repetto L, Venturino A, Gianni W. Prognostic evaluation of the older cancer patient. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:309–19. 13. Lippman SM, Spitz MR. Lung cancer chemoprevention: an integrated approach. J Clin Oncol 2001; 19(Suppl):74s–82s. 14. Kinzler KV, Vogelstein B, Cancer-susceptibility genes. Gatekeepers and caretakers. Nature 1997; 386:761–3. 15. Keller KL, Fenske N, Glass LF. Cancer of the skin in the older patient. Clin Geriatr Med 1997; 13:339–62. 16. Hong WK, Endicott J, Itri LM et al. 13-cis-Retinoic acid in the treatment of oral leukoplakia. N Engl J Med 1986; 315:1501–5. 17. Sakr WA, Partin AW. Histological markers of risk and the role of high grade prostate intraepithelial neoplasia. Urology 2001; 57: 115–20. 18. Steinbach G, Phillips RKS, Lynch PM. The effect of celecoxib, a cyclooxygenase 2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000; 342:1996–52. 19. Follen M, Meyskens FL, Atkinson EN et al. Why most randomized phase II cervical cancer chemoprevention trials are uninformative. J Natl Cancer Inst 2001; 93:1293–96. 20. Tan-Chiu E, Costantino J, Wang J et al. The effect of tamoxifen on benign breast disease. Findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial. Breast Cancer Res Treat 2001; 69:3:210. 21. Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for prevention of breast cancer: report from the National Adjuvant Breast and Bowel Project. J Natl Cancer Inst 1998; 90:1371–88. 22. Fisher B, Dignam J, Wolmark N et al. Tamoxifen in treatment of intraductal breast cancer: National Breast and Bowel Project B24 randomized controlled study. Lancet 1999; 353:1993– 2000.

Chemoprevention of cancer in the older person

639

23. Hong WK, Spitz MR, Lippman SM. Chemoprevention in the 21st century: genetics, risk modeling, and molecular targets. J Clin Oncol 2000; 18(Suppl):9s–18s. 24. Benner SE, Pajak TF, Lippman SM et al. Prevention of second primary tumors with isotretinoin in squamous cell carcinoma of the head and neck: long term follow up. J Natl Cancer Inst 1994; 86: 140–1. 25. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet 1998; 351:1451–67. 26. Guengerich FP. Metabolic activation of carcinogens. Pharmacol Ther 1992; 54:16–71. 27. Oesch F, Doehmer J, Friedberg T et al. Control of ultimate mutagenic species by different enzymes. Prog Clin Biol Res 1990; 340B:49–65. 28. Chung FL, Kelloff G, Steele V et al. Chemopreventive efficacy of arylalkyl isothiocyanates and N-acetyl-cysteine for lung tumorigenesis in Fisher rats. Cancer Res 1996; 56:772–8. 29. Hecht SS. Chemoprevention by isothiocyanates. J Cell Biochem 1995; 22(Suppl):195–209. 30. Stoner GD, Mukhtar H. Polyphenols as cancer chemopreventive agents. J Cell Biochem 1995; 22(Suppl):169–80. 31. Morse MA, Elkind KI, Amin SG et al. Effects of alkyl chain length on the inhibition of NNKinduced lung neoplasia in A/J mice by arylalkyl isothiocyanates. Carcinogenesis 1989; 10:1757–9. 32. Brady JF, Ishikazi H, Fukuto JM et al. Inhibition of cytochrome P-450 2E1 by diallyl sulfide and its metabolites. Chem Res Toxicol 1991; 4:642–7. 33. Chen L, Lee M, Hong JY et al. Relationship between cytochrome P450E1 and acetone catabolism in rats as studied with diallyl sulfide as an inhibitor. Biochem Pharmacol 1994; 48:2199–205. 34. Rao CV, Tokomo K, Kelloff G et al. Inhibition by dietary oltipraz of experimental intestinal carcinogenesis induced by azoxymethane in male F344 rats. Carcinogenesis 1991; 12:1051–5. 35. Hursting SD, Slaga TJ, Fisher SM et al. Mechanism-based cancer prevention approaches: targets, examples, and the use of transgenic mice. J Natl Cancer Inst, 1999; 91:215–25. 36. Sancar A. Mechanism of DNA repair. Science 1995; 266:1954–6. 37. Fischer SM, DiGiovanni J. Mechanisms of tumor promotion: epigenetic changes in cell signaling. Cancer Bull 1995; 47:456–63. 38. Furstenberger G, Marks F. Prostaglandin, epidermal hyperplasia, and skin tumor promotion. In: Prostaglandins, Leukotrienes and Cancer (Horn KV, Marnett LJ, eds). Boston: Martinus-Nijoff, 1985:22–37. 39. Kong AN, Yu R, Hebbar V et al. Signal transduction events elicited by cancer prevention compounds. Mutat Res 2001; 1:231–41. 40. Baron JA, Sandler RS. Nonsteroidal anti-inflammatory drugs and cancer prevention. Annu Rev Med 2000; 51:511–23. 41. Prescott SM, Fitzpatrick FA. Cyclooxygenase 2 and carcinogenesis. Biochem Biophys Acta 2000; 1470: M69–78. 42. Lippman SM, Brown PH. Tamoxifen prevention of breast cancer: an instance of the fingerpost. J Natl Cancer Inst 1999; 91:1809–19. 43. Meyskens FL, Gerner EW. Development of difluoromethylornithine as a chemopreventive agent. Clin Cancer Res 1999; 5:945–51. 44. Steele VE, Holmes CA, Hawk ET et al. Potential use of lipooxygenase inhibitors for cancer prevention. Expert Opin Invest Drugs 2000; 9:2121–38. 45. Livingstone LR, White A, Sprouse J et al. Altered cell cycle arrest and gene amplification potential accompany loss of wild type p53. Cell 1992; 70:923–35. 46. Agnusdei D, Liu-Lerae S, Augendre-Ferrant B. Results of international clinical trials with raloxifene. Ann Endocrinol (Paris) 1999; 60:342–6 47. Ettinger B, Black D, Cummings S et al. Raloxifene reduces the risk of incident vertebral fractures: 24 months interim analysis. Osteoporosis Int 1998; 8(Suppl 3):11.

Comprehensive Geriatric Oncology

640

48. Yaffe K, Krueger K, Sarkar S et al. Multiple Outcomes of Raloxifene Evaluation investigators. N Engl J Med 2001; 344:1207–13. 49. Brown P, Fuqua S, AUred C. Pathogenesis of ER-positive and ER-negative breast cancer. Endocrin Oncol (to be published). 50. Brzozowski AM, Pike AC, Dauter Z et al. Molecular basis of agonism and antagonism in the estrogen receptor. Nature 1997; 389:753–8. 51. Leygue E, Dotzlaw H, Watson PH et al. Expression of estrogen receptors β1, β2, and β5 messenger RNAs in human breast tissue. Cancer Res 1999; 59:1175–9. 52. Jordan VC, Lababidi MK, Langhan-Fahey S. Suppression of mouse mammary tumorigenesis by long-term tamoxifen therapy. J Natl Cancer Inst 1991; 83:492–6. 53. Minton SE. Chemoprevention of breast cancer in the older patient. Hematol Oncol Clin North Am 2000; 14:113–30. 54. Nicolaides C, Dimopoulos MA, Samantas E et al. Gemcitabine and vinorelbine as second-line treatment in patients with metastatic breast cancer progressing after first-line taxane-based chemotherapy: a phase II study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol 2000; 11:873–5. 55. Goss P, Grympass M, Qi S et al. The effects of exemestane on bone and lipids in the ovariectomized rat. Breast Cancer Res Treat 2001; 69:224(Abst 131). 56. Heshmati J, Bone mineral, Metabolism 1997; 12:S121(Abst 76). 57. Lieberman R, Nelson WG, Sakr WA et al. Executive summary of the National Cancer Institute Workshop: highlights and recommendations. Urology 2001; 57(Suppl 1):4–27. 58. Lieberman R. Androgen deprivation therapy for prostate cancer chemoprevention: current status and future directions for agent developments. Urology 2001; 58(Suppl 1):83–90. 59. Chambon B. The retinoid signaling pathway: molecular and genetic analysis. Semin Cell Biol 1994; 5:115–25. 60. Mangelsdorf DJ, Umesono K, Evans RM. The retinoid receptors. In: The Retinoids (Sporn MB, Roberts AB, Goodman DS, eds). New York: Raven Press, 1994:319–49. 61. Boehm MF, Zhang L. Synthesis and structure-activity relationship of novel retinoid X receptorselective retinoids. J Med Chem 1994; 37: 2930–41. 62. Oridate N, Lotan D, Xu XC et al. Differential induction of apoptosis by all-trans-retinoic acid and N-(4-hydroxyphenyl)retinamide in human head and neck squamous cell carcinoma cell lines. Clin Cancer Res 1996; 2:855–63. 63. Meyskens FL. Criteria for the implementation of large and multiagent clinical chemoprevention trials. J Cell Biochem 2000; 34(Suppl): 115–20. 64. Powles T, Eles R, Ashley S et al. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet 1998; 352:98–101. 65. Veronesi U, Maisonneuve P, Costa A et al. Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomized trial among hysterectomised women. Lancet 1998; 352:93–7. 66. Vestal RE. Aging and pharmacology. Cancer 1997; 80:1302–10. 67. Day R, Ganz PA, Costantino JP et al. Health-related quality of life and tamoxifen in breast cancer prevention: a report from the National Surgical Adjuvant Breast and Bowel Project Pl study. J Clin Oncol 1999; 17:2559–69. 68. Kerlikowske K, Salzman P, Phillips KA et al. Continuing screening mammography in women aged 70 to 79 years. JAMA 1999; 282: 2156–63. 69. Vineis P, Veglia F. Selection and validation of biomarkers for chemoprevention: the contribution of epidemiology. IARC Sci Publ 2001; 154:57–68. 70. Kensler TW, Davidson NE, Groopman JD et al. Biomarkers and surrogacy: relevance to chemoprevention. IARC Sci Publ 2001; 154: 27–47. 71. Hong WK, Lippman SM, Itri LM et al. Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med 1990; 323:795–801.

Chemoprevention of cancer in the older person

641

72. Jetten AM, Nervi C, Vollberg TM. Control of squamous differentiation in tracheoepithelial and bronchial cells: role of retinoids. J Natl Cancer Inst Monogr 1992; 13:93–100. 73. Mao L, El Naggar AK, Papadimitrakopoulou VM et al. phenotype and genotype in advanced premalignant head and neck lesions after chemopreventive therapy. J Natl Cancer Inst 1998; 90:1545–51. 74. La Vecchia C, Lucchini F, Negri E et al. Cancer mortality in the elderly: a worldwide approach. Oncol Spectrum 2001; 2:386–94. 75. Ahuja N, Issa JP. Aging, methylation and cancer. Histol Histopathol 2000; 15:835–42. 76. Lieber MR. Pathological and physiological double-strand break: roles in cancer, aging, and the immune system. Am J Pathol 1998; 153: 1323–32. 77. Turker MS. Somatic cell mutations: Can they provide a link between aging and cancer? Mech Ageing Dev 2000; 117:1–19. 78. Anisimov VN. Age-related mechanisms of susceptibility to carcinogenesis. Semin Oncol 1989; 16:10–19. 79. Anisimov VN, Gvardina OE. N-Nitrosomethylurea-induced carcinogenesis in the progeny of male rats of different ages. Mutat Res 1995; 316:139–45. 80. Ebbesen P. Papilloma development on young and senescent mouse skin treated with 12-Otetradecanoylphorbol-13-acetate. In: Age-Related Factors in Carcinogenesis (Likhacev A, Anisimov V, Montesano R et al, eds). Lyon: IARC Press, 1985:167–70. 81. Kraupp-Grasl B, Huber W, Taper H et al. Increased susceptibility of aged rats to hepatocarcinogenesis induced by the peroxisome proliferator nafenopin and the possible involvement of altered liver foci occurring spontaneously. Cancer Res 1991; 51:666–71 82. Balducci L, Khansur T, Smith T, Hardy C. Prostate cancer: a model of cancer in the elderly. Arch Geriatr Gerontol 1989; 8:165–87. 83. Moon TD. Prostate cancer in the elderly. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:725– 41. 84. Barbone F, Bovenzi M, Cavallieri F et al. Air pollution and lung cancer in Trieste, Italy. Am J Epidemiol 1995; 141:1161–9. 85. Collins K. Mammalian telomeres and telomerase. Curr Opin Cell Biol 2000; 12:378–83. 86. Liggett WH, Sidransky D. Role of the p16 tumor suppressor gene in cancer. J Clin Oncol 1998; 16:1197–206. 87. Campisi J. Aging and cancer: the double-edged sword of replicative senescence. J Am Geriatr Soc 1997; 45:482–8. 88. Franceschi C, Bonafe M, Valnesiu S et al. Inflamm-aging: an evolutionary perspective on immunosenescense. Ann NY Acad Sci 2000; 908:244–54. 89. Burns EA, Goodwin JS. Immunological changes of aging. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:158–70. 90. Ershler WB. The influence of an aging immune system on cancer incidence and progression. J Gerontol 1993; 48: B3. 91. Martin F. Frailty and the somatopause. Growth Hortnone IGF Res 1999; 9:3–10. 92. Rivard A, Fabre JE, Silver M et al. Age-dependent impairment of angiogenesis. Circulation, 1999; 99:111–20. 93. Swift ME, Kleiman HK, DiPietro LA. Impaired wound repair and delayed angiogenesis in aged mice. Lab Invest 1999; 79:1479–87. 94. Balducci L, Silliman RA, Diaz N. Breast cancer in the older woman: an oncologic perspective. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:662–703. 95. Costantino JP, Gail MH, Pee D et al. Validation studies of models projecting the risk of invasive and total breast cancer incidence. J Natl Cancer Inst 1999; 91:1541–8.

Comprehensive Geriatric Oncology

642

96. Clemons M, Goss P. Mechanism of diseases: estrogen and the risk of breast cancer. N Engl J Med 2001; 344:276–85. 97. Zhang Y, Kiel DP, Kreger BE et al. Bone mass and the risk of breast cancer among postmenopausal women. N Engl J Med 1997; 336: 611–17. 98. Cummings SR, Duong T, Kenyon E et al. Serum estradiol level and risk of breast cancer during treatment with raloxifene. JAMA 2001; 287:216–20. 99. Boyd NF, Byng JW, Jong RA et al. Quantitative classification of mammographic densities and breast cancer risk: results from the Canadian National Breast Screening Study. J Natl Cancer Inst 1995; 87:670–5. 100. Miettinen OS, Henschke CE, Pasmantier MW et al. Mammo-graphic screening: no reliable supporting evidence? Lancet 2002; 359:404–6. 101. Miller AB, To T, Baines CJ et al. Canadian National Breast Screen-ing Study-2:13-year results of a randomized trial in women aged 50–59 years. J Natl Cancer Inst 2000; 92:1490–9. 102. Cummings SR, Eckert S, Krueger KA et al. The effect of raloxifene on risk of breast cancer in postmenopausal women. JAMA 1999; 281:2189–97. 103. Baum M, on behalf of the ATAC Trialists’ Group. The ATAC (Arimidex, Tamoxifen Alone or in Combination) adjuvant breast cancer trial in post-menopausal women. Breast Cancer Res Treat 2001; 69:210 (Abst 8). 104. Decensi A, Gandini S, Guerrieri-Gonzaga A et al. Effects of blood tamoxifen concentration on surrogate biomarkers in a trial of dose-reduction in health women. J Clin Oncol 1999; 17:2633– 8. 105. Gail MH, Costantino JP, Bryant J et al. Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer. J Natl Cancer Inst 1999; 91:1829–46. 106. Paganini-Hill A, Clark LJ. Preliminary assessment of cognitive function in breast cancer patients. Breast Cancer Res Treat 2000; 64:165–76. 107. Chlebowski RT, Ernst T, Chang L et al. Tamoxifen and estrogen effect on brain chemistry determined by MRI spectroscopy. Proc Am Soc Clin Oncol 2001; 20:28a (Abst 108). 108. Vogel VG, Costantino JP, Wickerham DL et al. The study of tamoxifen and raloxifene: preliminary enrollment data from a randomized breast cancer risk reduction trial. Breast Cancer Res Treat 2001; 69:225 (Abstr 135). 109. Messina MJ, Loprinzi CL. Soy for breast cancer survivors: a critical review of the literature. J Nutr 2001; 13(11 Suppl):3095s–108s. 110. Presenti E, Masferrer JL, Di Salle E. Effect of exemestane and celecoxib alone or in combination on DMBA induced mammary carcinoma in rats. Breast Cancer Res Treat 2001; 69:288 (Abst 445). 111. Boyle P. Severi G. Epidemiology of prostate cancer chemoprevention. Eur Urol 1999; 75:370–6. 112. Chodak GW, Thisted RA, Gerber GS et al. Results of conservative management of clinically localized prostate cancer. N Engl J Med 1994; 230:242–8. 113. Horninger W, Reisigl A, Rogatsch H et al. Prostate cancer screening in Tyrol, Austria: experience and results. Eur J Cancer 2000; 36: 1322–35. 114. Labrie F, Candas B, Dupont A et al. Screening decreases prostate cancer death: first analysis of the Quebec randomized controlled trial. Prostate 1999; 38:83–91 115. Stanford JL, Ostrander EA. Familial prostate cancer. Epidemiol Rev 2001; 23:19–23. 116. Shaneyfelt T, Husein R, Bubley G et al. Hormonal predictors of prostate cancer: a metaanalysis. J Clin Oncol 2000; 847–54. 117. Moyad MA. Soy, disease prevention and prostate cancer. Semin Urol Oncol 1999 17:97–103. 118. Nelson WG, Wilding G. Prostate cancer prevention agent development: criteria for candidate chemoprevention agents. Urology 2001; 57:56–63. 119. Giovannucci E. Tomatoes, tomato-based products, lycopene and cancer: review of the epidemiologic literature. J Natl Cancer Inst 1999; 91:317–31.

Chemoprevention of cancer in the older person

643

120. Yoshizava K, Willett WC, Morris SJ et al. Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer. J Natl Cancer Inst 1998; 90:1219–24. 121. Bostwick DG. Prostatic intra-epithelial neoplasia is a risk factor for cancer. Semin Urol Oncol 1999; 17:187–98. 122. Bostwick DG, Montironi R, Sesterhenn IA. Diagnosis of prostatic intraepithelial neoplasia: Prostate Work Group Consensus Report. Scand J Urol Nephrol 2000; 205(Suppl):3–10. 123. Lieberman R, Bermejo C, Akaza H et al. progress in prostate cancer chemoprevention: modulators of promotion and progression. Urology 2001; 58:835–42. 124. van der Kast TH, Labrie F, Tetu B. Prostatic intra-epithelial neoplasia and endocrine manipulation. Eur Urol 1999; 35:508–10. 125. Messing EM, Manola J, Sarosdy M et al. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 2000; 341:1781–8. 126. Crawford ED, Rosembaum M, Ziada AM et al. Overview: hormone refractory prostate cancer. Urology 1999; 54(Suppl 6a):1–7. 127. Trump DL, Waldstreicher JA, Kolvenbag G et al. Androgen antagonists: potential role in prostate cancer prevention. Urology 2001; 57(Suppl 1):64–7. 128. Bostwick DG, Qian J. Effect of androgen deprivation therapy on prostatic intraepithelial neoplasia. Urology 2001; 58(Suppl 1):91–3. 129. Thompson IM, Goodman PJ, Tangen CM et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003; 349:215–24. 130. Raghow S, Kuliyev E, Steakley M et al. Efficacious chemoprevention of primary prostate cancer by flutamide in an autochronos transgenic model. Cancer Res 2000; 60:4093–7. 131. Steiner MS, Raghov S, Neubauer BL. Selective estrogen receptor modulator for the chemoprevention of prostate cancer. Urology 2001; 57:68–72. 132. Balducci L, Parker M, Hescock H et al. Systemic management of prostate cancer: an annotated review. Am J Med Sci 1990; 299:185–92. 133. Badawi AF, El-Sohemi A. Non-steroidal anti-inflammatory drugs in chemoprevention of breast and prostate cancer. Med Hypotheses 2001; 57:167–8. 134. Klein EA, Thompson IM, Lippman SM et al. SELECT: the Selenium and Vitamin E Cancer Prevention Trial: rationale and design. Prostate Cancer Prostatic Dis 2000; 3:145–51. 135. The α-Tocopherol, β-Carotene Cancer Prevention Study Group: the effect of vitamin E and pcarotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994; 330: 1029–35. 136. Jemal A, Tiwari RC, Murray T et al. Cancer Statistics 2004. CA Cancer J Clin 2004; 54:8–29. 137. Frazier AL, Colditz GA, Fuchs CS. Cost-effectiveness of screening for colorectal cancer in the general population. JAMA 2000; 284: 1954–61. 138. Winawer SJ, Zauber AG, Ho MN et al. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med 1993; 329:1977–81. 139. Mandel JS, Church Tr, Ederer F et al. Colorectal cancer mortality: effectiveness of biennial screening for fecal occult blood. J Natl Cancer Inst 1999; 91:434–7. 140. Thun MJ, Namboodiri MM, Heath CW Jr et al. Aspirin use and reduced risk of fatal colon cancer. N Engl J Med 1991; 325:1593–6. 141. Mukerjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001; 286:954–9. 142. Halpern MT, Gillespie BW, Warner KE. Patterns of absolute risk of lung cancer mortality in former smokers. J Natl Cancer Inst 1993; 17:457–64. 143. Sinha R, Kulldorff M, Swanson CA et al. Dietary heterocyclic amines and the risk of lung cancer among Missouri women. Cancer Res 2000; 60:3753–6. 144. Vineis P, Malats N. Strategic issues in the design and interpretation of studies on metabolic polymorphism and cancer. IARC Sci Publ 1999; 148:51–61.

Comprehensive Geriatric Oncology

644

145. Ooi WL, Elston RC, Chen VW et al. Increased familial risk for lung cancer. J Natl Cancer Inst 1986; 76:217–22. 146. Wei Q. Cheng L, Amos CI et al. Repair of tobacco-carcinogen induced DNA adducts and lung cancer risk. J Natl Cancer Inst 2000; 92:1764–72. 147. Wei Q. Cheng L, Hong WK et al. Reduced DNA repair capacity in lung cancer patients. Cancer Res 1996; 56:4103–7. 148. Wu XF, Hsu TC, Spitz MR. Mutagen sensitivity exhibits a dose-response relationship in casecontrol studies. Cancer Epidemiol Biomark Prev 1996; 5:577–8. 149. Marcus PM. Lung cancer screening: an update. J Clin Oncol 2001; 19(Suppl):83s–6. 150. Henschke C, Mccauley DI, Yankelevitz DF et al. Early Lung Cancer Action Project: overall design and finding from baseline screening. Lancet 1999; 354:99–105. 151. Gohagan JK, Porok PC, Hayes RB et al. The Prostate, Lung, Colorectal and Ovarian (PLCO) screening trial of the National Cancer Institute: history, organization, and status. Control Clin Trials 2000; 21(Suppl 6):251s–72s. 152. Heimburger DC, Alexander B, Birch R et al. Improvement in bronchial squamous metaplasia in smokers treated with folate and vitamin B12: report of a preliminary randomized doubleblind intervention trial. JAMA 1988; 259:1525–30. 153. Arnold AM, Browman GP, Levine MN et al. The effect of the synthetic retinoid etretinate on sputum cytology: results from a randomized trial. Br J Cancer 1992; 65:737–43. 154. Lee JS, Lippman SM, Benner SE et al. A randomized placebocontrolled trial of isotretinoin in chemoprevention of bronchial squamous metaplasia. J Clin Oncol 1994; 12:937–45. 155. Kurie JM, Lee JS, Khuri FR et al. N-(4-Hydroxyphenyl)retinamide in the chemoprevention of squamous metaplasia of the bronchial epithelium. Clin Cancer Res 2000; 6:2973–9. 156. McLarty JW, Holiday DB, Girard WM et al. β-Carotene, vitamin A and lung cancer chemoprevention: results of an intermediary end-point study. Am J Clin Nutr 1995; 62:1431S– 8S. 157. Omenn GS, Goodman GE, Thornquist MD et al. Effects of a combination of β-carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996; 334:1150–5. 158. Pastorino U, Infante M, Maioli M et al. Adjuvant treatment of stage I lung cancer with highdose vitamin A. J Clin Oncol 1993; 11:1216–22. 159. Van Zandwijk N, Dalesio O, Pastorino U et al. EUROSCAN: a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. J Natl Cancer Inst 2000; 92: 977–86. 160. Lippman SM, Lee JJ, Karp DD et al. Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small cell lung cancer. J Natl Cancer Inst 2001; 93: 605–18. 161. Wang X-D, Liu C, Bronson RT et al. Retinoid signaling and activator-protein 1 expression in ferrets given β-carotene and exposed to tobacco smoke. J Natl Cancer Inst 1999; 91:60–6. 162. Papadimitrakapoulou VA, Hong WK, Lee JS et al. Low dose isotretinoin versus β-carotene to prevent oral carcinogenesis: long term follow-up. J Natl Cancer Inst 1997; 89:257–8. 163. Chemoprevention Working Group. Prevention in the next millennium: Report of the Chemoprevention Working Group to the American Association for Cancer Research. Cancer Res 1999; 59: 4743–58.

29 Secondary prevention of cancer in the older person Claudia Beghe’, Lodovico Balducci Introduction Cancer is the second most common cause of mortality for Americans aged 65 and older and it may become the first during the next decade, as mortality from heart diseases is declining1,2 (see Chapter 4 of this volume3). The importance of cancer as a cause of mortality is highlighted by recent studies showing that cancer preferentially affects older individuals who are functionally independent and with low degree of comorbidity4,5 (see Chapter 26 of this volume6), and who probably would live even longer were it not for the fact they had developed cancer. In addition, cancer and cancer treatment are major causes of short-term disability and deterioration of quality of life.7–11 Both cancer and cancer treatment may cause pain, fatigue, nausea, depression, and cognitive deterioration, which may lead to long-term disability in cancer survivors. The issue of cancer-related disability in older individuals has been controversial. Whereas the Baltimore Longitudinal Study showed that, together with heart disease, cancer is a major cause of disability for older women,12 other studies found that musculoskeletal disorders and severe cardiovascular or pulmonary diseases were more common and more severe causes of disability.13–17 According to an estimate based on disease prevalence and mortality, elimination of cancer would increase the risk of disability for older individuals,18 because greater lifeexpectancy would result in higher prevalence of musculoskeletal disorders and other disabling conditions associated with age. Seemingly, its high mortality rate made cancer an unlikely cause of permanent dis-ability. As cancer survivorship is improving thanks to new forms of treatment that are beneficial also to older individuals,19 the prevalence of cancer-related disability is likely to increase as well. Cancer prevention represents the most obvious way to reduce both mortality and disability from cancer and to reduce the impact of cancer on quality of life.20 Secondary prevention of cancer through early detection by screening asymptomatic individuals has been successful in the case of common malignancies in younger individuals. This chapter explores the value of early detection of cancer in older individuals.

Comprehensive Geriatric Oncology

646

Principles of secondary prevention Secondary prevention of cancer is based on a threefold assumption (Figure 29.1):20 • Clinical manifestations of cancer are preceded by a prolonged preclinical phase. This may include asymptomatic invasive cancer, and so-called premalignant lesions, such as adenomatous polyps of the large bowel or ductal carcinoma in situ (DCIS) of the breast. Premalignant lesions also involve molecular abnormalities occurring in tissues that appear histologically normal and that be detected by genomic analysis. For example, detection of human papillomavirus 16 (HPV-16) genes in normal cervical cells

Figure 29.1 Early detection of precancerous lesions or early cancer may lead to improved surgical cure.

Secondary prevention of cancer in the older person

647

or obliteration of the Rb gene in normal colonic cells predict the development of cervical and colonic cancer, respectively.21 • During the preclinical phase, cancer may be diagnosable by screening tests. • Early diagnosis of cancer is associated with improved chances of surgical curability. These assumptions may prove true only in clinical trials, for which the choice of endpoints is critical. The controversy about what is an appropriate endpoint in trials of secondary cancer prevention has not been completely resolved, especially as far as older individuals are concerned. Currently, a reduction in cancer-related deaths is considered the final demonstration of the effectiveness of screening.20 This demonstration may require several years, during which many lives may be lost. Furthermore, when the trials are completed, they may have been made obsolete by newer and more effective screening techniques. For this reason, alternative endpoints, reachable over a short time period, have been proposed. These endpoints appear particularly attractive for older individuals, whose limited life-expectancy may render prolonged clinical trials impractical. However, these endpoints seem fatally fraught by biases, as illustrated in the following examples. Alternative endpoint: more prplonged cancer-related survival for patients who have undergone screening The value of this endpoint is negated by the so-called lead-time bias,20 which implies that patients whose cancer was diagnosed through screening experience a more prolonged survival from diagnosis because their cancer has been known for a more prolonged period of time, not because early detection has improved its curability. Alternative endpoint: screening is beneficial because cancers diagnosed at screening present at an earlier stage than those diagnosed in symptomatic patients While it is true that the prognosis of cancer worsens with more advanced stages, the value of this endpoint is denied by two types of bias. Length-time bias20 implies that only indolent tumors are diagnosed at screening, while rapidly dividing tumors ‘sneak through’ screening intervals (Figure 29.2); consequently, only slowly growing tumors, with late metastatic potential, whose late diagnosis probably would not affect the overall prognosis, are diagnosed at screening, whereas the majority of rapidly growing tumors with early

Comprehensive Geriatric Oncology

648

Figure 29.2 Length-time bias. Rapidly growing tumors (shaded circles) may become symptomatic during screening intervals (arrows). In this example, the rapidly growing tumor reaches a diagnosable size between screening intervals. Because of this effect, screening is more likely to diagnose slowly growing tumors (clear circles), whose prognosis may be better. Thus, screening may give the impression of improving a patient’s survival from diagnosis simply because it detects prevalently slowly growing, less aggressive tumors.

Secondary prevention of cancer in the older person

649

metastatic potential, for which early diagnosis appears desirable, escape screening. Overdetection bias20 implies that a number of cancers diagnosed at screening would never have become clinically detectable during a patient’s lifetime. This type of bias is of particular concern in persons with limited life-expectancy, for whom overdetection of cancer may result in a number of unnecessary, costly, and risky interventions. Reduction in cancer-related mortality avoids these potential biases, but even this endpoint involves two questions that need to be answered before it can be accepted as the definitive and only proof of the effectiveness of screening in older individuals. The first question is whether reduction of cancer-related mortality represents an adequate endpoint when the overall mortality is unaffected. This issue emerged very clearly in the case of prostate cancer. A randomized controlled study of radical prostatectomy versus observation in men up to age 75 in Sweden has conclusively demonstrated that radical prostatectomy is associated with a reduction in cancer-related mortality but not in overall mortality.22 One may infer from these results that screening asymptomatic men for prostate cancer may have only negligible effects on overall mortality. Clearly, screening for prostate cancer appears beneficial only for those men whose survival is improved and whose quality of life is enhanced by radical prostatectomy, but criteria to identify these patients are needed. For a number of older men with prostate cancer (maybe the majority), prostatectomy is a complicated, costly, and dangerous intervention that may compromise their quality of life without appreciable benefit.23 The second question concerns the effects of screening on quality of life. On one hand, it is possible that early detection of some cancers (such as breast cancer) might be associated with a reduced rate of cancer-related complications even if it does not reduce cancer-related mortality. On the other hand, screening itself may compromise the quality of life of older individuals, with the discomfort, cost, inconvenience, anxiety, and risk involved in the screening and diagnostic tests. Effects of aging on screening older individuals for cancer Age has diverging effects on screening, some of which favor and others disfavor early cancer detection. In favor of screening is the fact that the prevalence of common cancers, including, breast, colorectal, lung, and prostate cancers, increases with age2 (see Chapter 4 of this volume3). As the predictive value positive of diagnostic tests is a function of the prevalence of disease in the population examined, the accuracy of screening tests is expected to improve with age.20,24 In addition, the sensitivity of some tests to underlying abnormalities may increase with age. This appears to be the case with physical examination of the breast (since mammary tissues becomes more atrophic with age) and with screening mammography. Age-related factors that disfavor screening include, first, the reduced life-expectancy due to deteriorating function and comorbidity. Clearly, the benefits of screening are reduced in the face of decreased life-expectancy.19 Second, it may be that previous screening tests have eliminated all prevalence cases. The yield of subsequent examinations may thus be reduced. Third, age-related changes in tumor biology, in the case of breast and lung cancers, may lead to a more indolent and less lethal tumor.19

Comprehensive Geriatric Oncology

650

To establish a positive balance between benefits and risks of screening two combined approaches appear reasonable. In the first approach, the effects of screening on quality of life are assessed. It is reasonable to assume that early diagnosis of breast cancer may prevent the development of painful and disfiguring lesions in an older woman with multiple comorbidity, even if it does not reduce the cancer-related mortality. It is also reasonable to expect screening to cause unnecessary biopsies and unnecessary surgery, with iatrogenic morbidity, to raise the level of

Figure 29.3 Suggested application of the Comprehensive Geriatric Assessment (CGA) to screeningrelated decisions. ADL, Activities of Daily Living; IADL, Instrumental Activities of Daily Living. anxiety, and to increase the cost and inconvenience of treatment. It would be desirable to recognize a patient profile in whom the benefits of screening overwhelm the risks. Chen et al25 have discovered that certain older individuals are more prone to risk-taking than others, and the risk-taking personality is more likely to accept cancer chemotherapy even when the benefits are minimal. It appears legitimate to infer that the risk-taker will be also more likely to benefit from screening in terms of quality oflife.

Secondary prevention of cancer in the older person

651

The second approach tailors screening strategies to the characteristics of individual patients, including life-expectancy, function, comorbidity, risk of cancer, and personal values. This approach represents a major change from that used in younger individuals, for whom screening tends to be as comprehensive as possible, and acknowledges the degree of diversity of the older population. The Comprehensive Geriatric Assessment (CGA) represents a useful, albeit incomplete, means to separate patients who may or may not benefit from screening19,26 (Figure 29.3). Clearly, patients who are frail for dependence in Activities of Daily Living (ADL) (with the exception of continence), have a high degree of comorbidity, or exhibit one or more geriatric syndromes, would not benefit from screening, given their limited life-expectancy.27 For this purpose, the CGA may be complemented by proof of physical performance and laboratory tests. For example, gait disturbances herald non-Alzheimer dementia,28 and inability to get up from an armchair without using the arms or requiring more than 10 seconds to get up, walk 10 feet back and forward, and sit back down predict early mortality and disability.29

Table 29.1 Screening tests currently in use Cancer

Tests

Age-range (population at average risk)

Quality of evidence

Breast

• Mammography yearly or biennially

50–70

I

• Clinical breast examination (CBE), yearly

50–70

I–II

• Breast self-examination (BSE), monthly

40+

II

Cervix

• Pelvic examination and Pap smear every 3 years

18–60

II

Colorectal

• Fecal occult blood test (FOBT) yearly or biennially

50–80

I

• Colonoscopy every 5–10 years

50–80

II

• Sigmoidoscopy every 5–10 years 50–80

II

• Prostate-specific antigen (PSA) yearly or every 3 years

50+

I–II

• Digital rectal examination (DRE)

50+

II

• Chest radiograph, yearly

No age range

III

• Spiral computed tomography (CT) of the chest, yearly

No age range

III

Prostate

Lung, nonsmall cell

Likewise, increased concentrations of interleukin-6 (IL-6) and D-dimer in the circulation predict a fourfold increase in short-term death and disability,30 and increased circulating levels of reactive protein C predict enhanced risk of coronary events.31 To some extent,

Comprehensive Geriatric Oncology

652

screening may also be tailored to individual risk of cancer. In a decision analysis, Kerlikowske et al32 calculated that limiting screening mammography to women in the upper quintile of mineral bone density, who are those at higher risk of breast cancer, would not compromise the accuracy of the screening, but would markedly reduce cost and inconvenience. Without pretending to provide a ‘fit-all recipe’, the sensible application of these principles may improve the benefits and minimize the complications of screening asymptomatic older individuals for cancer. Approach to individual diseases A number of screening tests have reduced the cancer-related mortality in the general population (Table 29.1). In this section, we examine the benefits and risks of these tests for older individuals. Breast cancer Three screening examinations have been promoted for breast cancer: serial mammography, clinical breast examination (CBE), and breast self-examination (BSE). Of these, only screening mammography has proved effective in randomized controlled trials (level 1 evidence) (Table 29.2).33–38 All of these trials, with one exception,34 demonstrated a reduction in breast cancer-related mortality of 20–30% for women aged 50–70, and in three cases35,37 the difference in mortality between the screened and control groups was statistically significant. Women over 70 were involved in only two studies, and the benefit of screening mammography was not conclusively demonstrated in this age group.38 A meta-analysis of randomized trials claimed that no benefits from screening mammography are detectable, since the six positive studies were biased in the randomization, and only the two negative studies were not biased.39 As expected, this position elicited a lot of controversy, which has not been completely resolved. In general, however, the claims of this study are considered inaccurate for the following reasons:

Table 29.2 Randomized controlled studies of screening mammography Study

HIP36 Malmö

35

Kopparberg

35 35

Ostergotland 35

Stockolm

35

Gothenburg

Age range

Interval (months)

Number of examinations

RR cancer death RR women (age 50 and aged 70+ older)

40–64

12

4

0.65 (0.46–0.92)

NE

45–69

18–24

6

0.81 (0.61–1.07)

NE

40–74

24–33

5–6

0.64 (0.45–0.90)

Trend

40–74

24–33

5–6

0.74 (0.55–0.99)

Trend

40–64

28

2

0.8 (0.53–1.22)

NE

40–59

18

2

0.86(0.54–1.37)

NE

Secondary prevention of cancer in the older person

Edinburg37 33

Canadian 2

653

45–64

24

4

0.84 (0.63–1.12)

NE

50–59

12

5

0.97(0.62–1.52)

NE

RR, relative risk; NE, not established.

• One of the two trials that was considered negative (the Malmo trial) demonstrated a beneficial effect of mammography at the time of the last analysis.35 • The amount of bias in the positive trials was unlikely to cause the dramatic difference in effect that had been observed; furthermore, in the Edinburgh trial, the bias would have minimized the effects of mammography.40,41 • The Canadian study, which is the other negative study, has been criticized because it used single-view mammograms, which are considered to be inadequate 33,34 For all of these reasons, the meta-analysis did not affect the recommendations of the major organization, including the US Preventive Services Task Force (USPSTF), that women aged 50–70 undergo regular screening mammography. A number of considerations related to screening mammography are particularly germane to older individuals.38 First, in some studies, the intervals between screening mammography varied from 18 to 36 months. Clearly, the optimal intervention between screening examinations is unestablished. For older women, bearing tumors that in general are more indolent, intervals longer than 1 year may reduce the cost, discomfort and inconvenience of screening, without compromising its effectiveness. Second, only a limited number of examinations were performed (from 4 to 7) during the study period. The value of continuing mammography throughout a woman’s lifetime has not been established, although this is a current recommendation. It is reasonable to expect that the reduction in breast cancer-related mortality would have been even higher had more sessions been held. New randomized and controlled studies of screening mammography in women aged 70 and older are neither feasible nor desirable. They are not feasible, because the popular opinion that screening mammography is beneficial would render it all but impossible to enroll control patients, and would generate insurmountable ethical objections. They are not desirable, because the rapid pace at which new diagnostic technology is developing would render these studies obsolete by the time they are completed. Furthermore, most clinicians would have problems in investing a substantial amount of time and resources in studies that at best may provide negative findings. At present, the decision whether to screen older women for breast cancer is based on circumstantial evidence. A Dutch retrospective study showed screening mammography to be associated with decreased breast cancer mortality in women aged 70–75. Peculiar to this study was the finding that screening mammography was associated with higher breast cancer-related mortality after age 75, probably because only women with previous history of breast cancer underwent mammography after that age.42 A review of the US National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) data showed that women aged 70 and older undergoing at least two mammographic evaluations after age 70 were 2½-fold less likely to die from breast cancer than women who had not undergone mammography after age 70.43 Unfortunately, this study could not provide any mammographic history before age 70; it is not unreasonable to assume that women who had regular mammographic examination after 70 were also more compliant

Comprehensive Geriatric Oncology

654

with screening before 70. Thus, the decreased breast cancer mortality might have resulted from screening before age 70. Another analysis of the SEER data showed that women who had undergone screening mammography after age 75 presented with earlier-stage breast cancer than those of the same age who had not undergone screening.44 Another SEER study showed that whereas breast cancer reduces by 10% the survival of women under 60, it does not affect the survival of woman aged 75–80, and may be associated with increased survival of women over 80.4 This data suggests that breast cancer affect preferentially healthy elderly women, with a life-expectancy more prolonged than average, for whom early detection appears particularly beneficial. Given the negligible mortality of partial and total mastectomy, which nowadays may even be performed under local anesthesia, it is not unreasonable to assume that early treatment of breast cancer may lead to a decreased risk of local complications and improve patients’ quality of life, even when it does not prolong overall survival. On the basis of these considerations, some form of breast cancer screening in women aged 70 and older appears to be indicated. The most reasonable approach may involve mammographic examinations every 2 years for women with a life-expectancy of 5 years or longer, since the initial benefits of screening are seen 5 years from the institution of the screening program.32 The addition of a physical examination of the breast once a year by any physician or nurse-who has the opportunity to examine the patient also appears reasonable. These recommendations will evolve as the results of a number of studies will become available. The roles of digital mammography and magnetic resonance imaging (MRI) in the early diagnosis of breast cancer should become clear. It is not yet known whether these more expensive and complicated techniques have improved sensitivity over standard twoview mammograms. So far, their use has largely been limited to better visualization of abnormalities seen at mammography or examination of breasts not suitable for mammography (with implants and multiple cysts). CBE may turn out to play a role as a complement or an alternative to mammography. In a randomized controlled Canadian study,34 CBE proved similar to mammography in preventing breast cancer-related death. These data are consistent with the analysis of the Breast Cancer Detection Demonstration Project (BCDDP) demonstrating that the majority of cancers diagnosed at mammography only were DCIS.45 Early detection of DCIS is probably irrelevant for older women, whose limited life-expectancy makes negligible the risk of developing invasive cancer from DCIS. The use of screening CBE in lieu of mammography is very appealing in older individuals, because CBE may be performed during a routine medical visit, obviating the inconvenience and cost of an additional visit and the discomfort of mammography. It may become possible to identify a group of older women at high risk of breast cancer and to focus the screening effort on these individuals. In addition to being costeffective, this approach may minimize the risks related to screening. Kerlikowske et al32 examined the effects of limiting screening mammography to women aged 70–79 within the highest quintile of bone mineral density (BMD), who are the ones at highest risk for breast cancer. The authors calculated that the cost of screening all women aged 70–79 would be $119000 per year of life saved, while the cost of screening only women with the highest BMD would be $66000 per year of life saved. The accuracy of this interesting decisional model needs confirmation in the clinical arena.

Secondary prevention of cancer in the older person

655

In several randomized and controlled studies, BSE failed to affect breast cancerrelated mortality. The main benefit of this screening technique appears to be the promotion of breast cancer awareness (see Chapter 51 of this volume46). Although the risks and contraindications of BSE appear minimal, it should be emphasized that a negative BSE may foster an unwarranted sense of security and delay the application of more effective screening measures. Colorectal cancer Serial examination of voided stools for fecal occult blood (FOB) has reduced the mortality of colorectal cancer in a number of randomized controlled studies.47–50 The population studied was aged 50–80, and the benefits were evenly distributed among different age groups. The best interval between subsequent examinations remain controversial. Screening at 2-year intervals appear to be beneficial, but not as effective as yearly screening.50 The reduction in cancer-related mortality from serial sigmoidoscopic or colonoscopic examinations is supported by retrospective studies (evidence level II-2). Colonoscopy is strongly favored by the demonstration that removal of adenomatous polyps prevents invasive cancer.51,52 As polyps may occur exclusively in the proximal colon, full colonoscopy appears preferable to rectosigmoidoscopy.51,52 Whereas the benefit of screening is universally accepted, the best screening strategy remains controversial. In a decision analysis, full colonoscopy every 10 years appeared to be more cost-effective than biennial examination of FOB and sigmoidoscopy every 5 years,48 mainly because of low compliance with more frequent examinations. Current evidence allows the following conclusions to be drawn: • Some forms of screening for colorectal cancer is reasonable for persons aged 50 and older with a life-expectancy of 3–5 years. This recommendation is supported by the increasing incidence of colorectal cancer after age 802 (see Chapter 4 of this volume4), by the fact that the majority of recurrences and death occur within 5 years from diagnosis, and by the fact that early detection may obviate the need for emergency surgery to deal with obstruction or perforation. As mortality and morbidity of emergency surgery increase with age after 70, early detection may be life-saving for these patients.53 In favor of early detection is also the demonstration that adjuvant chemotherapy for colorectal cancer is as beneficial for persons over 70 as it is for younger individuals.54 • Full colonoscopy every 5 or 10 years appears the most practical approach to older individuals, when proper stool collection for FOB may be problematic. • Examination for FOB every 2 years should be recommended to older persons who are able to execute it properly. Furthermore, hospitalized older patients should have their stools checked. Prostate cancer Whereas it has been conclusively established that serial determinations of prostatespecific antigen (PSA) leads to early diagnosis of prostate cancer,55,56 controversy lingers over the value and the proper way of screening asymptomatic men. The main areas of controversy include the effectiveness of early detection in preventing cancer-related

Comprehensive Geriatric Oncology

656

deaths, the age at which screening should be initiated and discontinued, whether it should be performed at all, the optimal interval between assessments, and the PSA values at which prostate biopsy should be performed. In the following discussion, each of these issues is examined separately. Does early detection of prostate reduce cancer related death? The evidence concerning early detection includes the following. Two randomized and controlled studies support screening. The male population of two alpine villages in Tyrol was the subject of one study: adult men of one village were screened, and those of the other village were not.55 In the other study, the male population of Quebec city was randomized to screening versus no screening, and cancer-related mortality decreased among screened men;57,58 only a minority of eligible individuals eventually accepted randomization, which substantially reduced the power of the study. The mortality from prostate cancer in Olmstead County, Minnesota has declined since the introduction of PSA screening.59 The American Cancer Society instituted the Prostate Cancer Awareness Week in 1986. During this week, which is repeated every year, PSA screening is promoted to the USA male population aged 50 and older. After 5 years, the incidence of advanced-stage newly diagnosed prostate cancer had declined from 20% to less than 5%, suggesting that early detection is effective in preventing metastatic disease.60,61 Although by itself it is no proof of reduced mortality, this observation refutes both the overdetection and the lengthtime biases in the case of prostate cancer. If these biases were present, one would have seen an increased detection of early disease, but not a reduction in the incidence of advanced disease as a result of screening. Determination of PSA on blood banked during the Physician Health Study, involving several thousand American male physicians aged 40 and older, indicates that PSA concentration in the serum increases approximately 6 years before the clinical diagnosis of prostate cancer, and the median survival of these physicians was approximately 8 years since the time of diagnosis.62 This observation suggests that prostate cancer is lethal in the majority of patients once it is symptomatic, and there is a prolonged preclinical phase during which diagnosis of prostate cancer may be life-saving. The main evidence contradicting the value of screening and early detection is represented by a number of studies, summarized by Chodak et al,63 that showed that the majority of patients aged 70 and older with early-stage prostate cancer will die of a condition unrelated to prostate cancer. This conclusion, however, was refuted by a recent randomized controlled study in which men up to age 75 with localized prostate cancer were randomized to radical prostatectomy and observation.28 Radical prostatectomy was associated with a significant reduction in prostate cancer-related mortality, although the overall mortality rate of the two groups was similar. It is clear that early diagnosis of prostate cancer results in a reduction of cancer-related mortality, but the question persists as to what extent this reduction is beneficial for a population at high mortality risk for other conditions, especially in view of the fact that radical prostatectomy as well as other forms of local treatment of prostate cancer are a cause of significant morbidity.

Secondary prevention of cancer in the older person

657

What values of PSA should be considered abnormal? Original studies considered abnormal any value of PSA above 4 ng/ml.61,64 It soon became clear, however, that the predictive value positive for PSA values between 4 and 10 ng/ml was only around 20%. To improve the specificity of the test, a number of adjustments have been proposed,65 including PSA density (i.e. the ratio between the PSA value and the prostate volume),66 PSA velocity (i.e. the yearly rate of increase in PSA concentration),67 the adoption of age-adjusted PSA normal standards,64 the ratio between free and total PSA (which is lower in patients with cancer than in those with benign prostatic hypertrophy, BPH), and the simultaneous measurement of PSA and kallikrein-2 levels.68,69 At the same time that efforts were dedicated to improve the specificity of serum PSA levels, it became clear that the sensitivity of these values was also inadequate, because a substantial number of cancers were present in patients with PSA values below 4 ng/ml. Examination of serum serially banked during the Physician Health Study showed that the risk of prostate cancer increased linearly with levels of PSA above 1 ng/ml.62 Of 478 men undergoing radical prostatectomy at the Erasmus University in Rotterdam between 1994 and 1997, 36% had PSA values between 2 and 4 ng/ml.70 Catalona et al71 showed that 22% of 332 men with PSA levels below 4 ng/ml had prostate cancer and that in 63% of the patients the cancer was clinically significant. Even among older persons, prostate cancer may be commonly found for PSA values below 4 ng/ml.72 At present, it appears reasonable to add the measurement of free PSA (or of kallikrein-2 should this test prove more reliable than free PSA), to the screening of prostate cancer. What is the optimal screening interval? At what age should screening be instituted and at what age discontinued? The screening intervals are determined by the accuracy of the initial screening, the reliance on PSA velocity, the expected growth rate of the cancer, and cost and risk minimization. Two decision analyses that provided reasonable (albeit different) conclusions illustrate the current uncertainty about the best screening strategy. Etzioni et al73 concluded that biannual screening for PSA values of 4 ng/ml or higher was preferable to annual screening for age-adjusted PSA, since it reduced by 50% the false-positive rate, while retaining at the same time 93% of life-years saved. According to this model, screening was initiated at age 50 and continued at regular intervals up to age 75. Ross et al74 calculated that biennial determination of PSA, with 2.6 ng/ml as the cut-point value at which biopsy should be performed, was the most cost-effective strategy for men aged 45– 75. The evolution of prostate cancer screening will depend on a number of factors, including (i) the development of more accurate laboratory tests; (ii) the development of more accurate radiological tests to direct prostate biopsy (currently, transrectal ultrasound is used for this purpose, but spiral MRI seems more accurate, although more costly); (iii) determination of when screening may be interrupted because new incident cases are rare and unlikely to influence a person’s life-expectancy; and (iv) the greater life-expectancy

Comprehensive Geriatric Oncology

658

of the male population, so that prostate cancer may become a significant cause of death even for older men. At present, the following approach appears to be reasonable: • Screening may reduce the mortality from prostate cancer for men aged 50–65 (or 70). These men should be informed of the potential risk and benefits of screening. For men at high risk, including those with a family history of prostate cancer, screening may be instituted at an earlier age. • After two normal PSA determinations 1 year apart, it is reasonable to space following determinations every 2–3 years. • When available, free PSA should also be determined. • More information is necessary to establish the benefit of screening for older men (over 65–70). Lung cancer New trends in the epidemiology of lung cancer have special interest for older individuals, including the progressive increase in incidence after age 70, the development of lung cancer in previous, rather than current, smokers, and the development of more indolent forms of lung cancer, with adenocarcinoma becoming progressively more and small cell lung cancer less prevalent2,75 (see Chapter 4 of this volume3). These trends suggest that as more and more people have quit smoking, their life-expectancy has increased owing to a decline in deaths related to cardiovascular disease, but their risk of late lung cancer has been enhanced.75 Although lung cancer may become more indolent with age, especially after prolonged abstention from smoking,76 it is still a deadly disease, for which the only opportunity for cure is surgical resection.77 Hence, older ex-smokers appear to be ideal candidates for early detection of lung cancer. A number of studies conducted in the 1970s explored the screening of asymptomatic smokers for lung cancer.20 These studies are generally regarded as negative. Nonetheless, a critical consideration of them is in order. Each study compared yearly chest radiography with chest radiography plus sputum cytology. In no study was there a control group that had received neither interven-tion. The only legitimate conclusion is that the addition of sputum cytology to chest radiography does not improve lung cancer-related mortality. The question whether serial radiographic examinations of the chest might have reduced the risk of cancer-related mortality was simply not addressed. In this light, it is appropriate to notice that in one study, patients whose cancer had been diagnosed at screening had a 5-year survival rate of around 35%. This is substantially higher than the 5% 5-year survival rate of persons whose cancer was diagnosed when they had become symptomatic. The lead-time bias might have accounted for these results. The studies were focused on smokers, whose survival might have been curtailed by a number of concomitant conditions, including second malignancies. The screening landscape is quite different at present, since the candidates for screening would be mainly ex-smokers. Not only are ex-smokers healthier than smokers and have a more prolonged life-expectancy, but in addition abstention from smoking likely helps reduce the aggressiveness of lung cancer and makes it more susceptible to surgical cure.

Secondary prevention of cancer in the older person

659

New and more accurate imaging tests have become available, including computed tomography (CT) and MRI. In addition, molecular diagnosis of precancerous lesions may further improve the effectiveness of early diagnosis. Of special interest is a study showing that yearly spiral CT of the chest increased the yield of early lung cancer and reduced the mortality from lung cancer in ex-smokers.78 Also, the Prostate, Colon, Lung, and Ovary (PCLO) program is studying the value of serial chest radiography in ex-smokers. Although definitive recom- inendations cannot be issued, it is reasonable to offer some type of imaging screening to older ex-smokers with a life-expectancy of 5 years or longer. Cervical cancer Although the incidence of cervical cancer decreases with age, the mortality for metastatic cervical cancer has been increasing among older women2 (see Chapter 43). It is difficult to establish whether increased mortality is due to inadequate screening or to a completely different biology of the disease in older and younger individuals. In a retrospective study, Celentano and Klassen79 demonstrated that at least one Papanicolau screening between ages 60 and 70 reduced the mortality for cervical cancer among women who had not undergone regular screening before 60. Thus, it appears reasonable to recommend serial Papanicolau screening for women aged 60 and older who had not undergone regular screening—especially those at increased risk of cervical cancer. Age-related barriers to cancer prevention A number of barriers to cancer prevention have been identified in older individuals (Table 29.3)80 (see Chapter

Table 29.3 Age-related barriers to cancer prevention Provider-related

Patient-related

Ageism

Lack of information

Lack of enthusiasm

Lack of information

Cultural barriers

Inadequate resources Inadequate support by family Inadequate support by primary care provider

30 of this volume81). Interventions in public and professional education may help overcome these barriers. Ageism may be overcome by providing information about life-expectancy and carcinogenesis to both practitioners and patients, illustrating how older individuals may benefit from both primary and secondary cancer prevention. Cultural barriers are still very important. The rate of screening mammography in the USA is lower for minority older women, especially Hispanic women. At least in part,

Comprehensive Geriatric Oncology

660

cultural barriers are due to illiteracy and to poor understanding of English. Promising interventions include educational material in languages other than English and educational efforts focused on minority physicians, who are more likely to serve these patients. In addition to providing current information, educational effort should concentrate on improving the practitioner’s communication skills and level of enthusiasm for cancer prevention. Perhaps the most important factor in determining compliance with screening programs for all older patients has been the recommendation by the primary care physician. This trend may change as a new generation of patients, more used to taking primary responsibility for their own health management, will age. At present, however, the role of the physician in facilitating a successful prevention program for older individuals cannot be overemphasized. More than 50% of individuals aged 65 and older lack a primary care provider, although they may be attending specialty clinics.82 This unfortunate situation may have two negative effects: older individuals are underutilizing preventive services and overutilizing specialty treatment services, with increased risk of iatrogenic morbidity and treatment cost. Whatever the role of primary care in the general population, it is clear that a professional in charge of coordinating the care of older individuals is highly desirable. Conclusions It is reasonable to implement screening for breast cancer and colorectal cancer in persons with a life-expectancy of 5 years and longer. No definite recommendation may be issued at present related to screening for prostate, lung, and cervical cancers. Ongoing clinical trials may answer some of these questions. References 1. Berlin A. The conquest of cancer. Cancer Invest 1995; 13:540–50. 2. Yancik R, Ries LAG. Aging and cancer in America: demographic and epidemiologic perspectives. Hematol Oncol Clin North Am 2000; 14: 17–24. 3. Yancik RM, Ries LAG. Cancer in older persons: magnitude of the problem and efforts to advance the aging/cancer research interface. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004: 38– 46. 4. Diab SG, Elledge RM, Clark GM. Tumor characteristics and clinical outcome of elderly women with breast cancer. J Natl Cancer Inst 2000; 92:550–6. 5. Stanta G, Campagner L, Cavallieri F et al. Cancer of the oldest old: what we have learned from autopsy studies. Clin Geriatr Med 1997; 13:55–68. 6. Repetto L, Venturino A, Gianni W. Prognostic evaluation of the older cancer patient. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:309–19. 7. Demetri GD, Kris M, Wade J et al. Quality of life benefits in chemotherapy patients treated with epoietin alfa is independent from disease response and tumor type. Result of a prospective community oncology study. The Procrit Study Group. J Clin Oncol 1998; 16: 3412–20.

Secondary prevention of cancer in the older person

661

8. Glaspy J, Bukowski R, Steinberg C et al. Impact of therapy with epoietin alfa on clinical outcomes in patients with non-myeloid malignancies during cancer chemotherapy in community oncology practices. J Clin Oncol 1997; 5:1218–34. 9. Schagen SB, Van Dam FSAM, Muller MJ et al. Cognitive deficit after postoperative adjuvant chemotherapy for breast carcinoma. Cancer 1999; 85:640–50. 10. Barnabei R, Gambassi G, Lapana K et al. Management of pain in elderly patients with cancer. SAGE study group. Systematic assessment of geriatric drug use via epidemiology. JAMA 1998; 17: 1877–82. 11. Cleary JF. Cancer pain in the elderly. In: Comprehensive Geriatric Oncology, 1st edn (Balducci L, Lyman GH, Ershler WB, eds). Amsterdam: Harwood Academic Publishers, 1998:753–64. 12. Fried LP, Bandeen Roche K, Kasper JD et al. Association of comorbidity with disability in older women: the Women’s Health and Aging Study. J Clin Epidemiol 1999; 52:27–37. 13. Crimmins EM, Saito Y, Reynolds SL. Further evidence on recent trends in the prevalence and incidence of disability among older Americans from two sources: the LSOA and the NHIS. J Gerontol B Psychol Sci Soc Sci 1997; 52:S59–71. 14. Manton KG, Stallard E, Corder L. Changes in age dependence of mortality and disability. Demography 1997; 34:135–7. 15. Nusselder WJ, van der Velden K, van Sonsbeek JL et al. The elimination of selected chronic diseases in a population: the compression and expansion of morbidity. Am J Publ Health 1996; 86:187–94. 16. Picavet HS, van de Bos GA. The contribution of six chronic conditions to the total burden of mobility, disability in the Dutch population. Am J Publ Health 1997; 87:1680–2. 17. Raina P, Dukeshire S, Lindsay J et al. Chronic conditions and disabilities among seniors: an analysis of population-based heath and activity limitations surveys. Ann Epidemiol 1998; 8:402– 9. 18. Boult C, Altmann M, Gilbertson D et al. Decreasing disability in the 21st century: the future effects of controlling six fatal and non-fatal conditions. Am J Public Health 1996; 86:1388–93. 19. Repetto L, Balducci L. A case for geriatric oncology. Lancet Oncol 2002; 3:289–97. 20. Balducci L, Beghe’ C. Prevention of cancer in the older person, Clin Geriatr Med 2002; 18:505–28. 21. Traverso G, Shuber A, Levin B et al. Detection of APC mutations in fecal DNA from patients with colorectal cancer. N Engl J Med 2002; 346:311–20. 22. Holmberg L, Bill-Axelson A, Hegelsen F et al. A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med 2002; 347:781–9. 23. Steineck G, Helgesen F, Adolfsson J et al. Quality of life after radical prostatectomy or watchful waiting. N Engl J Med 2002; 347:790–6. 24. Silverman MA, Zaidi U, Barnett S et al. Cancer screening in the elderly population. Hematol Oncol Clin North Am 2000; 14:89–112. 25. Chen H, Haley W, Extermann M et al. Treatment preference in the elderly cancer patients. In: Proceedings ofthe American Association for Cancer Research (to be published). 26. Balducci L, Beghe’ C. The application of the principles of geriatrics to the management of the older person with cancer. Crit Rev Hematol Oncol 2000; 35:147–54. 27. Balducci L, Stanta G. Cancer and frailty: the incoming epidemics. Hematol Oncol Clin North Am 2000; 14:235–50. 28. Verghese J, Lipton RB, Hall CB et al. Abnormality of gait as predictor of non-Alzheimer dementia. N Engl J Med 2002; 347:1761–8. 29. Gill TM, Baker DI, Gottschalk M et al. A program to prevent functional decline in physically frail elderly persons who live at home. N Engl J Med 2002; 347:1068–74. 30. Cohen HJ, Harris T, Pieper CF. Coagulation and activation of inflammatory pathways in the development of functional decline and mortality in the elderly. Am J Med 2003; 114:180–7. 31. Harris TB, Ferrucci L, Tracy RP et al. Associations of elevated interleukin 6 and C-reactive protein levels and with mortality in the elderly. Am J Med 1999; 106:506–12.

Comprehensive Geriatric Oncology

662

32. Kerlikowske K, Salzman P, Phillips KA et al. Continuing screening mammography in women aged 70 to 79 years. JAMA 1999; 282: 2156–63. 33. Miller AB, Baines CJ, To T et al. Canadian National Breast Screening Study 2: breast cancer detection and death rates among women aged 50–59 years. Can Med Assoc J 1992; 147:1477– 88. 34. Miller AB, To T, Baines CJ et al. Canadian National Breast Screening Study 2:13-year results of a randomized trial in women aged 50–59 years. J Natl Cancer Inst 2000; 92:1490–9. 35. Nystrom L, Rutqvist LE, Wall S et al. Breast cancer screening with mammography: overview of the Swedish randomized trials. Lancet 1993; 341:973–8. 36. Shapiro S. Periodic Screeningfor Breast Cancer: The Health Insurance Pilot Project and Its Sequelae, 1963–1986. Baltimore: Johns Hopkins University Press, 1988. 37. Wald N, Chamberlain J, Hackshaw A, and EUSOMA Evaluation Committee. Report of the European Society for Mastology Breast Screening Evaluation Committee. J Eur Soc Mastol 1993; 13:1–25. 38. Kerlikowske K, Grady D, Rubin SM et al. Efficacy of screening mammography. A metaanalysis. JAMA 1995; 273:149–54. 39. Gotzsche PC, Olsen O. Is screening for breast cancer with mammography justifiable? Lancet 2000; 355:129–33. 40. Roberts C, Torgerson DJ. Baseline imbalance in randomized controlled trials. BMJ 1999; 319:185–91. 41. de Koning HJ. Assessment of nationwide cancer-screening programmes. Lancet 2000; 355:80– 81. 42. Van Dijck JAAM, Holland R, Verbeeck ALM et al. Efficacy of mammographic screening in the elderly: a case-reference study in the Nijmegen program in the Netherlands. J Natl Cancer Inst 1994; 86:934–8. 43. Mccarthy EP, Burns RB, Freund KM et al. Mammography use, breast cancer stage at diagnosis, and survival among older women. J Am Geriatr Soc 2000; 48:1226–33. 44. Randolph WM, Goodwin JS, Mahnken JD et al. Regular mammography use is associated with elimination of age-related disparities in size and stage of breast cancer at diagnosis. Ann Intern Med 2002; 137:783–90. 45. Mitra I. Breast screening: the case for physical examination without mammography. Lancet 1994; 343:342–4. 46. Balducci L, Silliman RA, Diaz N. Breast cancer in the older woman: an oncological perspective. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:662–703. 47. Burt RW. Colon cancer screening. Gastroenterology 2000; 119: 837–53. 48. Frazier AL, Colditz GA, Fuchs CS. Cost-effectiveness of screening for colorectal cancer in the general population. JAMA 2000; 284: 1954–61. 49. Kronborg O, Fenger C, Olsen J et al. Randomised study of screening for colorectal cancer with fecal occult blood test. Lancet 1996; 348:1467–71. 50. Mandel JS, Chrch TR, Ederer F et al. Colorectal cancer mortality: effectiveness of biennial screening for fecal occult blood. J Natl Cancer Inst 1999; 91:434–7. 51. Nelson DB, McQuaid KR, Bond JH et al. VA cooperative colonoscopy screening study group. Population based colonoscopy screening for colorectal cancer is feasible and safe: preliminary results from the VA colonoscopy screening trial. Gastrointest Endosc 1999; 49:Abst 65. 52. Winawer SJ, Zauber AG, Ho MN et al. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med 1993; 329:1977–81. 53. Kemeny MM, Bush-Devereaux E, Merriam LT et al. Cancer surgery in the elderly. Hematol Oncol Clin North Am 2000; 14:169–92. 54. Sargent DJ, Goldberg RM, Jacobson SD et al. A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med 2001; 345:1091–7.

Secondary prevention of cancer in the older person

663

55. Horninger W, Reisigl A, Rogatsch H et al. Prostate cancer screening in Tyrol, Austria, experience and results. Eur J Cancer 2000; 36: 1322–35. 56. Schoder FH, Alexander FE, Bangina CH et al. Screening and early detection of prostate cancer. Prostate 2000; 44:1255–63. 57. Labrie F, Candas B, Dupont A et al. Screening decreases prostate cancer death: first analysis of the Quebec randomized controlled trial. Prostate 1999; 38:83–91. 58. Candas B, Cusan L, Gomez JL et al. Evaluation of prostate specific antigen and digital rectal exam screening tests for prostate cancer. Prostate 2000; 45:19–35. 59. Roberts RO, Bergstrahl EJ, Katusic SK et al. Decline in prostate cancer mortality from 1980 to 1997 and an increase in incidence trend in Olmsted County, Minnesota. J Urol 1999; 16:529– 33. 60. Mettlin C. Screening and early treatment of prostate cancer are accumulating strong evidence and support. Prostate 2000; 43: 223–4. 61. Mettlin C, Murphy GP, Babaian RJ et al. The results of a five year early prostate cancer detection intervention. Investigators of the American Cancer Society National Prostate Cancer Detection Project. Cancer 1996; 77:150–9. 62. Gann PH, Hennekens PH, Stampfer MJ. A prospective evaluation of plasma prostate specific antigen for early detection of prostate cancer. JAMA 1995; 273:289–94. 63. Chodak GW, Thisted RA, Gerber GS et al. Results of conservative management of clinically localized prostate cancer. N Engl J Med 1994; 230:242–8. 64. Oesterling JE, Jacobsen SJ, Chute CG et al. Serum prostate specific antigen in a communitybased population of healthy men. Establishment of age-specific reference ranges. JAMA 1993; 270:860–4. 65. Gunby P. Prostate detection possibility. JAMA 1999; 281:2274–5. 66. Meshref AW, Bazinet M, Trudel C et al. Role of prostate-specific antigen density after applying age-specific prostate specific antigen references ranges. Urology 1995; 45:972–9. 67. Babaian RJ, Kojima M, Ramirez EI et al. Comparative analysis of prostate specific antigen and its indexes in the detection of prostate cancer. J Urol 1996; 156:432–7. 68. Catalona WJ, Partin AW, Slawin KM et al. Use of the percentage of free-prostate specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA 1998; 279:1542–7. 69. Carsten S, Jung K, Lein M et al. Molecular forms of prostate-specific antigen and human kallikrein 2 as promising tools for early diagnosis of prostate cancer. Cancer Epidemiol Biomark Prev 2000; 9:1133–48. 70. Schroder FH, van der Crijisen-Koeter I, De Koning HJ et al. Prostate cancer detection at low prostate specific antigen. J Urol 2000; 163: 806–12. 71. Catalona WJ, Smith DS, Ornstein DK et al. Prostate cancer detection in men with serum PSA concentration up to 4.0 ng/ml and benign prostate examination. Enhancement of specificity with free PSA measurements. JAMA 1997; 277:1452–5. 72. Carter HB, Landis PK, Metter EJ et al. Prostate-specific antigen testing of older men. J Natl Cancer Inst 1999; 91:1733–7. 73. Etzioni R, Cha R, Cowen ME. Serial prostate specific antigen screening for prostate cancer: a computer model evaluates competing strategies. J Urol 1999; 162:741–8. 74. Ross K, Carter HB, Pearson JD et al. Comparative efficiency of prostate specific antigen screening strategies for prostate cancer detection. JAMA 2000; 284:1399–405. 75. Halpern MT, Gillespie BW, Warner KE. Patterns of absolute risk of lung cancer mortality in former smokers. J Natl Cancer Inst 1993; 17: 457–64. 76. Holmes FF, Hearne E. Cancer stage to age relationship: implications for cancer screening in the elderly. J Am Geriatr Soc 1981:29:55–61. 77. Antonia SJ, Robinson LA, Ruckdeschel JC, Wagner H. Lung cancer. In: Comprehensive Geriatric Oncology, 1st edn (Balducci L, Lyman GH, Ershler WB, eds). Amsterdam: Harwood Academic Publishers, 1998:611–28.

Comprehensive Geriatric Oncology

664

78. Henschke C, McCauley DI, Yankelevitz DF et al. Early Lung Cancer Action Project: overall design and finding from baseline screening. Lancet 1999; 354:99–105. 79. Celentano DD, Klassen AC. The impact of aging on screening for cervical cancer. In: Geriatric Oncology (Balducci L, Lyaman GH, Ershler WB, eds). Philadelphia: JB Lippincott, 1992:105– 17. 80. Fox SA, Roetzheim RG, Kington RS. Barriers to cancer prevention in the older person. Clin Geriatr Med 1997; 13:79–96. 81. Fox SA, Roetzheim RG, Kington RS. Barriers to cancer prevention in the older person. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:376–86. 82. Clarfield AM, Bergman H, Kane R. Fragmentation of care for frail elderly people: an international problem. Experience from 3 countries: Israel, Canada, and the United States. J Am Geriatr Soc 2001; 49:1714–21.

30 Barriers to cancer prevention in the older person Sarah A Fox, Richard G Roetzheim Introduction The barriers to the older person using preventive services regularly or at all are numerous. Examples of types of barriers covered in this chapter are (i) demographic barriers, such as insufficient income to purchase services or differential utilization of services by racial/ethnic groups; (ii) physician-patient communication patterns, which are differentially effective in improving patient compliance; (iii) knowledge gaps, which can affect screening compliance; (iv) attitudinal barriers, such as anxiety about the outcome of screening, which may impede obtaining services, or a belief that a preventive procedure is ineffective; and (v) community-based barriers, such as the lack of a reminder system to assist providers in maintaining patient compliance. Strategies to improve compliance with screening should ideally be multilevel and include individual-level (physician and/or patient), cohort-level (physician and patient), practice-level, and communitylevel efforts. Research studies are currently underway at all levels to develop, refine, and improve strategies for reducing barriers to prevention. Much of current research knowledge about the appropriate or inappropriate utilization of screening services is applicable only to younger persons; the older person has only recently been included in or focused upon in research protocols. Nevertheless, although much can be learned from the body of research that focuses on persons under 60, this chapter is devoted to findings derived from older samples, since there are unique differences between age groups. Demographic and socioeconomic variation in the use of preventive cancer screening services Comparison of utilization rates for cancer screening procedures across demographic groups provides important information for addressing potential barriers to their use. The rates of utilization of a wide range of healthcare services vary across demographic groups, but most analyses of utilization have focused on acute care services. Analyses of utilization rates are based on theoretical behavioral or descriptive models that attempt to describe patterns of use or explain why some individuals use certain healthcare services and others do not. Perhaps the most widely used descriptive utilization model in health services research is the Andersen model, which divides potential causal factors into three broad categories: societal, health services systems, and individual determinants.

Comprehensive Geriatric Oncology

666

Individual determinants are in turn classified as predisposing factors such as age and sex, enabling factors such as income or health insurance, and illness level or medical need.1 Although most individual-level factors (e.g. education levels) are not likely to change in the short term, the finding of differences in rates across demographic groups suggests that clinical and public health interventions to promote the appropriate use of services should take into account differences across relevant demographic and socioeconomic groups. Interpretation of differences in the rates of utilization of preventive cancer screening services, like that of acute care services, is complex because for many cancer screening procedures there is no clear consensus on the appropriate use of the services. For example, there is wide agreement in the medical community that screening for lung cancer using chest radiography is not an effective means for improving health.2 However, even for procedures for which there is a broad consensus (e.g. mammography for breast cancer), there is often a significant variation in the details of screening recommendations because across sets of recommendations issued by various organizations.2,3 This lack of consensus is important, identification of a demographic group with a low utilization rate may have limited policy or clinical implications if there is no agreement that the use of the procedure for screening has a positive impact on health. Nevertheless, the available evidence suggests a substantial variation in the use of widely accepted preventive cancer screening services across demographic groups. Relatively few national datasets provide information on demographic variation in the utilization of preventive cancer services, and the data that are available and have been analyzed focus on screening for breast, cervical and colorectal cancers—three cancers for which there is considerable agreement about the effectiveness of screening in reducing mortality. The primary demographic factors for which we have good evidence on utilization rates are gender, age, race and ethnicity, income, education, and urban versus rural residence. Based on effectiveness trials, in 2002 the US Preventive Task Force recommended screening for colorectal cancer, including fecal occult blood testing (FOBT) and sigmoidoscopy alone or in combination with FOBT.4 They did not find any direct evidence that screening colonoscopy is effective in reducing colorectal cancer mortality.4 The original FOBT trial, however, found that either annual or biennial testing significantly reduces the incidence of colorectal cancer and thus the American Cancer Society (ACS) and the American College of Gastroenterology recommend annual FOBT plus sigmoidoscopy every 5 years or colonoscopy every 10 years.5–7 Using national data from the 2000 National Health Interview Survey (NHIS), the most comprehensive ongoing survey of the health of the US population, there appear to be no significant gender differences in the use of recommended cancer screening services. Eleven percent of males aged over 55 received all gender-specific recommended tests, including an FOBT in the previous year and a sigmoidoscopy or colonoscopy within the past 5 years, whereas 9% of females received these same tests plus mammograms and Pap smears within the past 2 years. Age Although there used to be large discrepancies in the use of cancer screening services between older and younger adults, this is now less likely. In fact, the 2000 Behavioral

Barriers to cancer prevention in the older person

667

Risk Factor Surveillance System (BRFSS) data across all states show that 81% of women aged 55–64 had received a mammogram in the past 2 years versus 80% of women aged 65–75 years. There was more discrepancy regarding Pap smear use, with 76% of the younger women reporting one in the past 2 years versus 68% of the older women. The use of colorectal cancer screening tests in 2001 BRFSS national data document similar trends, with 17% of adults aged 55–64 reporting both an FOBT within 2 years as well as either a sigmoidoscopy or colonoscopy within 5 years; 21% of adults aged 65–75 report this utilization rate. Race and ethnicity Members of disadvantaged minority groups receive poorer healthcare than Whites.8 This disparity also applies to cancer prevention and cancer screening. Nationally (NHIS 2000), 11% of Whites, 9% of Blacks, 5% of Asians, and 5% of Hispanics aged 55–75 were fully screened by recommended tests (mammogram, Pap smear, FOBT, sigmoidoscopy, or colonoscopy). This racial disparity continued in 2001 (BRFSS) for colorectal cancer screening, with 20% of Whites, 15% of Blacks, and 7% of Hispanics reporting both regular FOBT and sigmoidoscopy or colonoscopy use. The disparity was less for mammogram use (BRFSS 2000), with 81% of Whites, 83% of Blacks and 78% of Hispanics reporting one in the last 2 years. Little is known about details of specific relative patterns of use across racial and ethnic minorities (e.g. across specific Latino or Asian subpopulations). Differences across these subpopulations may have important implications for eliminating barriers. Socioeconomic status Socioeconomic status, typically measured by education and income, is an important predictor of access to health-care services in general, and, as is true with many healthcare procedures, low-income persons and those with less education are less likely to undergo cancer screening compared with high-income and better-educated persons. Among adults aged 55–75, only 7% of those below the poverty threshold were fully adherent to gender-specific cancer screening tests (mammogram, Pap smear, FOBT, sigmoidoscopy, or colonoscopy); 12% of adults over the poverty threshold were adherent (NHIS 2000). Rates of specific test utilization showed the same trends. BRFSS 2000 data reported that 70% of women aged 55–75 with less than $15000 income versus 83% of women aged 55–75 with more than $15000 income had mammograms in the past 2 years. Similarly, 62% of women versus 75% had Pap smears in the past 2 years, depending on income status. Finally, data from BRFSS (2001) showed that 12% of 55 to 75-year-olds with household incomes below $15000 were screened for colorectal cancer versus 20% of those with incomes over $15000. Urban versus rural Residence in a rural community may present barriers to access to a range of healthcare services, and the available evidence suggests that persons who live in rural settings are also less likely to undergo cancer screening. Among women aged 40 or older in the 1992

Comprehensive Geriatric Oncology

668

NHIS, 38% of urban women above 40 received a mammogram, compared with 33% for rural women (N Breen, tabulations communicated to SA Fox, 1995). Analysis of data from a Canadian population found similar findings: in spite of comparable access to physician services, women in rural areas were less likely to report a clinical breast examination or a mammogram.9 The urban-rural difference may increase racial differences. In the analysis of 1986 Medicare, the relative risk among White versus Black women for under-going mammography increases from 1.67 to 2.64 when urban and rural populations are compared.10 Access to care A number of studies have stressed the importance of access to primary care in order to accomplish cancer screening. The NHIS, for example, has consistently shown higher rates of breast cancer screening among women who report a regular source of medical care.11 Women who lack health insurance have likewise been found to have much lower rates of breast and cervical cancer screening12–14 and are more likely to be diagnosed with cancer at an advanced stage.15 Presence of health insurance may, of course, be less of a problem for older patients, who are almost uniformly insured by Medicare. Medicare, however, only began to provide reimbursement for Pap smears and mammography in 1990 and 1991 and for FOBT, flexible sigmoidoscopy, colonoscopy, and barium enema in 1998. Furthermore, these tests are reimbursed only after appropriate deductibles have been met, and patients are still responsible for copayments. For some elderly patients, therefore, costs of cancer screening may still be a burden.16 The available literature suggests that poor insurance reimbursement for cancer screening is a barrier for some Medicare-insured patients. Patients with Medicare supplement policies, for example, have significantly higher cancer screening rates than those who cannot afford them.15 Interventions that have provided first-dollar Medicare coverage of cancer screening tests have also shown increased rates of cancer screening.17 Physicians frequently cite cost and lack of insurance reimbursement as a barrier to screening, and may therefore be reluctant to recommend tests such as flexible sigmoidoscopy for poor patients.18–20 Two other points about screening costs and insurance reimbursement are apparent. First, while financial costs and poor reimbursement are certainly important barriers for some patients, it is unlikely that they are the major barrier for most patients. The Medicare benefit for mammography, Pap smears, and colorectal cancer screening,21 for example, has not so far led to increased screening rates except among those who had no previous insurance prior to Medicare coverage.22 A number of prior studies had also hinted that cost was not the main barrier for tests such as mammography.23,24 Also, interventions directed primarily at reducing screening costs have not been particularly effective unless supplemented with patient education.25 Second, it seems clear that the poor will face barriers to screening even when provided with adequate health insurance. Cancer screening rates, for example, are considerably lower among poor people even in countries with universal health insurance.26 The structure of primary medical care may also play an important role in cancer screening. Some studies have found that patients enrolled in managed care health

Barriers to cancer prevention in the older person

669

maintenance organizations (HMOs) receive more cancer screening services and have earlier stage at diagnosis.27–29 It is not known, however, if this is due to a greater emphasis on prevention, better reimbursement for screening procedures, or simply the result of prevention-oriented individuals self-selecting into HMOs. Impact of communication between the physician and the older patient on cancer screening Physician-patient communication is a topic of considerable interest among those who investigate patient compliance and barriers to as well as enablers of patient compliance. What impact, if any, does communication have on an older patient’s compliance with cancer screening? An annotated bibliography produced by Beisecker30 provides a thoughtful review of the communication literature relevant to patients and their doctors and their communication’s possible relevance to health outcomes. Additionally, Beisecker31 reviewed the different components of the relationship between doctor and older patient that might impact communication and compliance, such as provider and patient characteristics (e.g. gender and race), the context of care (e.g. the patient’s companion and the length of the encounter), the content of the encounter (e.g. what is communicated factually), the process within the encounter (e.g. patient assertiveness), and the outcomes of the encounter (e.g. patient satisfaction, recall, compliance, and health status).32 These reviews are incorporated into the following sections. Demographic characteristics and communication Patient characteristics (e.g. race, health insurance status, and age) and physician characteristics (e.g. race and specialty) are potentially strong predictors of effective doctor-patient communication about cancer screening. Although the importance of these characteristics has been examined for younger patients, fewer studies of older patients and the influence of their characteristics on communication exist. The literature on the impact of physician characteristics on communication is even smaller.32 Nevertheless, the match of physician-patient gender has been shown to interface with preventive services in the office setting. In one study, male patients over 70 had the highest probability of being offered DRE (92%) when they were seen by male physicians; male patients seen by female physicians were offered the examination considerably less often (55%).33 Additionally, there was much less gender differentiation in the patient group aged 50–70. Beisecker’s review30 concluded that female physicians seem to be better communicators but that it was unclear what effect, if any, communication had on health status. Patient age also affects communication with physicians. Weinberger et al34 found that physicians were significantly more likely to forget to mention screening to 75-year-old patients as opposed to 50- and 65-year-olds. For example, physicians were significantly more likely to believe that a clinical breast examination alone was adequate breast cancer screening for patients aged 75 and older, but would more likely recommend mammography as well to their younger patients.34 These physicians cited comorbidities and an expected shortened life-expectancy as their rationale for these limited screening recommendations.34

Comprehensive Geriatric Oncology

670

Patient comorbidities are often believed to influence physician communication about screening, and can contribute to fewer physician recommendations for sereening in the older patient. For example, communication difficulties are inevitable and complicated when accompanied by a decline in cognitive skills that may also accompany aging.35 The older old (over 75) are far more likely to have problems: a decline in cognitive skills, hearing skills, physical impairments, financial concerns, transportation restraints, and mobility problems. All of these are possible contributors to increased barriers to screening that the younger old are less likely to experience. Communication content Older patients appear to have a more difficult time getting their needs met at the office visit. Rost and Fraubel36 found that among diabetic patients aged over 60, more than a quarter reported that their problems had not been addressed at the visit; this problem is compounded by the fact that older patients are more likely than younger ones to have multiple problems. In fact, over half had at least one important medical problem and one psychological problem that was never addressed.36 Adelman et al37 also found that older patients had difficulty getting their concerns acknowledged and that about two-thirds of the topics were ones raised by physicians rather than patients. Screening may be neglected if it is not on the physician’s agenda. There also is confusion among the elderly about what occurred during the visits. Greene et al38 found significantly less concordance for the older (65 and older) patientphysician dyadic interactions than for the younger dyads, especially in relation to what was discussed in general and discussed medically. Finally, what is communicated and by whom makes a difference. In focus groups conducted by the US National Cancer Institute (NCI), it was discovered that older patients shared a considerable anxiety about cancer and were fairly pessimistic about their ability to recover after a diagnosis.39 A physician’s reassurance and support could be essential in overcoming this pessimism to allow for screening compliance. Additionally, Fox et al40 found that the physician just mentioning a mammogram to patients was the strongest predictor of patients getting one, especially for patients over 65. The communication did not need to be lengthy, persuasive, or directive—it just had to occur.40 A physician’s belief in prevention—if belief was communicated—served as a strong inducement for eventual patient compliance. Communication process What is said or communicated—the content of messages—is important in influencing compliance with screening, as discussed above. How the content is communicated—the process of communication—is also (maybe more) important. Adelman and others41,42 found that audiotapes of primary care follow-up appointments showed that physicians favored younger patients (less than 45 versus over 65) in the following ways: they provided more information on physician-initiated issues, they provided more support on patient-initiated issues, and they were nicer. However, younger patients asked better questions and provided better information than the older patients. Although these findings might be attributable to physician ageism, they were also a result of the more successful

Barriers to cancer prevention in the older person

671

way in which younger patients handled their physician visits. Older patients also negatively influenced the outcomes of their visits to physicians by being more passive and giving more decision-making authority to physicians.42–45 Finally, Fox et al46 found that the enthusiasm with which physicians discussed screening mammography was the strongest predictor of patient follow-up with the referral. Being very or somewhat enthusiastic about discussing screening was a stronger predictor of eventual screening than the mention of screening neutrally or not enthusiastically.46 As women aged past 75, however, the enthusiasm for screening expressed by physicians dropped markedly, which served to contribute to a lowered screening rate in this group.46 Communication context The context in which physician-patient communication takes place can affect its outcome. For example, the presence of third parties at an office visit has a meaningful impact on interaction—both positive and negative. Beisecker47 examined audiotapes of 21 patients aged 60–85 with their physicians; 9 visits were with solo patients and 12 included a patient companion, all family members. The older the patient, the more likely a companion was to be involved. Companion presence did not affect the length of the visit’s length, but instead took time away from patients. Coe48 found that although the presence of a third party affected communication (e.g. physicians adjusted to include the presence of a third party), it was not clear whether the effect was positive or negative for the patient. Both authors agreed that more research is needed on the effects that third parties bring to the interaction between older patient and physician and subsequent screening rate compliance. Knowledge-based barriers to screening Patients and their providers generally need a minimal knowledge base that includes, for example, risk factors regarding disease, awareness of cancer screening procedures, and knowledge about the current guidelines for their use, for there to be patient compliance regarding utilization. Therefore, patient’s lack of awareness about the risk factors for breast cancer, screening procedures (e.g. mammography), or the recommended guidelines for their use can serve as barriers to patient screening compliance. Exceptions exist, however, especially when patients or providers resist or are unaware of current guidelines. For example, the recommended utilization of screening mammography for women aged 50–74 (US Preventive Task Force) is every year or two; the NCI recommends mammography every year or two from age 50, with no upper age restrictions. Nevertheless, most women in that age group still believe that annual screening is the recommended frequency, a frequency that is now endorsed only by the ACS (SA Fox, unpublished Los Angeles data, 1995). It is unclear if providers prefer annual screening. The research base, however, regarding the impact of knowledge on screening endorsements is not as broad as the literature supporting the impact of access to care or attitudes on screening. Furthermore, most studies have focused on patient knowledge instead of provider knowledge of risk factors or screening recommendations.

Comprehensive Geriatric Oncology

672

Exceptions are two surveys of general practitioners in Australia: one indicated confusion about guidelines for prostate and testicular cancer screening as well as under usage of these techniques with patients;49 the other determined that although general practitioners had a good working knowledge regarding skin cancer, there were significant gaps that needed correction.50 Several studies indicated a similar confusion about guidelines among patients. Older women demonstrated less awareness and use of Pap smears for cervical cancer screening. Mamon et al51 found that older women (over 45) were more likely to be underscreened as well as to not know the risk factors for cervical cancer. Additionally, older women were more likely to not recall being told about the guidelines by their providers and to be confused about actual guidelines. Mandelblatt et al52 had similar findings: older Black low-income women who reported low levels of knowledge about cervical and breast cancer also demonstrated low levels of utilization of screening tests. Other studies demonstrated a relationship between actual compliance with breast cancer screening, intended compliance, and knowledge about disease and detection. Fox et al53 and Champion54 found that the less compliant patient had lower levels of knowledge about breast cancer and detection issues. Richardson55 found, similarly, that women who intended to participate in regular breast cancer screening were more knowledgeable about breastcancer. Knowledge of risks also contributed to better patient compliance with screening. Rimer et al25 offered a health education program to retirement home residents that included teaching the older women about risk factors as well as detection techniques. These women were more likely to subsequently get screened than women who were offered subsidized mammograms. Alternatively, women who assessed their risks as high (younger women) were more likely to get screened than older women whose actual risks were higher; this provides a partial explanation of the lower screening rates among older women.56 Knowledge about risks tended to decrease with age and was related to a decrease in screening rates. Mah and Bryant57 found that although over half of the sample in their Canadian study had had a mammogram, the proportion decreased with age after the age of 60. Knowledge of breast cancer risk factors was generally low, as was knowledge of guidelines; both decreased with age. Finally, there were differences in knowledge levels by race/ethnicity. Ruiz et al58 found that Latinas needed to be reached about cancer issues through the Spanishlanguage media. However, if Latinas, especially the elderly, had acquired English and were acculturated, they were more likely to know more about cancer and to have been screened. Perez-Stable et al59 found that misconceptions about cancer were more prevalent among Latinos than Anglos. Attitudlnal barriers to screening Patient attitudes Health beliefs and attitudes are important components of several theoretical models of health behavior that have been examined in the context of cancer screening. Models such

Barriers to cancer prevention in the older person

673

as the Theory of Reasoned Action and the Health Belief Model have been found to have reasonably good predictive value for compliance with cancer screening, suggesting that patient attitudes are important determi-nants of screening behavior.60–63 Empirical studies have also found correlations between general health attitudes and cancer screening.64 Attitudes may play an even more important role in screening behavior for the elderly than in younger women.65 Poor cancer screening compliance among the elderly, therefore, may in part be the result of differing health beliefs and attitudes. Studies have shown that older patients possess a number of negative beliefs and attitudes about cancer and cancer screening. For example, despite the striking age-related increase in cancer incidence, many older persons paradoxically perceive less susceptibility to cancer, and this belief has been associated with lower levels of screening.57,62,66–70 The elderly also generally express more fatalistic views of cancer.18,39,69 Focus groups, for instance, discovered that most older Americans viewed cancer as a worst-case scenario, associated with radical and painful treatment, usually fatal, and accompanied by a greatly feared dependence on others. There was very little distinction made between early- and late-stage disease. Cancer cures were instead attributed more often to luck or personal character traits rather than early detection with screening. Empirical studies have found a number of negative attitudes about cancer screening that are held more frequently by the elderly. These include greater worries about radiation/safety of mammography,65,66 a greater reliance on symptoms to find cancer rather than asymptomatic detection with screening,39,59,68,69,71 lower perceived efficacy of screening,65 less concern about cancer prevention compared with current medical problems,39,67 and greater embarrassment with screening.72–74 Older men generally report more negative views about the role of prevention, are less likely to report symptoms, and report avoiding contact with physicians if possible.75 Although the elderly possess a great many negative cancer screening attitudes, their effects on screening compliance can be moderated by other factors. Social support, for example, has been shown to greatly limit the negative effects of fear and anxiety on cancer screening.76,77 A physician’s firm recommendation for screening will also likely overcome most negative health beliefs and attitudes.78 Most studies have indeed found that the effects of patient attitudes on screening are modest when compared with physician input.60 It is not clear why the elderly possess more negative views about cancer and screening. Some of these views may be the result of a cohort effect. Most elderly patients have lived much of their lives during a time when cancer treatments were generally unsuccessful, cancer was often fatal, and the potential for early detection with screening had not been realized. It is not surprising, therefore, that their experiences with cancer would be less positive than those of younger patients. The elderly’s perception that they are less susceptible to cancer may be a result of the failure to target screening educational programs to the elderly. Until recently, for instance, most breast cancer media promotions typically featured young women undergoing screening, leaving the impression that they were the most vulnerable.79 Finally, some waning of interest in cancer screening may be appropriate for persons with poor health status and other pressing health concerns. More research is needed into the effects of health status on cancer screening.

Comprehensive Geriatric Oncology

674

Physician attitudes and beliefs Physician attitudes and beliefs about preventive medicine and the elderly may in part be responsible for their acknowledged underscreening of older persons. Physicians (and others) generally underestimate the life-expectancy of older Americans.34 For example, the average life-expectancy of a 65-year-old woman is 18 years, for a 75-year-old woman it is 12 years, and for an 85-year-old woman it is 7 years.80 If physicians perceive a limited life-expectancy with poor quality of life for their elderly patients, they will understandably have less enthusiasm for preventive interventions. Although things are changing, medical education has also traditionally provided a strong disease orientation and has not emphasized preventive care.81 All of these factors may make prevention in general a low priority for physicians who care for older patients. Screening is also impacted to a great extent by the uncertainty of guidelines for older people. In addition, physicians recognize that the elderly population is quite heterogeneous with respect to health status, comorbidity, and quality of life. Patients likely differ in their preferences for screening, and their willingness to follow-up and treat abnormalities. Clearly these issues need to be discussed prior to undertaking screening interventions, but unfortunately this makes screening a more time-consuming and complicated endeavor. Physicians also have no simple methods to assess life-expectancy and functional life-expectancy to assist in these decisions.82 Physicians’ screening recommendations are also likely influenced by their perceptions of patients’ attitudes and beliefs. For example, physicians report that their elderly patients are less interested in preventive care compared with care for their acute and chronic medical problems.18 During focus group discussions, they also report that their patients find many screening tests unpleasant, or embarrassing.19 Physicians believe that older patients do not expect certain screening tests to be done (e.g. DRE), and are more likely to refiise cancer screening recommendations.83 On a positive note, primary care physicians do have some very encouraging attitudes about cancer screening in general. They overwhelmingly know and support ACS guidelines, often in preference to less aggressive guidelines such as those of the US Preventive Services Task Force.84–86 They also believe cancer screening to be effective19,83 and express strong interest in cancer screening education.87 Also, although the yield of cancer screening is generally low in a typical primary care practice, its emotional impact can be substantial. During focus groups, physicians report being affected greatly by the diagnosis of an early cancer by screening, and also are quite affected by caring for cancer patients with terminal disease. Diagnosing cancer is likely to be a critical event for physicians. Cancer screening attitudes are not uniform among primary care physicians. Most studies, for instance, have shown less favorable attitudes about cancer screening among older physicians. It is unclear if this is the result of a cohort effect reflecting training differences between younger and older physicians. It is also possible that attitudes about the value of preventive services change as physicians age or assume care for an older patient population. Although some studies have suggested gender differences in physicians’ preventive care, gender differences have not been apparent for older patients.

Barriers to cancer prevention in the older person

675

Community-based barriers to screening Office interventions Even physicians with a very strong commitment to screening must overcome a number of barriers, including remembering to offer screening, finding adequate time during patient encounters, and the many logistical problems of screening. Fairly substantial gaps between physicians’ intentions to screen and actual screening rates have usually been reported.32 A large number of interventions have been conducted to improve cancer screening in the primary care setting. Interventions have been directed at primary care physicians, their patients, and their staff. Physician-directed interventions have included health promotion checklists, flow sheets, and chart tags that serve as reminders for screening.88–93 These reminder systems increase screening rates by attempting to focus attention on selected cancer screening tests. In general, such reminders are effective, especially when directed at a small number of screening tests. They are less effective when directed at multiple screening tests, with some studies finding that non-targeted screening tests may actually decrease. Clearly, physicians cannot focus their attention on all screening interventions. Chart audit of screening compliance with feedback of screening rates to individual physicians has also been successfully used.94,95 Finally, computer-generated reminders have been studied extensively.95–101 These interventions have generally shown greater increases in screening rates than chart reminders do, and when directed at multiple screening tests have produced more uniform effects. Computer reminders were more cost-effective than audit with feedback.102 Patient interventions that have been found to be effective include mailed reminder postcards/letters,93,95,98,103,104 history/risk factor questionnaires,101 and patient-held minirecords.105,106 Telephone calls have not been found to be particularly effective.98,103 Interventions targeted at both physicians and patients (physician computer reminders and patient letters or postcards) have also been effective, and have generally shown additive effects.107–110 Several interventions have been directed at office nursing staff, and have been effective at increasing rates of breast and colorectal cancer screening.111–114 Although all of the above interventions have been successful to some extent, the longterm durability of their effects is not known. One would expect effects to wane over time as the novelty of reminder systems wears off.115 Community interventions A number of community-based interventions to promote cancer screening have been conducted.116–128 Most have studied breast and cervical cancer screening. Strategies to promote screening have generally been multifaceted, including efforts to educate and persuade primary care physicians to increase screening (CME and newsletters), efforts to educate/motivate women (posters, brochures, direct mailings, mass media, church/worksite programs, and use of celebrities and volunteers), and efforts to overcome logistic/access barriers (mobile vans, onsite nurse-practitioners, reminder systems, office

Comprehensive Geriatric Oncology

676

staff training, and subsidizing screening costs). The details of NCI-funded community interventions have been summarized.129 Several conclusions can be drawn from these trials. First multistrategy interventions have generally been more successful than more limited interventions. It is also clear that eliminating the costs of screening without addressing other barriers has not proven successful.25 Finally, well-structured community interventions have increased screening rates in an impressive variety of patient care settings, including HMOs, public hospital clinics, community health centers, and private physicians’ offices, and for patients of varied ethnicities and socioeconomic status. Several questions regarding community interventions remain unanswered. The costeffectiveness of community interventions in general has not been established, nor have individual strategies been compared with respect to their cost-effectiveness. Although community interventions have proven their effectiveness in research settings, it is also not always clear how they can be implemented in settings where resources are more limited, and specialized personnel are lacking. Conclusions The following are practice-based suggestions to reduce barriers to cancer prevention in the older person. Demographic barriers and suggestions for improvement • The following patient groups need special encouragement by clinicians if there is to be more equity in screening rates: older persons, especially those over 74; non-White patients, especially those who are non-English-speaking; and poverty-level and lowereducation persons. • Opposite-gender (to physicians) patients should be treated with age-appropriate screening practices, in spite of any clinician embarrassment. • The number of quality years of life-expectancy that older, still healthy, patients can expect is often under-estimated. Health status, instead of chronological age, should be the best indicator of whether to refer patients for prevention services. • Older people are not homogeneous. Not only do they differ in personalities, they also differ by age groups. All people aged 65 and over are often viewed as similar, when in fact 65-year-olds are quite different in comorbidities and other problems from 85-yearolds. • Problems with aging should not be assumed to be automatic with all aged patients, even though there will often be increased medical difficulties with patient aging, which need to be inquired about. Communication barriers and suggestions for improvement • Taking more initiative and asking patients about their concerns at the beginning of the visit will facilitate older patients getting their needs met. Likewise, patients should learn to be more verbally assertive about the reasons for the visit at its beginning.

Barriers to cancer prevention in the older person

677

• Compliance with screening guidelines is likely to suffer if their mention is not easily recalled by patients or reinforced with printed matter provided by the physician’s office. • Physicians who treat older patients would be more effective if they address patient fears about cancer directly. • Physicians have enormous influence over their older patients’ behaviors—even their screening behaviors. Cancer screening compliance rates can be increased significantly through more direct physicians’ communication of their wants for their patients—for example, that they want their patients to get screened for cancer. The way in which clinicians encourage patient behavior makes a difference in whether patients respond. Physicians can enjoy an increased level of screening by their patients if they recommend screening with enthusiasm. Knowledge barriers and suggestions for improvement • Knowledge levels of risk factors, awareness of screening procedures, and knowledge of screening guidelines are all predictors of higher levels of screening compliance. These issues should be reviewed with older patients. Ideally, patients should leave each visit with printed matter that reinforces verbal instructions. Attitudinal barriers and suggestions for improvement • Physicians’ enthusiasm for screening can be very effective in overcoming the older person’s pessimism regarding survival from a cancer diagnosis and accompanying pessimism regarding cancer screening. • Survey research and focus groups suggest that older persons are generally very receptive to getting regular screening. Thus, providers should not assume that older patients will resist screening recommendations. Community barriers and suggestions for improvements • Physician and patient reminders regarding screening tests improve compliance. • Multiple barriers to screening (e.g. reduction of screening costs and anxiety about a finding) need attention in order to increase patient compliance with screening.

Acknowledgements This investigation was supported in part by the US National Cancer Institute (NCI#SR01CA6587 and NCI#R01CA65880) to SAF, and the Health Resources Services Administration (#2T32PE 19001) to RGR. The authors acknowledge the assistance of Michael Zinkovitch in the preparation of this chapter.

Comprehensive Geriatric Oncology

678

References 1. Andersen R, Newman JF. Societal and individual determinants of medical care utilization in the United States. Milbank Memorial Fund Q 1973; 51:95–124. 2. Hayward RSA, Steinberg EP, Ford DE et al. Preventive care guidelines. Ann Intern Med 1991; 114:758–83. 3. Sox HC. Preventive health services in adults. N Engl J Med 1994; 330: 1589–95. 4. US Preventive Services Task Force. Screening for colorectal cancer: recommendations and rationale. Ann Intern Med 2002; 137:129–31. 5. Mandel JS, Church TR, Bond JH et al. The effect of fecal occultblood screening on the incidence of colorectal cancer. N Engl J Med 2000; 343:1603–7. 6. Rex DK, Johnson DA, Lieberman DA et al. Colorectal cancer prevention 2000: screening recommendations of the American College of Gastroenterology. Am J Gastroenterol 2000; 95:868–77. 7. Smith RA, von Schernbach AC, Wender R et al. American Cancer Society guidelines for the early detection of cancer: update of early detection guidelines for prostate, colorectal, and endometrial cancers; also update 2000—testing for early lung cancer detection. CA Cancer J Clin 2001; 51:38–75; quiz 77–80. 8. Smedley BD, Stith AY, Nelson AR (eds). Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care. Washington, DC: National Academies Press, 2003. 9. Bryant H, Mah Z. Breast cancer screening attitudes and behaviors of rural and urban women. Prev Med 1992; 21:405–18. 10. Escarce JJ Epstein KR, Colby DC, Schwartz JS. Racial differences in the elderly’s use of medical procedures and diagnostic tests. Am J Public Health 1993; 83:948–54. 11. Breen N, Kessler L. Changes in the use of screening mammography: evidence from the 1987 and 1990 National Health Interview Surveys. Am J Public Health 1994; 84:62–70 12. Hayward RA, Shapiro MF, Freeman HE, Corey CR. Who gets screened for cervical and breast cancer. Results from a New National Survey. Arch Intern Med 1988; 148:1177–81. 13. Woolhandler S, Himmelstein D. Reverse targeting of preventive care due to lack of health insurance. JAMA 1988; 259:2872–4. 14. Kirkman-Liff B, Kronenfeld J. Access to cancer screening services for women. Am J Public Health 1992; 82:733–5. 15. Blustein J. Medicare coverage, supplemental insurance, and the use of mammography by older women. N Engl J Med 1995; 332: 1138–43. 16. Partnership for Prevention. A better Medicare for healthier seniors: recommendations to modernize Medicare’s prevention policies. Washington, DC: http://www.prevent.org/, 2003. 17. Morrissey J, Harris R, Kincade-Norburn J et al. Medicare reimbursement for preventive care: changes in performance of services, quality oflife, and healthcare costs. Med Care 1995; 33:315–31. 18. Zapka J, Berkowitz E. A qualitative study about breast cancer screening in older women: implications for research. J Gerontol 1992; 47(Suppl):93–100. 19. Montano D, Manders D, Phillips W. Family physician beliefs about cancer screening: development of a survey instrument. J Fam Pract 1990; 30:313–19. 20. Frame P. Breast cancer screening in older women: the family practice perspective. J Gerontol 1992; 47(Suppl):131–3. 21. Ko CW, Kreuter W, Baldwin LM. Effect of Medicare coverage on use of invasive colorectal cancer screening tests. Arch Intern Med 2002; 162:2581–6. 22. McWilliams JM, Zaslavsky AM, Meara E, Ayanian JZ. Impact of Medicare coverage on basic clinical services for previously uninsured adults. JAMA 2003; 290:757–64.

Barriers to cancer prevention in the older person

679

23. Burg M, Lane D. Mammography referrals for elderly women: Is Medicare reimbursement likely to make a difference? Health Serv Res 1992; 27:505–16. 24. Urban N, Anderson G, Peacock S. Mammography screening: How important is cost as a barrier to use? Am J Public Health 1994; 84:50–5. 25. Rimer BK, Resch N, King E et al. Multistrategy health education program to increase mammography use among women ages 65 and older. Public Health Reports 1992; 107:369–80. 26. Katz S, Hofer T. Socioeconomic disparities in preventive care persist despite universal coverage: breast and cervical cancer screening in Ontario and the United States. JAMA 1994; 272:530–4. 27. Bernstein A, Thompson G, Harlan L. Differences in rates of cancer screening by usual source of medical care. Med Care 1991; 29:196–209. 28. Zapka J, Hosmer D, Costanza M et al. Changes in mammography use: economic, need, and service factors. Am J Public Health 1992; 82:1345–51. 29. Riley G, Potosky A, Lubitz J, Brown M. Stage of cancer at diagnosis of Medicare, HMO and fee-for-service enrollees. Am J Public Health 1994; 84:1598–604. 30. Beisecker AE. Older patients and their doctors: annotated bibliography. University of Kansas Medical Center, unpublished report commissioned by the National Institute on Aging, 1995. 31. Beisecker AE. Older patients and their doctors. University of Kansas Medical Center, unpublished report commissioned by the National Institute of Aging, 1995. 32. Roetzheim R, Fox S, Leake B. Physician-reported determinants of screening mammography in older women: the impact of physician and practice characteristics. J Am Geriatr Soc 1995; 43:1–5. 33. Levy S, Dowling P, Boult L et al. The effect of physician and patient gender on preventive medicine practices in patients older than fifty. Fam Med 1992; 24:58–61. 34. Weinberger M, Saunders AF, Samsa GP et al. Breast cancer screening in older women: practices and barriers reported by primary care physicians. J Am Geriatr Soc 1991; 39:22–9. 35. Erber NP. Communicating with elders: effects of amplification. J Gerontol Nursing 1994; 20:6–10. 36. Rost K, Frankel R. The introduction of the older patient’s problems in the medical visit. J Aging Health 1993; 5:387–401. 37. Adelman RD, Greene MG, Charon R, Friedmann E. The content of physician and elderly patient interaction in the medical primary care encounter. Comm Res 1992; 19:370–80. 38. Greene MG, Adelman RD, Charon R, Friedmann E. Concordance between physicians and their older and younger patients in the primary care medical encounter. J Gerontol Soc Am 1989; 29:808–13. 39. Sutton S, Eisner E, Burklow J. Health communications to older Americans as a special population: the National Cancer Institute’s consumer-based approach. Cancer 1994; 74:2194–9. 40. Fox SA, Murata PJ, Stein JA. The impact of physician compliance on screening mammography for older women. Arch Intern Med 1991; 151:50–6. 41. Adelman RD, Greene MG, Charon R. Issues in the physician-elderly patient interaction. Aging Society 1991; 2:127–48. 42. Street RL. Information-giving in medical consultations: the influence of patients’ communicative styles and personal characteristics. Soc Sci Med 1991; 32:541–8. 43. Beisecker AE. Aging and the desire for information and input in medical decisions: patient consumerism in medical encounters. Gerontologist 1988; 28:330–5. 44. Kreps GL. A systematic analysis of health communication with the aged. In: Communication, Health and the Elderly (Giles H, Coupland N, Wuemann JM, eds). London: Manchester University Press, 1990; 135–54. 45. Waitzkin H. Information giving in medical care. J Health Soc Behav 1985; 26:81–101. 46. Fox SA, Siu AL, Stein JA. The importance of physician communication on breast cancer screening of older women. Arch Intern Med 1994; 154:2058–68.

Comprehensive Geriatric Oncology

680

47. Beisecker AE. The influence of a companion on the doctor-elderly patient interaction. Health Comm 1989; 1:55–70. 48. Coe RM. Communication and medical care outcomes: Analysis of conversations between doctors and elderly patients. In: Health in Aging (Ward RA, Tobin SS, eds). New York: Springer, 1987. 49. Sladden MJ, Dickinson JA. General practitioners’ attitudes to screening for prostate and testicular cancers. Med J Aust 1995; 162:410–13. 50. Paine SL, Cockburn J, Noy SM, Marks R. Early detection of skin cancer. Knowledge, perceptions and practices of general practitioners in Victoria. Med J Aust 1994; 161:188–9, 192–5. 51. Mamon JA, Shediac MC, Crosby CB et al. Inner city women at risk for cervical cancer: behavioral and utilization factors related to inadequate screening. Prev Med 1990; 19:363–76. 52. Mandelblatt J, Traxler M, Lakin P et al. Mammography and Papanicolaou smear use by elderly poor black women. The Harlem Study Team. J Am Geriatr Soc 1992; 40:1001–7. 53. Fox SA, Klos DS, Tsou CV, Baum JK. Breast cancer screening recommendations: current status of women’s knowledge. Fam Comm Health 1987; 10:39–50. 54. Champion VL. Compliance with guidelines for mammography screening. Cancer Detect Prev 1992; 16:253–8. 55. Richardson A. Factors likely to affect participation in mammographic screening. NZ Med J 1990; 103:155–6. 56. Harris RP, Fletcher SW, Gonzalez JJ et al. Mammography and age: Are we targeting the wrong women? A community survey of women and physicians. Cancer 1991; 67:2010–14. 57. Mah Z, Bryant H. Age as a factor in breast cancer knowledge, attitudes and screening behavior. Can Med Assoc J 1992; 146: 2167–74. 58. Ruiz MS, Marks G, Richardson JL. Language acculturation and screening practices of elderly Hispanic women. The role of exposure to health-related information from the media. J Aging Health 1992; 4:268–81. 59. Perez-Stable EJ, Sabogal F, Otero-Sabogal R et al. Misconceptions about cancer among Latinos and Anglos. JAMA 1992; 268:3219–23. 60. Montano D, Taplin S. A test of an expanded theory of reasoned action predict mammography participation. Soc Sci Med 1991; 32: 733–41. 61. Stein J, Fox S, Murata P, Morisky D. Mammography usage and the health belief model. Health Educ Q 1992; 19:1–16. 62. Aiken L, West S, Woodward C, Reno R. Health beliefs and compliance with mammographyscreening recommendations in asymptomatic women. Health Psychol 1994; 12:122–9. 63. Hyman R, Baker S, Ephraim R et al. Health belief model variables as predictors of screening mammography utilization. J Behav Med 1994; 17:391–406. 64. O’Connor A, Perrault D. Importance of physician’s role highlighted in survey of women’s breast screening practices. Can J Public Health 1995; 86:42–5. 65. Taplin S, Montano D. Attitudes, age, and participation in mammographic screening: a prospective analysis. J Am Board Fam Pract 1993; 6:612–23. 66. Vernon S, Vogel V, Halabi S et al. Breast cancer screening behaviors and attitudes in three racial/ethnic groups. Cancer 1992; 69:165–74. 67. Burg M, Lane D, Polednak A. Age group differences in the use of breast cancer screening tests. J Aging Health 1990; 2:514–30. 68. Costanza M, Stoddard A, Gaw V, Zapka J. The risk factors of age and family history and their relationship to screening mammography utilization. J Am Geriatr Soc 1992; 40:774–8. 69. King E, Resch N, Rimer B et al. Breast cancer screening practices among retirement community women. Prev Med 1993; 22:1–19. 70. Lerman C, Rimer B, Trock B et al. Factors associated with repeat adherence to breast cancer screening. Prev Med 1990; 19:279–90.

Barriers to cancer prevention in the older person

681

71. Rimer B, Keintz M, Kessler H et al. Why women resist screening mammography: patient related barriers. Radiology 1989; 172:243–6. 72. Burack R, Liang J. The acceptance and completion of mammography by older Black women. Am J Public Health 1989; 4:721–6. 73. Richardson J, Marks G, Solis J et al. Frequency and adequacy of breast cancer screening among elderly Hispanic women. Prev Med 1987; 16:761–74. 74. Morisky D, Fox S, Murata P, Stein J. The role of needs assessment in designing a communitybased mammography education program for urban women. Health Educ Res 1989; 4:469–78. 75. Greg G, Goys J. Men’s Health Project Focus Groups Reports. Washington, DC. American Association of Retired Persons, 1994. 76. Suarez L, Lloyd L, Weiss N et al. Effect of social networks on cancer screening behavior of older Mexican-American women. J Natl Cancer Inst 1994; 86:775 77. Kang S, Bloom J. Social support and cancer screening among older Black Americans. J Natl Cancer Inst 1993; 85:737–42. 78. Slenker S, Grant M. Attitudes, beliefs and knowledge about mammography among women over forty years of age. J Cancer Educ 1989; 4:61–5. 79. Roetzheim R, Van DD, Brownlee H et al. Reverse targeting in a media-promoted breast cancer screening project. Cancer. 1992; 70: 1152–8. 80. Costanza M. The extent of breast cancer screening in older women. Cancer 1994; 74(Suppl):2046–50. 81. Williams P, Williams M. Barriers and incentives for primary care physicians in cancer prevention and detection. Cancer 1988; 61: 2382–90. 82. Cohen H. Breast cancer screening in older women: the geriatrician/internist perspective. J Gerontol 1992:47:134–6. 83. Clasen C, Vernon S, Mullen P, Jackson G. A survey of physician belief and self-reported practices concerning screening for early detection of cancer. Soc Sci Med 1994; 39:841–9. 84. Czaja R, McFall S, Warnecke R et al. Preferences of community physicians for cancer screening guidelines. Ann Intern Med 1994; 120:602–8. 85. Weinberger M, Saunders A, Bearon L et al. Physician-related barriers to breast cancer screening in older women. J Gerontol 1992; 47:111–17. 86. Stange K, Kelly R, Chao J et al. Physician agreement with US Preventive Services Task Force recommendations. J Fam Pract 1992; 34: 409–16. 87. Warner S, Worden J, Solomon L, Wadland W. Physician interest in breast cancer screening education. J Fam Pract 1989; 29:281–5. 88. Cohen D, Littenberg B, Wetzel C, Neuhauser D. Improving physician compliance with preventive medicine guidelines. Med Care 1982; 20:1040–5. 89. Prislin M, Vandenbark M, Clarkson Q. The impact of health screening flow sheet on the performance and documentation of health screening procedures. Fam Med 1986; 18:290–2. 90. Cheney C, Ramsdell J. Effect of medical records’ checklists on implementation of periodic health measures. Am J Med 1987; 83:129–36. 91. Schreiner D, Petrusa E, Rettie C, Kluge R. Improving compliance with preventive medicine procedures in a housestaff training program. South Med J 1988; 81:1553–7. 92. Robie P. Improving and sustaining outpatient cancer screening by medicine residents. South Med J 1988; 81:902–5. 93. Pierce M, Lundy S, Palanisamy A et al. Prospective randomized controlled trials of methods of call and recall for cervical cytology screening. BMJ 1989; 299:160–2. 94. Winickoff R, Coltin K, Morgan M et al. Improving physician performance through peer comparison feedback. Med Care 1984; 22: 527–34. 95. McPhee S, Bird J, Jenkins C, Fordham D. Promoting cancer screening: a randomized, controlled trials of three interventions. Arch Intern Med 1989; 149:1866–72. 96. McDonald C, Hui S, Smith D et al. Reminders to physicians from an introspective computer medical record a two-year randomized trial. Ann Intern Med 1984; 100:130–8.

Comprehensive Geriatric Oncology

682

97. Tierney W, Hui S, McDonald C. Delayed feedback of physician performance versus immediate reminders to perform preventive care. Med Care 1986; 24:659–66. 98. McDowell I, Newell C, Rosser N. Computerized reminders to encourage cervical screening in family practice. J Fam Pract 1989; 28:420–4. 99. Chambers C, Balaban D, Carlson B et al. Microcomputer generated reminders: improving the compliance of primaiy care physicians with mammography screening guidelines. J Fam Pract 1989; 29:273–80. 100. Chodroff C. Cancer screening and immunization quality assurance using personal computer. Qual Rev Bull 1990; 16:279–87. 101. Turner B, Day S, Borenstein B. A controlled trial to improve delivery of preventive care: physician or patient reminders? J Gen Intern Med 1989; 4:403–9. 102. Bird J, McPhee S, Jenkins C, Fordham D. Three strategies to promote cancer screening: How feasible is wide-scale implementation? Med Care 1990; 28:1005–12. 103. Petravage J, Swedberg J. Patient response to sigmoidoscopy recommendations via mailed reminders. J Fam Pract 1988; 27:387–9. 104. Wolosin R. Effect of appointment scheduling and reminder postcards on adherence to mammography recommendations. J Fam Pract 1990; 30:542–7. 105. Dioptric A, Duhamel M. Improving geriatric preventive care through a patient-held checklist. Fam Med 1989; 21:195–8. 106. Dickey L, Petitti D. A patient-held minirecord to promote adult preventive care. J Fam Pract 1992; 34:457–63. 107. Nattinger A, Panzer R, Janus J. Improving the utilization of screening mammography in primary care practices. Arch Intern Med 1989; 149:2087–92. 108. McPhee S, Bird J, Fordham D et al. Promoting cancer prevention activities by primary care physicians. JAMA 1991; 266:538–44. 109. Becker D, Gomez E, Kaiser D et al. Improving preventive care at a medical clinic. How can the patient help? Am J Prev Med 1989; 5: 353–9. 110. Ornstein S, Garr D, Jenkins R et al. Computer-generated physician and patient reminders: tools to improve population adherence to selected preventive services. J Fam Pract 1991; 32:82–90. 111. Davidson R, Fletcher S, Retchin S, Duh S. A nurse-initiated reminder system for the periodic health examination: implementation and evaluation. Arch Intern Med 1984; 144:2167–70. 112. Thompson R, Michnich M, Gray J et al. Maximizing compliance with Hemoccult screening for colon cancer in clinical practice. Med Care. 1986; 24:904–14. 113. Belcher D. Implementing preventive services: success and failure in an outpatient trial. Arch Intern Med 1990; 150:2533–41. 114. Foley E, D’Amico F, Merenstein J. Improving mammography recommendation: a nurseinitiated intervention. J Am Board Fam Pract 1990; 3:87–92. 115. Dioptric A, Sox C, Tosteson T, Woodruff C. Durability of improved physician early detection of cancer after conclusion of intervention support. Cancer Epidemiol Biomark Prev 1994; 3:335–40. 116. Suarez L, Nichols D, Brady C. Use of peer role models to increase Pap smear and mammogram screening in Mexican-American and Black women. Am J Prev Med 1993; 9:290– 6. 117. Herman C, Speroff T, Cebul R. Improving compliance with breast cancer screening in older women: results of a randomized controlled trial. Arch Intern Med 1995; 155:717–22. 118. Lantz P, Stencil D, Lippert M et al. Breast and cervical cancer screening in a low-income managed care sample: the efficacy of physician letters and phone calls. Am J Public Health 1995; 85:834–6. 119. Costanza M, Zapka J, Harris D et al. Impact of a physician intervention program to increase breast cancer screening. Cancer Epidemiol Biomark Prev 1992; 1:581–9.

Barriers to cancer prevention in the older person

683

120. Trock B, Rimer B, King E et al. Impact of an HMO based intervention to increase mammography utilization. Cancer Epidemiol Biomark Prev 1993; 2:151–6. 121. Zapka J, Harris D, Hosmer D et al. Effect of a community health center intervention on breast cancer screening among Hispanic American women. Health Ser Res 1993; 28:223–235. 122. Lane D, Polednak A, Burg M. Effect of continuing medical education and cost reduction on physician compliance with mammography screening guidelines. J Fam Pract 1991; 33:359–68. 123. Mandelblatt J, Traxler M, Lakin P et al. A nurse practitioner intervention to increase breast and cervical cancer screening for poor, elderly, Black women. The Harlem Study Team. J Gen Intern Med 1993; 8:173–8. 124. Metcher S, Harris R, Gonzalez J et al. Increasing mammography utilization: a controlled study. J Natl Cancer Inst 1993; 85:112–120. 125. Forsyth M, Fulton D, Lane D et al. Changes in knowledge, attitudes and behavior of women participating in a community outreach education program on breast cancer screening. Patient Educ Counsel 1992; 19:241–50. 126. Zapka J, Costanza M, Harris D et al. Impact of a breast cancer screening community intervention. Prev Med 1993; 22:34–53. 127. Bastani R, Marcus A, Maxwell A et al. Evaluation of an intervention to increase mammography screening in Los Angeles. Prev Med 1994; 23:83–90. 128. Lane D, Burg M. Strategies to increase mammography utilization among community health center visitors: improving awareness, accessibility, and affordability. Med Care 1993; 31:175– 81. 129. Haynes S, Mara J. The Picture of Health: How to Increase Breast Cancer Screening in Your Community. Bethesda, MD: National Cancer Institute, 1993.

PART 6 Management of cancer in the older person

31 Perspectives on training in geriatrics and oncology John M Bennett Introduction Cancer remains a significant cause of mortality at all ages, and is the second most common cause of death after heart disease. As mentioned in other chapters of this textbook, over 60% of cancers occur in adults over the age of 65 and 70% of cancer deaths are in this same age population. It is estimated that by the year 2030 more than 20% of the US population (70 million people) will be older than 65. Medicare expenses are projected to increase by 50% over this same period. Therefore, there is an impetus to train academic specialists who will recognize the substantial opportunities that will exist in prevention, early detection, diagnosis and management in geriatric oncology, arbitrarily defined as dealing with patients aged 65 or older. In addition, since the burden of care responsibilities will continue to reside in the hematology/medical oncology clinical community, enhanced skills and expertise can only be met by new educational initiatives that will be provided by specialists cross-trained in medical oncology and geriatrics. Recognizing this need, a project was implemented in conjunction with the John A Hartford Foundation to develop a combined medical oncology/geriatric fellowship program at selective medical centers in the USA that had expertise in both disciplines. Successful completion of this program, designed to be of 3 years’ duration, would result in eligibility for the Subspecialty Board of Internal Medicine and the Added Qualifications in Geriatrics (CAQ). The seeds of this program were sown after a Medical Oncology/Geriatrics Retreat sponsored by the Hartford Foundation in early 1977, which brought together academic leaders in medical oncology and geriatrics. Program development A series of position papers were published after this successful retreat, including one on a combined fellowship program.1 In the fall of 1977, faculty members from five of the institutions that attended the retreat met and agreed to submit a proposal to the Hartford Foundation to: (i) develop pilot fellowship programs that would encourage medical residents in internal medicine to seek out subspecialty training in both medical oncology and geriatrics; (ii) encourage current trainees to cross-train in the respective specialty, leading to board eligibility; (iii) develop a national interest in the combined specialties by

Comprehensive Geriatric Oncology

686

involving the respective American Subspecialty Boards of Internal Medicine; and (iv) promote research and education by establishing liaisons with the National Cancer Institute (NCI), the National Institute of Aging (NIA), the American Cancer Society (ACS), and the American Society for Clinical Oncology (ASCO). In addition to providing a modest amount of funding for up to 12 programs, the University of Rochester Medical Center was proposed as the coordinating center, with responsibities for evaluation as well as interaction with a variety of agencies. A 2½-year grant was awarded in July 1998. A 2-day planning conference was held that resulted in an extensive report defining the opportunities in laboratory and clinical research on older patients with cancer and three tracks for obtaining Specialty Boards in both disciplines. These included the traditional 2 years of medical oncology and 1 year of geriatric training in either order or the much preferred integrated 3-year program that would permit considerable time for research as well as clinical training. An example of a combined 3 year program would include rotations in medical oncology clinics for ½ day/week over 3 years (75 days in toto), radiation/gynecologic oncology clinics for ½ day/week for a total of 30 days in each discipline, geriatric clinics for ½ day/week over 3 years (75 days in toto), neuropsychiatric experience (30 days), rehabilitation medicine (30 days), and nursing home visits (30 days), for a total of 300 days. Inpatient rotations would include hematology/medical oncology floor and consults for 6 months, bone marrow transplant service for 1 month, hospice/palliative care for 1 month, ‘acute care of the elderly’ service or its equivalent for 1 month, for an additional 270 days. The balance of the time (in excess of 1 year) would be devoted to basic science, clinical, and/or translational research studies. Approval from the Medical Oncology Subspecialty Board of the American Board of Internal Medicine has been obtained for the 3-year combined program. Each university program can modify the rotations, provided that the spirits of the individual specialty requirements are preserved. Eleven centers received financial support for at least 1 year, with three programs being granted an additional year of funding. Seven fellows were formally enrolled, with projects that ranged from evaluation of prostate cancer patients and their socioeconomic needs, reasons for delayed referral of older women with localized breast cancer, evaluation of anemia in individuals over 75, mechanisms of resistance in acute leukemia of the elderly, and immunologic therapy of prostate cancer. The overall impression of the program has been that success is directly related to having an enthusiastic and supportive faculty in both specialties, with excellent mentoring. Inability to provide additional financial support to fully fund new fellows and partial support for junior faculty has proven to be a disincentive to collaboration and fellowship recruitment. Future directions The American Board of Internal Medicine (ABIM) monitors the number of fellows enrolled in the nine approved specialty programs in internal medicine. There has been a steady erosion in all of the specialties, and for hematology/medical oncology the number of fellows is currently 16% lower than in 1995–96.2 In contrast, there has been a significant gain in geriatric medicine (78% in the same time frame). This may reflect, in part, the reduction in training to 1 year to qualify for the CAQ, but also a reflection of

Perspectives on training in geriatrics and oncology

687

increased interest in geriatrics among recent graduates. The is a need to reach medical residents early in their generic training to influence their decisions about specialization, and this may be particularly true regarding geriatrics and oncology. An increase in the number of faculty dedicated to the interface between geriatrics and medical oncology could serve to create the critical mass necessary to increase the exposure of medical residents to the opportunities in a combined or integrated program. Such specialized centers could become the focus for training as well as for basic and clinical research. These centers would be particularly appealing for fellows, early in their carrier, to launch projects with appropriate mentoring. Board certification in medical oncology and the achievement of the CAQ in geriatrics are two credentials of importance to the academician who is responsible for training and research in age-related cancers. These certificates serve as a benchmark of essential training and a measure of specialized competence and expertise. Topics covered in the medical oncology certification examination include psychological and social issues, ethics and end-of-life discussions, and supportive and palliative care, as well as areas of prevention, diagnosis, and treatment. All of these areas include critical insight into and understanding of the aging individual with cancer. An understanding of the most important geriatric syndromes such as dementia, delirium, depression, osteoporosis, and falls can best be achieved through an integrated program. The products of such programs will be well positioned to obtain grants for necessary research and to function as teachers for the community of care providers who will be confronted with the enormous challenge of management issues over the next several decades. With the support of a large 5-year grant from the John A Hartford Foundation, ASCO has initiated a geriatric oncology training grant at 10 medical institutions in the USA. In addition, ASCO has developed a geriatric oncology curriculum and has published a syllabus entitled ‘Cancer Care in the Older Population’. ASCO has increased the number of Young Investigator and Career Development Awards in this area of interest. It is anticipated that cancer center directors will become challenged to develop new initiatives in aging-related cancer research as new opportunities become available from the NCI and the NIA. Successful programs that have integrated medical oncology and geriatrics have already emerged. What is necessary now is to continue the momentum will collaboration and support from foundations, industry and other granting agencies. References 1. Bennett JM, Sahasrabudhe DM, Hall WJ. Medical oncology and geriatric medicine; Is it time for fellowship integration? Cancer 1997; 80; 1351–3. 2. American Board of Internal Medicine News Update; Spring/Summer issue, 2000.

32 Management of cancer in the older aged patient Lodovico Balducci, Charles E Cox, Harvey Greenberg, Gary H Lyman, Rafael Miguel, Richard Karl, Peter J Fabri Introduction The management of cancer in the older aged person is an increasingly common aspect of oncologic practice.1 The central questions concern effectiveness and safety of antineoplastic therapy, clinical criteria to identify patients who may benefit from treatment, and individualized management plans. To address these questions, in this chapter we review the influence of age on various forms of cancer treatment, explore the basis of treatment-related decisions in older persons with cancer, and propose areas for future investigation. Age itself is not a contraindication to cancer treatment. Individualized treatment plans, based on appropriate diagnosis, staging, and Comprehensive Geriatric Assessment (CGA), are most beneficial to older patients. Cancer treatment and aging Surgery The mortality and perioperative morbidity of elective surgical oncologic procedures are little affected by patient age.2 Our review of the records of 70 patients who under-went major surgical procedures at the Moffitt Cancer Center shows that the mortality, length of stay, length of procedure, estimated blood loss, and major complication rate for all patients undergoing Whipple operations, major liver resections, and esophagogastrectomy were similar for patients aged 70 and over and for younger patients, with the exception of the complication rate of liver resection, which was higher among older persons (55% versus 14%). While age itself is not a risk factor, other factors of comorbidity, such as cardiopulmonary dysfunction and malnutrition, may increase with the age of the patient and may inhibit appropriate surgical treatment of cancer.3 For a cancer patient undergoing emergency surgery, the risk of death and surgical complications increases dramatically with the patient’s age.2 The major cause of mortality is sepsis. The increased risk of surgical complications is not surprising in the emergency situation, since age is associated with a progressive decline in the functional reserve of major organ systems, and the ability of older persons to cope with physical stress is consequently more limited. One may postulate that the success of cancer surgery in the older person is determined largely by the previous commitment of that person to health maintenance. In addition to regular physician visits, this commitment includes regular exercise, abstinence from

Management of cancer in the older aged patient

689

smoking and drugs, adequate nutrition, avoidance of unnecessary medication, and cancer screening.4 Early diagnosis of cancer can avoid the complications of emergency surgery. Recent innovations in anesthesia and in surgery may be particularly beneficial to older patients. Cox et al5 confirmed that breast cancer surgery can be accomplished successfully on an outpatient basis under local anesthesia. Modified radical mastectomies or lumpectomies with complete axillary dissection to level III lymph nodes were performed in 20 patients, using local anesthetic, with monitored anesthetic techniques. The mean age of the group was 76±14, and 15 patients were aged 65–95. Six patients had significant comorbid conditions, which either contraindicated general anesthesia or would have altered the outcome if surgery could not be done with local anesthetics. These conditions included three cases of congestive heart failure, severe pulmonary disease, recent myocardial infarction, and Alzheimer’s disease. The remaining 14 patients elected local anesthesia as a personal preference. The only complication of surgery was a hematoma in one wound, requiring reoperation under local anesthesia. Epidural anesthesia during abdominal surgery lessens the surgical stress and reduces considerably the intensity and risks of general anesthesia.6,7 Yaeger et al8 compared general anesthesia with and without epidural anesthesia in abdominal surgery. The rate of lethal and non-lethal complications declined with epidural anesthesia. Important surgical advances include modification of current surgical techniques, endoscopic surgery, and stereotactic surgery. There has been a consistent trend toward limiting the extent of surgical resections. Examples of this trend include partial mastectomy for breast cancer, low anterior resection for rectal cancer, and the adoption of small (1 cm) skin margins for malignant melanoma.9,10 Endoscopic surgery can allow palliation of some tumors of the digestive tract and of the urinary bladder with minimal morbidity. In the case of small lesions, endoscopic surgery may even be curative.11 Stereotactic techniques have made possible the biopsy and resection of small tumors in previously inaccessible regions of the brain.12 Stereotactic breast biopsy of mammographic lesions can be performed as an outpatient procedure in all ages, and this approach has reduced the need for operative management for diagnosis. Progress in endoscopic and stereotactic surgery is in part due to safer and more effective laser beams.11 Radiation therapy One of the traditional roles of radiation therapy has been the management of resectable cancer in patients who have a high risk of morbidity or mortality from surgery. In some conditions, such as early prostate cancer, the outcomes of surgery and radiation therapy for local control are comparable.13 Radiation therapy may have an increased role to play in the management of older persons, whose comorbidity represents an elevated surgical risk. Several studies attest to the safety of radiation therapy for cancer in the aged. Wyckoff et al14 compared the total dose of radiation, the number of treatment interruptions, and the incidence of soft tissue complications among women aged 65 and younger and among older women receiving irradiation of the breast after partial mastectomy. Radiation therapy was equally well tolerated by women of all ages. Casey et al15 studied the tolerance of radiation therapy by 44 patients aged 80 and older receiving treatment for cancer of the upper aerodigestive tract, the chest, and the pelvis. Of these

Comprehensive Geriatric Oncology

690

patients, only 5 failed to complete treatment. All other patients received the planned dose of radiation, without delay and with minimal morbidity. Radiation therapy to the pelvis was tolerated less well by older patients, with the most common complications being mucositis and diarrhea. Aging in experimental animals is associated with increased proliferation of the epithelial cells of the digestive mucosa and by depletion of the mucosal stem cells.16 These changes may make the mucosa of older individuals particularly vulnerable to cellcycle-active treatment, such as radiation therapy and chemotherapy. The risk of mucositis may be minimized by reducing the fractional dose of radiation, while timely hospitalization and aggressive fluid resuscitation are effective in reversing the complications of mucositis. Of special interest to older individuals, Casey et al17 demonstrated that the malnutrition complicating irradiation of the upper airways and the chest may be prevented or reversed by nutrition counsel

Table 32.1 Pharmacokinetic parameters that may be altered in the older person • Absorption • Volume of distribution – Decreased total body water – Increased total body fat – Reduced concentration of circulating albumin • Hepatic uptake – Reduced hepatic blood flow – Reduced hepatocyte function • Hepatic metabolism – Type I reactions (cytochrome P450-mediated activating reactions) – Type II reactlons (glucuronidation, deactivating reactions) • Excretion – Renal – Hepatic

ing and aggressive nutrition. Important advances in radiation therapy that may avoid surgery in the aged include brachytherapy of prostate cancer and radiosurgery of intracranial malignancies.12,13 Cytotoxic chemotherapy Aging may be associated with changes in the pharmacokinetics and pharmacodynamics of cytotoxic agents and with increased susceptibility to the organ-related toxicity of these compounds. Most pharmacokinetic parameters may undergo age-related derangements

Management of cancer in the older aged patient

691

(Table 32.1), but the most consistent and predictable physiologic change is a progressive decline of the glomerular filtration rate with increasing age.18 The excretion of methotrexate, carboplatin, the oxazaphosphorine alkylators (cyclophophosphamide and ifosfamide), and fludarabine is consequently reduced (see Chapter 39 of this volume19). Dosing of these agents should be adjusted to the measured creatinine clearance in persons aged 65 and older to avoid excessive toxicity.20 Inadequate renal excretion of uridine arabinoside, an intermediate metabolite of cytarabine (cytosine arabinoside), may be responsible for the age-related cerebellar toxicity from high-dose cytarabine.19 This form of treatment should be closely monitored and possibly avoided for creatinine clearance less than 50 ml/min. At least three age-related physiologic changes may alter the hepatic metabolism of drugs: diminished hepatic blood flow and consequently lessened hepatic drug uptake, reduced activity of cytochrome P450-dependent microsomal enzymes,19 and reduced volume of distribution of water-soluble agents.20 The cytochrome P450 system is also a major center of drug interactions. Drug interactions are more likely in the aged, due to the high incidence of polypharmacy. The clinical relevance of age-

Table 32.2 Pharmacodynamic parameters that may be altered in tumors occurring in older persons • Decreased drug uptake –

P-glycoprotein-mediated multidrug resistance (MDR)

–

Abnormal transport mechanisms

• Abnormal drug metabolism –

Reduced activation

–

Enhanced catabolism

• Decreased sensitivity to the mechanism of action of the drug –

Increased incidence of tumor cell anoxia

–

Increased concentration of glutathione reductase

–

Abnormal target enzymes

related changes in hepatic metabolism to cancer chemotherapy has never been convincingly demonstrated. The volume of distribution of water-soluble drugs is influenced by body composition, albumin concentration, and hemoglobin. A number of studies have shown that anemia is associated with an enhanced risk of myelotoxicity, because the concentration of free drug in the circulation may be increased, owing to a simultaneous reduction in the proportion of drug bound to red blood cells21,22 (see Chapter 37 of this volume23). Pharmacodynamic changes, which are at present mostly theoretical, may lead to therapeutic refractoriness (Table 32.2). This possibility is supported by experimental findings as well as clinical observations.18,24–26 For some neoplasms, for example acute myeloid leukemia (AML), intermediate-grade non-Hodgkin lymphoma (NHL), and epithelial cancer of the ovary, the response rate to chemotherapy becomes lower and the

Comprehensive Geriatric Oncology

692

duration of chemotherapy-induced cancer remission becomes shorter in the older person. This poorer outcome may be due to clones of chemotherapy-resistant neoplastic cells. The most likely mechanisms of drug resistance include P-glycoprotein-mediated multidrug resistance (MDR), cellular anoxia, and abnormal target enzymes of chemotherapy.27 P-glycoprotein, a transmembrane protein encoded by the MDR1 gene, is a slow Ca2+ channel-dependent pump that extrudes naturally occurring cytotoxic agents from the cell, and may be responsible for tumor refractoriness to anthracyclines, anthraquinones, alkaloids, and epipodophyllotoxins.28 P-glycoprotein is detectable in the myeloblasts of the majority of patients with myelodysplastic syndrome, an entity that becomes more common with age.18 The incidence of tumor anoxia, which may reduce the sensitivity of neoplastic cells to alkylating agents, increases with the age of the tumor host in experimental systems. Structural abnormalities of target enzymes, such as dihydrofolate reductase, may prevent drug-effected metabolic inhibition. These aberrations may Table 32.3 Complications of chemotherapy whose risk increases with the age of the tumor host • Myelosuppression • Mucositis • Peripheral neuritis • Central neurotoxicity • Cardiotoxicity

become more common with aging because the incidence of cellular protein abnormalities from anomalous synthesis increases. Several complications of chemotherapy are more common and more severe in the aged (Table 32.3).18,19 Age-associated restrictions in functional reserve are probably responsible for these higher complication rates. Chemotherapy-induced myelotoxicity is more severe and more prolonged in older persons with hematologic malignancies, such as acute leukemia or lymphoma. In these conditions, the neoplasm, rather than age, may cause a depletion of hematopoietic stem cells. As in the case of radiation therapy, the incidence and severity of chemotherapyinduced mucositis increases with patient age. This complication may be fatal to older persons unless it is promptly recognized and treated in a timely fashion. The incidence of peripheral neuropathy is more common in older patients receiving vincristine for lymphoma. In addition to an increased risk of cytarabineinduced cerebellar toxicity, age may be a risk factor for cognitive and other neurologic abnormalities following intrathecal medications or combined treatment with systemic chemotherapy and central nervous system irradiation. The incidence of congestive heart failure following treatment with anthracyclines or anthraquinones increases progressively after the age of 70. These agents cause the formation of free radicals in the myocardium and lead to a loss of myocardial fibrils. Unexpectedly, the risk of nephrotoxicity from cisplatin does not increase with patient age. The severity of chemotherapy-induced nausea and vomiting

Management of cancer in the older aged patient

693

may become less intense with age, but delayed nausea (48–72 hours after chemotherapy) may become more common. Despite the increased likelihood of therapeutic refractoriness and treatment complications, chemotherapy may be very beneficial to older patients. Prolonged remissions (lasting 1 year or longer) occur in 30%-40% of patients over 60 with AML, and in 40–50% of those with Hodgkin lymphoma, NHL, multiple myeloma, stage III ovarian cancer, and small cell lung cancer.29 Chemotherapy can also afford effective palliation to persons with metastatic cancer of the breast, colorectum, prostate and bladder. Adjuvant chemotherapy reduced by 30% the risk of cancer death in patients aged 65 and over with stage III colorectal cancer.30 In combination with radiation therapy, chemotherapy can obviate surgical resection of the larynx, the urinary bladder, the anus, and the esophagus in patients with locally advanced tumors involving these organs.30 Functional and anatomic organ preservation is particularly important to older persons, for whom organ rehabilitation and colostomy management may be problematic. Problems related to the use of chemotherapy should not dissuade the practitioner from treating older patients. Rather, awareness of these problems should allow a more rational and effective use of chemotherapy in the elderly. The treatment of persons over 65 with chemotherapy for lymphoma and breast cancer at the H Lee Moffitt Cancer Center in Tampa, Florida has been reviewed. In our experience, chemotherapy has been highly beneficial to older persons with these malignancies and has not caused excessive therapeutic complications. Of special interest to older individuals has been the development of oral forms of chemotherapy, which is particularly interesting for older individuals both from the standpoint of convenience and from that of toxicity: daily oral administrations allow titration of the doses to individual needs.31 In addition to capecitabine, oral etoposide, and temolozamide, already on the market, oral forms of platinum and taxane derivatives, topotecan, and vinorelbine are being developed. A major advance in the field of cytotoxic chemotherapy has been the development of hematopoietic growth factors for clinical use.32 In addition to granulocyte colonystimulating factor (G-CSF) and granulocytemacrophage colony-stimulating factor (GMCSF), which are currently available, several other compounds are undergoing clinical trials. Of these, interleukin-3 (IL-3) and stem cell factor (SCF) have almost completed the clinical evaluation phase and should be released soon for general use. G-CSF and GMCSF shorten the duration of chemotherapy-induced myelosuppression and reduce the risk of neutropenic infections. IL-3 and SCF may also shorten the duration of thrombocytopenia and reduce the risk of hemorrhage. Hematopoietic growth factors are as effective in older persons as in younger persons.33 Hormonal therapy Three common neoplasms that occur more frequently in older persons—cancers of the prostate, the breast, and the endometrium—may be responsive to hormonal manipulations. Endocrine agents of current use include estrogen antagonists, progesterone derivatives, luteinizing hormone-releasing hormone (LHRH) analogs, and aromatase inhibitors.19 Although the incidence of deep vein thrombosis from tamoxifen may increase after the age of 70, the tolerance of these compounds by patients of all ages

Comprehensive Geriatric Oncology

694

is excellent overall. The incidence of tamoxifeninduced hypercalcemia in patients with bone metastasis from breast cancer is not affected by age. Whenever possible, hormonal manipulations are preferred to cytotoxic chemotherapy in the aged. Biologic therapy Of the agents currently available in clinical practice -recombinant interferon-α (rIFN-α) and IL-2—only rIFN-a has been tested extensively in the older person. At low doses (3– 5×106 units daily or thrice weekly), rIFN-α is well tolerated regardless of the patient’s age. At higher doses, unpredictable complications, such as cerebritis, have occasionally been reported.19 Targeted therapy In the last few years, a number of agents have been developed that target a specific tumor protein or neoplastic metabolic process. A number of these agents are already available commercially, and many more are under study. The mechanism of targeting include prodrug cytotoxic agents activated prevalently in the neoplastic tissues (e.g. capecitabine), monoclonal antibodies directed against specific tumor antigens (e.g. rituximab) or growth factor receptors (e.g. trastuzumab and cetuximab), toxins or radioisotopes bound to a carrier that targets specific tumor proteins (surface antigens and growth factor receptors), and thymidine phosphokinase inhibitors. The antitumor specificity may maximize the therapeutic index of these agents, but some unpredictable adverse effects have emerged that may be of special concern for older individuals. These include cardiac toxicity for trastuzumab,34 fluid retention and renal insufficiency for denileukin diftitox,35 and prolonged myelosuppression and deep vein thrombosis with gemtuzumab ozogamicin.36 Despite these caveats, there is no question that targeted therapy is the most promising form of therapy for all cancer patients—not only the elderly. Special issues related to the management of older persons with cancer The decisions involved in the management of older persons with cancer are based on assumptions underlying any type of therapeutic intervention (Figure 32.1). Briefly, treatment is indicated when (i) it may improve the disease outcome and (ii) the likelihood of treatment-related benefits exceeds that of treatment-related risks. In the case of older persons, the assessment of benefits and risks may be problematic, and may need to be individualized. The main components of this problem are definition of treat-

Management of cancer in the older aged patient

695

Figure 32.1 Basic assumptions of the therapy of diseases: the outcome is positively weighted by treatment. ment goals and assessment of the older person for life-expectancy, quality of life, and risk of treatment-related toxicity.37 Goals of treatment Cure is the preferable outcome of most diseases. In older persons, however, the benefits of cure may be tempered by competitive causes of death and by the risk of therapeutic complications. This possibility is epitomized well by prostate cancer. When diagnosed in men aged 70 and older, well-differentiated, localized (stages I and II) prostate cancer does not reduce the life-expectancy of these individuals.38 Thus, the risks associated with treatment—either radical prostatectomy or external-beam irradiation—may not be warranted in this population. More complex but equally instructive is the example of breast cancer. Women aged 70 and older with early (stage I and II) breast cancer have comparable survival when treated surgically or medically.39 Surgical treatment is generally preferred in terms of quality of life because of superior cosmetic results and a lower risk of local progression. These examples suggest that survival gain may not always represent a realistic goal of cancer treatment in all circumstances, and quality of life considerations may direct the management of some older persons. These suggestions should not be generalized to all cancers or to all patients. Cancer is a common cause of death for older individuals, and aggressive management of cancer may be lifesaving even in advanced ages. For example, large cell NHL may be curable with chemotherapy.25 The median survival of untreated

Comprehensive Geriatric Oncology

696

patients with large cell NHL is 18 months, which is shorter than the life-expectancy of a 90-year-old person. In individual clinical situations, the choice of the best course of action requires knowledge of the natural history of the disease, of the anticipated outcome of treatment, and of the life-expectancy and the quality of life of each individual. A rewarding experience for us has been the aggressive management with chemotherapy of an almostmoribund 82-year-old woman with bulky lymphoma of the stomach. She celebrated her 86th birthday, surrounded by an extended family and free of life-threatening or qualityof-life-compromising diseases. Assessment of the older person Aging is multidimensional, and involves the functional, cognitive, emotional, and socioeconomic domains.40 Alterations in any of these domains may influence the manifestations and the outcome of diseases, as well as the effects of treatment. The Comprehensive Geriatric Assessment (CGA)40 is most useful in evaluating the special needs and the rehabilitative potential of older persons with chronic diseases and disabilities. In oncology, the CGA may reveal unsuspected conditions that can interfere with cancer treatment, may indicate unexpected social and rehabilitative needs, and may provide information on life-expectancy, quality of life, and treatment tolerance.40 All patients referred to the geriatric service of the Moffitt Cancer Center are screened with a CGA. A person’s life expectancy is determined by age, comorbidity, and functional status.29 The importance of functional status as an independent variable has emerged only fairly recently. In a cohort of persons aged 70 and older, Siu found that the 2-year mortality rate varied from 8% for totally independent to 40% for institutionalized or homebound individuals (A Siu, personal communication, April 1993). Health-related quality of life may be assessed by well-validated instruments measuring one’s satisfaction in the physical functional, emotional, social, and spiritual domains.41 These instruments measuring one’s satisfaction in the physical, functional, emotional, social, and spiritual domains are questionnaires in which each answer is scored according to a categorical or visual analog scale.42 There is concern that these questionnaires may not be appropriate for older individuals for several reasons, including content, length, and complexity.41 Given the diversity of the older population, individualized instruments may be desirable. Another difficulty is the assessment of quality of life in the cognitively impaired. For this purpose, every effort should be made to obtain some type of direct and consistent information from the patient. Several studies have demonstrated that the assessment of quality of life by proxy is inadequate. Psychosocial medicine and the geriatric program at the Moffitt Cancer Center are developing a number of projects to study the accuracy of existing instruments and to explore the generation of customized instruments for the assessment of quality of life in the older person. A person’s functional status is an important predictor of treatment tolerance and outcome. In general, functional status is measured according to the Karnofsky or Zubrod scales. The instruments are not calibrated to persons with chronic diseases and disability, whose incidence increases with age. For many older persons, assessment of the activities of daily living (ADL) and instrumental activities of daily living (IADL) are more

Management of cancer in the older aged patient

697

informative than the Karnofsky or Zubrod Performance Status.3 As the functional status of the older person may decline very rapidly owing to serious diseases, information on premorbid functional status is paramount. We might have denied lifesaving chemotherapy to our 82-year-old patient with lymphoma of the stomach because she was bedridden if we had not known that less than a month earlier she had been fully functional. Formal decision analysis may be extremely helpful in supporting difficult and controversial decisions related to the management of cancer in older persons. Lyman has provided a framework of reference for the application of the principles of decision analysis to individual clinical situations involving the aged and has described a reliable instrument to predict individual outcome of treatment in terms of survival and cost (see Chapter 2 of this volume42). Several other areas of geriatric oncology deserve further study. These include the natural history of cancer in the older person, the influence of chronic diseases on tumor growth and treatment tolerance, the risk of drug interactions from polypharmacy, the management and the significance of malnutrition, and the impact of depression, cognitive function, income, and social support on medical access and outcome. We believe that the proper context in which to explore these issues is a longitudinal study of a large cohort of older individuals undergoing uniform evaluation and regular follow-up and receiving treatment according to flexible protocols capable of accommodating the diversity of this population. Whenever possible, these individuals should be evaluated and treated in the community in which they live, under the attention of personal physicians, to minimize discomfort and expenses related to travel. The management of such a cooperative study is a major purpose of our geriatric oncology program at the Moffitt Cancer Center. Cultural competence A critical component of the preparation of the elderly patient for cancer treatment is the communication between the provider and the patient. Within the more general topic of physician-patient vommunication, there is a special category referred to as ‘cultural competence’. This term, although non-specific, addresses the need for physicians and other healthcare providers to recognize the existence of special barriers to communication that are related to an individual’s particular background (culture) and to make every effort to understand and/or accommodate to these barriers (competence). As described in the Cultural Competence Compendium of the American Medical Association, ‘The current groundswell of exploration into cultural awareness is a logical extension of longstanding concerns about the role of communication in the doctor-patient relationship. There is a well-known disconnect between the demonstrated high intellect required to become a physician and the ability of many physicians to communicate effectively with patients.’ Whether or not we agree with this statement, communication with patients, particularly elderly patients, is a vital part of preparing the patient for a major operation. The term cultural competence has been applied to many groups: children, AfricanAmericans, Hispanics, gay men and lesbians, and others, but cultural competence is in fact more complicated than just the existence of defined groups with different backgrounds, language, or sensitivities. Perhaps as much as any factor, aging, with all its varied components, creates unending opportunities for miscommunication and mistrust.

Comprehensive Geriatric Oncology

698

Yet little has been written about the geriatric group, perhaps because it is so diverse and represents a variety of potential communication problems. Nevertheless, cultural competence is emerging as an important issue in the care of the aged, and must be considered, on an individual basis, in each patient encounter with an elderly patient. Several areas stand out as potential problems: age difference between patient and physician, generation gap, national origin/language, comorbid conditions that affect communication, and adverse effects of medications. Age difference Particularly in teaching facilities and tertiary care facilities, the majority of practicing surgeons are younger than the majority of patients. This problem is frequently recognized by medical students, but it doesn’t disappear just because a physician’s experience has broadened. Elderly patients may not identify well with young surgeons, may not provide the ‘expected’ deference, or may feel uncomfortable with current variations in the dress code, such as sports clothes and running shoes. This difference may be exaggerated as the elderly patient becomes more rigid in response to memory changes and other limitations. Generation gap While seemingly similar to age difference, ‘generation gap’ refers to the marked difference in values and experience of individuals born ‘long ago’ and many physicians. The elderly were all born before the Second World War, most before the Depression, many before the First World War, and they have internal values derived from those experiences. The elderly antedated most modern electric appliances and electronics. Some antedate the airplane. While they probably enjoy modern comforts, these are perhaps not as central to their sense of self. Since they grew up in a world that was different, the things that they value and cherish are different. They may have different interpretations of quantity and quality of life, of the desire to continue to live alone, and of dependency. These differences may be magnified as elderly patients lose spouses, friends, and familiar surroundings and seem to retreat into their past. Often isolated, elderly patients may be unwilling to share personal thoughts, may be more concerned about personal privacy, and may be reluctant to put their trust in someone whom they perceive as being ‘different’. National origin/language Although there has been a resurgence in the number of immigrants to the USA in recent years, the great waves of immigration occurred in the early decades of the 20th century. Many elderly were raised in ethnic households and perhaps spoke another language as a child. Even if they have lived in the USA all of their lives, they very often continue to feel attached to their ethnicity and increasingly relate to ‘the old neighborhood’. Loss of these attachments in a hospital environment increase the sterility of the environment and isolate the patient from his or her surroundings.

Management of cancer in the older aged patient

699

Comorbid conditions Loss of vision, hearing disorders, early dementia, and other sensory deficits can directly impair an individual’s ability to understand an explanation of a complex surgical procedure and its complications. Less obvious limitations might include chronic sleep deficit, pain, or depression. Adverse effects of medications Most elderly depend on a substantial number of medications. Many have impairment of renal function or pathways of eliminating drug metabolites. Consequently, the sideeffects of medications may be additive, enhanced, or both. Although cognitive function may appear intact, reasoning, evaluating, and decision making may be impaired. Other side-effects—gastrointestinal, cutaneous, or cardiopulmonary—may become limiting and interfere with attention span or focus. Elderly patients have many reasons to explain errors in their understanding of the expected result and the risks of a complicated surgical procedure. Awareness, understanding, and ‘cultural competency’ are essential attributes of the physician who prepares the elderly patient for an operation. Conclusions Antitumor treatment is beneficial to the majority of older patients with cancer, and age should not be considered a contraindication to treatment. The management of some older individuals is best planned around a Comprehensive Geriatric Assessment, including life-expectancy, functional status, and the likelihood of therapeutic complications. Quality of life represents a major endpoint of cancer treatment in older individuals: the assessment of the quality of life in the aged with cancer is a highpriority research program. The most appropriate solution to persistent questions of cancer and aging would be a community-based clinical trial that could include the creativity of individual practitioners and accommodate the diversity of the geriatric population. References 1. Ershler WB, Balducci L. Cancer and aging. N Engl J Med (to be published). 2. Donegan WL. Operative treatment of cancer in the older person by general surgeons. In: Comprehensive Geriatric Oncology (Balducci L, Lyman GH, Ershler WB, eds). Philadelphia: JB Lippincott, 1992: 151–9. 3. Balducci L, Beghe’ C, Chausmer A et al. Prognostic evaluation in geriatric oncology. Arch Gerontol Geriatr 1991; 13:31–41. 4. Woolf SH, Kamerow DB, Lawrence RS et al. The periodic health examination of older adults: the recommendations of the U.S. Preventive Services Task Force—Pt II. J Am Geriatr Soc 1990; 38: 933–42.

Comprehensive Geriatric Oncology

700

5. Cox CE, Miguel R, Bosek V. Outpatient lumpectomy, axillary node dissection and modified radical mastectomy under local anesthesia. In: Proceedings of 15th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, 1992:180. 6. Tuman KJ, McCarthy RJ, March RJ et al. Effects on epidural anesthesia and analgesia on coagulation and outcome after major vascular surgery. Anesth Analg 1991; 73:696–704. 7. Breslow MJ, Jordan DA, Christopherson R et al. Epidural morphine decreases postoperative hypertension by attenuating sympathetic nervous system hyperactivity. JAMA 1989; 261:3577– 81. 8. Yaeger MP, Glass DD, Neff RK et al. Epidural anesthesia and analgesia in high risk surgical patients. Anesthesiology 1987; 66:729–36. 9. Patterson WB. Surgical options in the treatment of cancer: How are they affected by the patient’s age? In: Comprehensive Geriatric Oncology (Balducci L, Lyman GH, Ershler WB, eds). Philadelphia: JB Lippincott, 1992:145–50. 10. Veronesi U, Luini A, Del Vecchio M et al. Radiotherapy after breast-preserving surgery in women with localized cancer of the breast. N Engl J Med 1993; 328:1587–91. 11. Pinkas H. Gastrointestinal cancer ablation via endoscopy. In: Comprehensive Geriatric Oncology (Balducci L, Lyman GH, Ershler WB, eds). Philadelphia: JB Lippincott, 1992:199– 207. 12. Zachariah S, Zachariah B, Wang T et al. Primaiy brain tumors in the older patient: an annotated review. J Am Geriatr Soc 1992; 40: 1265–71. 13. Balducci L, Trotti A, Pow-Sang J. Advances and controversies in the prevention and treatment of prostate cancer. Annee Gerontol 1992; 2:97–110. 14. Wyckoff J, Greenberg H, Sanderson R et al. Breast irradiation in the older woman: a toxicity study. J Am Geriatr Soc 1994; 42:150–2. 15. Casey L, Zachariah B, Balducci L. A profile of cancer patients aged 80 and older treated with radiation therapy: analysis of tolerance and effectiveness. J Am Geriatr Soc 1992; 40:SA–43. 16. Balducci L, Phillips DM, Davis KM et al. Systemic treatment of cancer in the elderly. Arch Gerontol Geriatr 1988; 7:119–50. 17. Casey L, Balducci L, Jensen C et al. Preventing weight loss in the older man during radiation therapy for cancer. J Am Geriatr Soc 1992; 40:SA–43. 18. Balducci L, Mowrey K. Pharmacology and organ toxicity of chemotherapy in older patients. Oncology 1992; 6:62–8. 19. Cova D, Balducci L. Cancer chemotherapy in the older patient. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004: 463–88. 20. Gelman RS, Taylor SG IV. Cyclophosphamide, methotrexate and 5-fluorouracil chemotherapy in women more than 65 years old with advanced breast cancer: the elimination of age trends in toxicity by using doses based on creatinine clearance. J Clin Oncol 1984:2: 1404–13. 21. Schijvers D, Highley M, DuBruyn E et al. Role of red blood cell in pharmakinetics of chemotherapeutic agents. Anticancer Drugs 1999; 10:147–53. 22. Balducci L, Hardy CH, Lyman GH. Hematopoietic growth factors in the older cancer patient. Curr Opin Hematol 2001; 8:170–87 23. Balducci L, Hardy CL. Anemia and aging: relaevance to the management of cancer. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:442–52. 24. Ballester OF, Moscinski LC, Morris D et al. Acute myelogenous leukemia in the elderly. J Am Geriatr Soc 1992; 40:277–84 25. 22. Ballester OF, Moscinski LC, Spiers ASD et al. Non-Hodgkin’s lymphoma in the older person. J Am Geriatr Soc 1993; 41:1245–54. 26. Thigpen T, Brady MF, Omura GA et al. Age as a prognostic factor in ovarian carcinoma: the Gynecologic Oncology Group Experience. Cancer 1993; 71:606–14.

Management of cancer in the older aged patient

701

27. Dietel M. Meeting report: Second International Symposium on Cytostatic Drug Resistance. Cancer Res 1993; 53:2683–8. 28. Holzmayer TA, Hilsenbeck S, Von Hoff DD et al. Clinical correlates of MDRI (P-glycoprotein) gene expression in ovarian and small cell lung carcinomas. J Natl Cancer Inst 1992; 84:1486– 91. 29. Beghe’ C, Balducci L. Geriatric oncology: perspectives from decision analysis. Arch Gerontol Geriatr 1990; 10:141–62. 30. Balducci L, Lyman GH. Adjuvant treatment of cancer in older persons. In: Comprehensive Geriatric Oncology (Balducci L, Lyman GH, Ershler WB, eds). Philadelphia: JB Lippincott, 1992:284–302. 31. Carreca I, Balducci L. Oral chemotherapy for the older cancer patient. Am J Cancer 2002; 1:101–8 32. Shank W. Clinical use of hematopoietic growth factors in patients with cancer. In: Comprehensive Geriatric Oncology (Balducci L, Lyman GH, Ershler WB, eds). Philadelphia: JB Lippincott, 1992:208–20. 33. Shank W Jr, Balducci L. Recombinant hemopoietic growth factors: comparative hemopoietic response in younger and older subjects. J Am Geriatr Soc 1992; 40:151–4. 34. Seidman A, Hudis C, Pierri MK et al. Cardiac dysfunction in the trastuzumab clinical trials. J Clin Oncol 2002; 20:1215–21 35. Talpur R, Apisamthanarax N, Ward S et al. Treatment of refractory peripheral T cell lymphoma with denileukin diftitox. Leuk Lymph 2002; 43:121–6. 36. Stadtmauer EA. Gemtuzumab ozogamicin in the treatment of acute myeloid leukemia. Curr Oncol Rep 2002; 4:375–80. 37. Applegate WB, Curb JD. Designing and executing randomized clinical trials involving elderly persons. J Am Geriatr Soc 1990; 38:943–50. 38. Chodak GW, Thiste RA, Gerber GS et al. Results of conservative management of clinically localized prostate cancer. N Engl J Med 1994; 330:224–8. 39. Bates T, Riley DL, Houghton J et al. Breast cancer in elderly women: a Cancer Research Campaign trial comparing treatment with tamoxifen and optimal surgery with tamoxifen alone. The Elderly Breast Cancer Working Party. Br J Surg 1991; 78:591–4. 40. Beghe’ C, Robinson B. Comprehensive Geriatric Assessment: diagnostic, therapeutic, and prognostic value. Cancer Control J Moffitt Cancer Center 1994; 1:121–5. 41. Balducci L. Perspectives on quality of life of older patients with cancer. Drugs Aging 1994; 4:313–24. 42. Lyman GH. Essentials of clinical decision analysis: a new way to think about cancer and aging. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:11–25.

33 Surgical approaches to the older patient with cancer Peter J Fabri Introduction A surgical procedure in an elderly oncology patient must be planned with consideration of the differences in physiology of the patient, the response to anesthesia and stress, and particular aspects of nutrition in surgical illness. Just as surgical procedures in neonates cannot be considered treatment of ‘small adults’, nor can the surgical management of the elderly simply be considered treatment of ‘older adults’. This chapter provides an overview of the physiologic, pharmacologic, ethical, and functional issues that play an important role in the surgical treatment of the elderly. It is necessarily succinct, and the interested reader is referred to the comprehensive references, which address specific issues in much greater detail. As far back as 1907, the literature suggests that the risks of surgical procedures in the elderly were high enough to warrant calling age a contraindication.1 By the late 1930s, it became apparent that surgical procedures in the elderly were a necessary aspect of the modern therapeutic age,2 and throughout subsequent years continued advances in our understanding of the physiology of aging3,4 have evolved. As people have lived to greater ages, the surgical horizon has expanded, as described in a report on the management of patients over the age of 100.5 As surgeons began to treat a larger number of elderly patients, interest emerged in evaluating outcome, and the result of applying objective data to improve surgical treatment was reported.6 Effect of age on cancer A quick review of the published effects of aging on the state and biologic activity of cancer yields a very complex and confusing picture, since different studies conducted at different times and at different institutions yield markedly divergent results.7–10 While it is possible that a real difference in the behavior of cancer as a direct effect of age might exist, the small sizes of most studies preclude any confident determination of differences in stage or survival. It is most likely that there is a marked variation in stage at diagnosis and in biologic behavior regardless of age and that in reviews of small series, no difference will be seen on looking at different tumors. Therefore, in the absence of more convincing data, it seems prudent to take each patient as a unique individual with a unique cancer and to base prognosis on more objective parameters, such as traditional survival for a specific tumor, the effect of associated disease, etc. In lung, breast, and

Surgical approaches to the older patient with cancer

703

colorectal cancers, however, it appears likely that real differences exist and that elderly patients may actually be in a more favorable situation than their juniors.11 Nevertheless, each patient should still be treated individually, since the effects of associated illness and altered physiology are probably of greater planning significance in most patients than the effect of age on tumor biology. Epidemiologists will continue to search for relationships between age and cancer, but it is not likely that these will be of major value in decision making for an individual patient in the near future. Many alterations in organ function have been described as a consequence of age. Significant changes in tidal volume and respiratory response12 and a significant increase in the incidence of respiratory comorbidity13 suggest that the elderly patient is often encumbered by pulmonary alterations that will alter the response to a surgical procedure. Changes in cardiac regulatory function14 and response to cardiac medications15 may have a dramatic effect on the perioperative surgical patient who develops cardiac dysfunction. Patients with acute myocardial infarction, for example, have worse prognosis as a function of age.16 This probably applies as well to postoperative surgical patients who have perioperative myocar- dial infarction, and perhaps even to those who have an underlying cardiac abnormality but without infarction. Alterations in thyroid function17 can impact on the metabolic demands of a superimposed surgical procedure, and the relative hypothyroidism of old age may contribute to the ‘euthyroid sick’ syndrome that occurs in critical illness.17 Alterations in liver function18,19 have effects not only on protein synthesis but also on the detoxification and excretion of a wide variety of pharmacologic agents. Drugs for the management of peptic ulcer disease, for example, have a significantly different metabolism in the elderly.20 At the same time, alterations in gastrointestinal, pancreatic, and hepatobiliary functions with age can have a significant effect on gastrointestinal motility as well as on response to pharmacologic agents used in the management of abnormalities of these organs.21 It is therefore necessary to have a broad and comprehensive understanding of the pharmacotherapeutic differences of the geriatric oncology patient.22 Choice of drugs, dose of drugs, and interactions of drugs must all be considered individually. Anesthesia in particular is a significant stress for all patients, and major changes in the handling of anesthetic agents as well as the response to these agents have been described in the elderly.23 Agents such as midazolam24 that are often used during the conduct of outpatient procedures should be particularly noted because of the marked increase in the frequency of outpatient and minimally invasive procedures during which such agents are likely to be a component of the conscious sedation/anesthetic plan. Accordingly, a detailed understanding of the effects of anesthesia in the elderly patient25 is essential. Neuromuscular blocking agents26,27 and changes in responsiveness to epidural narcotics28 can have substantial effects on intraoperative management and, more importantly, postoperative ventilatory status. Elderly patients typically receive multiple medications for their associated medical illnesses. An understanding of the drug interactions between anesthetic agents and coexisting pharmaceutical agents should be high on the operative and postoperative lists.29 Recognized changes in autonomic responsiveness30 may necessitate a change in the type of anesthetic agent used, as well as in postoperative pain management and sedation. Management of the elderly patient in the postoperative period31 requires an understanding of changes in physiology, particularly of the heart, lungs, and kidney. In addition, however, alterations in drug metabolism in the liver32 and

Comprehensive Geriatric Oncology

704

changes in the handling of fluid and electrolytes by the kidney33 have a substantial effect on the risk of surgical procedures in elderly patients.34 Assessment of the overall risk in the elderly patient35 as well as an awareness of quantitative estimates of the cardiac and pulmonary risks of abdominal and thoracic procedures36 should be used in preoperative preparation. Preparation for the comorbid illnesses37,38 should include recognition of the increased incidence and severity of deep vein thrombosis (DVT) and pulmonary embolus39,40 in the elderly cancer patient. Most risk-classification systems for thromboembolic disease list cancer and age as independent factors for DVT and therefore all elderly surgical patients should be considered to be at high risk of DVT and treated with appropriate prophylactic measures. Sequential calf vein compression devices are probably indicated for all elderly patients undergoing surgical procedures for oncologic disease. In addition, certain factors (previous DVT, high-dose estrogen use, and obesity) increase the risks independently and may justify the use of low-dose subcutaneous heparin 5000 units every 8 hours in addition to calf compression. Nutrition Early enthusiasm for aggressive nutritional support in minimizing perioperative and postoperative risks of malnutrition may have been overly optimistic.41 Nevertheless, malnutrition is an important cofactor in postoperative morbidity, and its preoperative identification in the elderly patient is an important part of patient assessment. The increased incidence of malnutrition in the elderly42–44 is multifactorial and probably cannot be fully addressed in the preoperative period, but can be included in peri- and postoperative planning. The preoperative serum albumin level is an excellent indicator of nutritional status,45 but the increased risk associated with hypoalbuminemia cannot be remedied by the infusion of albumin. Even though elderly patients have a relative decrease in their caloric requirement,46 and while it may be appropriate to allow a week of relative starvation in postoperative patients of younger age, this may not be appropriate in the elderly patient. Early and aggressive attention to nutritional deficiencies in the postoperative period appears to be warranted. Alterations in wound healing are often related to diabetes,47 and are aggravated by malnutrition and other premorbid factors. The best way to avoid such problems is early identification of malnutrition and a plan to provide appropriate and safe postoperative nutritional support. Although the use of total parenteral nutrition (TPN) has been largely supplanted in many centers by aggressive tube feeding, it should be recognized that the actual need is for nutrition and that there is currently no evidence of a superiority of route of administration in most cases. Most patients can be fed enterally using the gastrointestinal tract, thus maintaining the integrity of the gastrointestinal mucosa, but careful attention must be paid to assure its safe and effective use.48 In particular, patients should be assessed for risk of aspiration, which depends largely on neurologic status and degree of sedation/analgesia.

Surgical approaches to the older patient with cancer

705

Ethical issues As a larger number of elderly patients present for surgical treatment of major oncologic problems, the ethical issues associated with such treatment assume even greater significance. The perioperative responsibilities of the surgeon in geriatric oncology are more frequent49 and more difficult but nevertheless rewarding challenges. Recent changes in the US code of law have guaranteed that individuals have the right to participate in their healthcare choices. Advance directives are now offered to all patients at the time of admission to the hospital. Rather than view these advance directives as intrusions, perhaps we should accept them as a welcome way of identifying our patients’ wishes before major surgical procedures. It is far easier to address these preoperatively than it is to try to deal with family members in a complicated postoperative period. The ethical associations in geriatric care50 and some of the moral dilemmas that develop51 pose opportunities to improve communication with patients and family and to enhance preoperative preparation and informed consent. A more difficult situation is the issue of resuscitation in the operating room. Often anesthesiologists are reluctant to administer care to patients with ‘do-not-resuscitate’ (DNR) orders. In the intensive care unit, where resuscitation is frequently an issue, we can usually recognize the difference between ‘no CPR’ and ‘no treatment’. In the operating room, however, where resuscitation is uncommon and perhaps more ‘threatening’, the decision to treat has already been made and the individuals involved feel compelled to proceed with CPR since the success of resuscitation may be greater than in the general hospital environment.48,53 Often the solution to the dilemma is the temporary reversal of the DNR order for the time-limited perioperative period. Nevertheless, there will be a particular subgroup of patients for whom an operation is appropriate but the patient is clearly terminal such that resuscitation would not be warranted under any circumstances. Cases such as this should be handled individually and with open communication among all members of the family and the healthcare team. The hospital’s ethics committee may be helpful. Our understanding of the management of critical surgical illness in the elderly comes largely from studies done in trauma patients and burn patients. Changes in metabolism, cytokine release, etc. in the elderly patient54–62 identify the management issues associated with elderly patients with severe, acute illness. Similarly, studies in burn patients63–65 have shown that there is shortened length of stay and improved outcome when burns are treated aggressively with early surgical excision in the elderly to minimize the hypermetabolic risk and the risk of sepsis. Information from both trauma and burn groups has provided us with an improved understanding of the management of the elderly patient who becomes acutely ill, septic, or hypermetabolic. Release of cytokines (interleukins-1 and -6 and tumor necrosis factor) following acute injury produces fever, hypermetabolism, neutrophilia, and a hyperdynamic state. Aggressive early diagnosis and treatment to minimize this inflammatory response syndrome would appear to be justifiable in the management of complications in the elderly oncologic patient based on the results obtained from the treatment of elderly trauma/burn patients, since patients who develop complications have a high incidence of additional complications and subsequent

Comprehensive Geriatric Oncology

706

death. Age and comorbid illnesses may be independent causes of decreased survival, as has been reported from patients with acute respiratory distress syndrome (ARDS).66 Critical care Complicated, elderly patients consequently consume a significant percentage of healthcare costs when they require prolonged intensive care use.67 Preadmission functional status (i.e. the ability to perform the activities of daily living such as transfer from bed, feeding, and maintenance of bodily functions) seems to predict outcome in the intensive care unit.68 With careful attention to the unique problems of the elderly, particularly postoperative pulmonary function,69 and the recognition of the impact of age on respiratory tract disease,70 it is possible to gain very acceptable results in the elderly oncology patient in the surgical intensive care unit.71 Even in the extreme elderly, procedures that require surgical intensive care should not be avoided only on the basis of age.72,73 It is important to realize, however, that comorbid illness and the adverse effect of postoperative complications lead to a significant failure rate at 1 year.74 Although new technological advances such as percutaneous tracheostomy75 and changes in the management of critically ill patients76 will continue to improve our ability to care for elderly patients in the intensive care unit, technology will not replace sound decision making, careful attention to details, and avoidance of complications. Infections As previously indicated, elderly patients do not tolerate complications well. In elderly patients undergoing treatment for complex oncologic disease, infection and/or sepsis often occur and can significantly influence the outcome of the procedure. Infectious diseases in the elderly require careful consideration and prompt recognition and treatment.77,78 Antibiotic use may require attention to drug interactions, altered organ system function, and poorly tolerated side-effects.79 Simultaneous surgical problems Although the ‘Principle of Parsimony’ states that all of a patient’s symptoms can usually be explained by a single disease, elderly patients not uncommonly present with more than one serious medical problem. A commonly faced dilemma, for example, is the patient who presents with an abdominal aortic aneurysm and who is found to have a colon carcinoma, or vice versa. When both problems present as clean surgeiy, the option of simultaneous surgical procedures may be considered (a typical example is carotid artery disease and coronary artery disease), but in most oncologic situations, this is a less desirable or suitable option. While there is occasionally some disagreement among surgeons about the order or preference for sequential or staged procedures, most surgeons agree that the most immediate life-threatening problem should be addressed first. A symptomatic aneurysm should be repaired before an ‘incidental’ colon cancer, whereas a

Surgical approaches to the older patient with cancer

707

nearly obstructing colon cancer should be resected before an asymptomatic 5 cm aneurysm is addressed. Emergency operations and procedures At all ages, emergency procedures carry higher risks than the same procedures in an elective environment. In some circumstances (e.g. tracheostomy), the difference may be absolute—life or death. In others (e.g. drainage of a wound abscess), the difference is minimal. In most circumstances, however, the addition of an emergency component to an operation is of intermediate significance and results in a substantial increase in risk. Colon operations without bowel preparation, for example, carry a three- or fivefold higher risk of infection. And even surgical procedures whose excess risk would appear to be minimum (e.g. biliary obstruction), can have a three- to fourfold increase in complications and death. Wherever possible, emergency procedures in the elderly should be avoided. Attention to fluid and electrolytes, antibiotics, hemodynamic monitoring and optimization, etc. are each contributory to improved outcome. When an emergency situation does not allow delay (e.g. biliary obstruction with suppurative cholangitis and central nervous system alterations), an initial non-surgical approach (percutaneous cholangiography or endoscopic retrograde cholangiopancreatography (ERCP)) is often preferable to committing the patient and surgeon to a major surgical procedure with unanticipated and avoidable hazards. Occasionally, a procedure that is not usually indicated or used (e.g. cholecystostomy) offers an alternative to a major operation, buys time, and allows patient preparation. This is even more true when it can be done percutaneously. But when an operation cannot be postponed and a less hazardous alternative does not exist, the surgeon and patient must be prepared for the increased risk of an operation. Very careful hemodynamic preparation with Swan-Ganz catheter is often indicated. Induction of anesthesia using cardiac surgical techniques may minimize the acute physiologic stress. Efforts to perform the simplest and most direct procedure that will address the problem at hand are preferable to complex and elaborate procedures that attempt to provide the most comprehensive solution. Common outpatient procedures • Node biopsy • Breast biopsy (needle localization) • Laparoscopy • Colonoscopy • Mastectomy, quadrantectomy • Percutaneous g-tube • Line and port placement

Comprehensive Geriatric Oncology

708

Minimally invasive and ambulatory surgery Healthcare changes of the past decade have led to an increased use of ambulatory surgery programs for larger surgical procedures.80 ‘Minimally invasive’ procedures, such as laparoscopy,81–83 appear to be physiologically less stressful, may require a shorter hospital stay, and may allow an earlier return to normal functional activity. It is important to realize, however, that most of these procedures require a general anesthetic (which may carry a higher risk in the elderly patient). In addition, since most elderly surgical oncology patients have several comorbid illnesses, the comorbidity is often the limiting factor in the length of hospitalization and the speed of recovery, and therefore minimizes the effect of minimally invasive technology and length of stay, time to recovery, etc. The preparation of patients undergoing ambulatory surgery is focused on the recognition and treatment of underlying medical problems. Age alone is not a factor in deciding about the ambulatory approach. Availability of caregivers is important, as is the recognition of the physiologal effect of age on pulmonary function (decreased) and hepatic function (decreased). A wide variety of anesthetics and sedatives are available, and different authors have their own preferences. It is crucial, however, to anticipate the need to change dosing. Midazolam, a widely used benzodiazepine, is safe and effective in a small dose (1 mg) either intravenously or intramuscularly. Adequate time must be allotted before a subsequent dose to avoid respiratory depression. The rapid onset and short duration (1 hour), together with both anterograde and retrograde amnesia, make this agent quite suitable for outpatient procedures as long as subsequent redosing is avoided. Similarly, fentanyl (50–100 mg) or meperidine (10–25 mg) can be given intravenously for analgesia during monitored procedures with local or regional anesthesia. Agents that are not reversible should be avoided, since wide variation in metabolic clearance is possible in the elderly because of intrinsic alterations in clearance or competition with other medications. Wound healing Although surgical expertise inside a body cavity is the ultimate determinant of the success of a major surgical procedure, it is the external wound that is most noticed by patients and their families. Wound healing may be affected by factors that are common in oncologic practice and may be aggravated in the elderly. Factors such as competition of the tumor for nutrients, tumor-induced malnutrition, and perhaps tumor-derived wound factors may all inhibit the rate of intrinsic wound healing.84 Similarly, chemotherapy and radiation therapy are known to adversely affect wound healing, and may be additive to other risk factors.85 It is possible that available nutrient supplementation (e.g. with vitamin A) or investigational factors (e.g. growth hormones and growth factors) may restore wound healing to normal.1 In the elderly oncology patient, wounds should be closed per primam whenever possible (to minimize the metabolic stimulus), and perhaps even with subcuticular closure to allow a more rapid return to normal function and to avoid the need for the patient to come back for suture removal. Conversely, however,

Surgical approaches to the older patient with cancer

709

when there is a high risk for wound infection, wounds should be allowed to heal by secondary intention, because the secondary complications of inadequately treated infection are usually poorly tolerated in the elderly. Thoughtful decision making and finely honed judgment are essential in assuring an excellent outcome. Rehabilitation Many cancer patients have already lost function prior to surgery. Rapid recovery86 of function may be a critical factor in patient outcome. Likewise, return to normal function has significant social as well as economic implications for many of these individuals. In the management of younger patients, discharge from the hospital usually represents a marker of the completeness of care. In the elderly, however, rehabilitation, which may be extended and multifactorial, may be an equally important phase of the total surgical process.86–92 For example, elderly patients recover less well from extremity amputation92 owing to loss of muscle mass, underlying osteoporosis, degenerative joint disease, and vascular disease. In preoperative evaluation, it is crucial for the primary care physician and healthcare team to begin to plan for postoperative rehabilitation to allow ongoing continuity and a transition to longer-term care. Surgical care is thus one phase in a continuous process of care that begins with diagnosis but ends only when the patient has been returned to a pre-illness state of function. Advance directives As indicated earlier, the discussion of advance directives, including intraoperative DNR orders, becomes an important part of the overall surgical management of the elderly cancer patient. While each institution may approach the specifics differently, all institutions should have an organized program for assuring that each elderly patient has been appropriately informed about the opportunity for an advance directive prior to a major oncologic surgical procedure.93 In many cases, the patient’s wishes can be best met by the choice of a less aggressive surgical procedure than might ordinarily be recommended in a younger patient.94,95 Since elderly patients are usually very aware of issues and values that are important to them, they are typically quite prepared to discuss matters related to dying and quality of life—matters that may be critical in the decision process and that may be pivotal if a major complication occurs. All of this is much easier to discuss and clarify with patients themselves before a procedure is carried out. Once the patient develops a complication that forebodes a long phase of in-hospital treatment— perhaps in an intensive care unit where social isolation is often prevalent—the decisionmaking process becomes even more complex. Careful estimation of prognosis and frequent communication with the patient’s family greatly facilitate decisions to forego additional treatment,96,97 or to withdraw treatment when the likelihood of success seems small.98 These decision-making issues in the final phase of an individual’s life are important, potentially costly, and emotionally challenging.95

Comprehensive Geriatric Oncology

710

Case study 1: Advance directive and do not resuscitate An 85-year-old male is admitted to the hospital for management of a low-lying rectal carcinoma. Sigmoidoscopic examination demonstrates the lesion to be 8 cm from the anal verge. There is no evidence of metastatic disease on preoperative evaluation. The patient indicates that he will not agree to an abdominoperineal resection—no matter what. Furthermore, he has met with an attorney, and has created an advance directive and granted durable power of attorney to his son. Following a transrectal excision of the lesion, the patient has a cerebrovascular accident and requires intubation and mechanical ventilation. The patient’s wife—the stepmother to his son—wants everything to be done. How should you proceed? Case study 2: Comorbid illness An 80-year-old woman is referred for management of a 1.5 cm pigmented lesion on the right leg. Biopsy by the dermatologist showed a melanoma, superficial spreading. Because of a prior history of myocardial infarction, the operative risk is considered to be high. The planned procedure is a local excision of the lesion, using local incision and intravenous sedation. In addition, sentinel lymph node mapping is planned to stage the patient. Summary Just as pediatric surgical patients are not ‘small adults’, nor are elderly and geriatric patients ‘old adults’. Elderly oncology patients present with a variety of unique problems that require forethought, preparation, and accuracy. The identification and management of associated health problems is paramount. The choice of an appropriate operation may be different from that used in a younger patient. Attention to the need for social considerations, such as advance directives, takes on a greater importance in the elderly patient with cancer. Similarly, postoperative recovery of function, response to complications, and the length and complexity of rehabilitation may all be markedly different in this age group. Good results often depend on thoughtfiilness, attention to details, and communication skills. References 1. Smith KP, Zardiackas LD, Didlake RH. Cortisone, vitamin A, and wound healing: the importance of measuring wound surface area. J Surg Res 1986; 40:120–5. 2. Brooks B. Surgery in patients of advanced age. Ann Surg 1937; 105: 481–95. 3. Marshall WH, Fahey PJ. Operative complications and mortality in patients over 80 years of age. Arch Surg 1964; 88:896–904. 4. Glenn F. Surgery in the care of the elderly. Gerontol Geriatr Educ 1980; 1:107–10. 5. Katlic MR. Surgery in centenarians. JAMA 1985; 253:3139–41.

Surgical approaches to the older patient with cancer

711

6. Seymor DG, Pringle R. A new method of auditing surgical mortality rates: application to a group of elderly general surgical patients. BMJ 1982; 284:1539–42. 7. Goodwin JS, Sarnet JM, Key CR et al. State at diagnosis of cancer varies with the age of the patient. J Am Geriatr Soc 1986; 34:20–6. 8. Holmes FF. Clinical evidence for a change in tumor aggressiveness with age. Semin Oncol 1989; 16:34–40. 9. Kant AK, Glover C, Horm J et al. Does cancer survival differ for older patients? Cancer 1992; 70:2734–40. 10. Kennedy BJ. Aging and cancer. J Clin Oncol 1988; 16:1903–11. 11. Mor V, Guadagnoli E, Masterson-Allen S et al. Lung, breast and colorectal cancer: the relationship between extent of disease and age at diagnosis. J Am Geriatr Soc 1988; 36:873–6. 12. Brandstetter RD, Kazemi H. Aging and the respiratory system. Med Clin North Am 1983; 67:419. 13. Beernaeris A. Surgery in the aged. Associated pathologies of aged people. Acta Chir Belg 1993; 93:112–4. 14. Lakatta EG. Cardiovascular regulatory mechanisms in advanced age. Physiol Rev 1993; 73:413–67 15. Rich MW, Imburgia M. Inotropic response to dobutamine in elderly patients with decompensated congestive heart failure. Am J Cardiol 1990; 65:519–21. 16. Sinclair D. Myocardial infarction. Consideration for geriatric patients. Can Fam Phys 1994; 40:1172–7. 17. Burrows V, Shenkcman L. Thyroid function in the elderly. Am J Med Sci 1982; 283:8–17. 18. Kampmann JP, Sinding J, Moller-Jorgensen I. Effect of age on liver function. Geriatrics 1975; 30:91–95. 19. James OFW. Gastrointestinal and liver function in old age. Clin Gastroenterol 1983; 12:671– 91. 20. Chiverton SG, Hunt RH. Pharmacokinetics and pharmacodynamics of treatments for peptic ulcer disease in the elderly. Am J Gastroenterol 1988; 83:211–15. 21. Altman DF. Changes in gastrointestinal, pancreatic, biliary and hepatic function with aging. Gastroenterol Clin North Am 1990; 19: 227–34. 22. Delafuente JC. Perspectives on geriatric pharmacotherapy. Pharmacotherapy 1991; 11:222–4. 23. Djokovic JL, Hedley-Whyte J. Prediction of outcome of surgery and anesthesia in patients over 80. JAMA 1979; 242:2301–6. 24. Greenblatt DJ, Abernathy DR, Loeniskar A et al. Effect of age, gender, and obesity on midazolam kinetics. Anesthesiol 1984; 61:27–35. 25. Kreehel SW. Anesthesia for surgical care of the elderly. In: Surgical Care of the Elderly (Meakins JL, McClaran JC, eds). Chicago: Year Book, 1988:276–87. 26. Matteo RS, Backus WW, McDaniel DD et al. Pharmacokinetics and pharmacodynamics of dtubocurarine and metoeurine in the elderly. Anesth Analg 1985; 64:23–9. 27. Rupp SM, Castagnoli KP, Fisher DM et al. Pancuronium and vecuroniurn pharmacokinetics and pharmacodynamics in younger and elderly adults. Anesthesiology 1987; 67:45–9. 28. Moore AK, Vilderman S, Lubenskyi W et al. Differences in epidural morphine requirements between elderly and young patients after abdominal surgery. Anesth Analg 1990; 70:316–20. 29. Mattison RA. Anesthesia drug interaction in the elderly. In: Problems in Anesthesia. Philadelphia: JB Lippincott, 1989:589–601. 30. Taseh MD. The autonomic nervous system and geriatric anesthesia. Intl Anesthesiol Clin 1988; 26:143–51. 31. Watters JM, McClaran JC. The Elderly Surgical Patient. In: Scientific American Surgery (Wilmore DW, Cheung LY, Harken AH et al, eds). New York: Scientific American, 1996:1–31. 32. Woodhouse KW, Mutch E, Williams FM et al. The effect of age on pathways of drug metabolism in human liver. Age Ageing 1984; 13: 328–34.

Comprehensive Geriatric Oncology

712

33. Zawada ET Jr, Horning JR, Salem AG. Renal, fluid, electrolyte, and acid-base problems during surgery in the elderly. In: Geriatric Surgery (Katlic MR, ed). Baltimore: Urban & Schwarzenberg, 1990:85–96. 34. Denny JL, Denson JS. Risk of surgery in patients over 90. Geriatrics 1972; 27:115–18. 35. Johnson JC. Surgical assessment in the elderly. Geriatrics 1988; 43(Suppl): 83–90. 36. Gerson MC, Hurst JM, Hertzberg VS et al. Prediction of cardiac and pulmonary complications related to elective abdominal and noncardiac thoracic surgery in geriatric patients. Am J Med 1990; 88:101–7. 37. Kauder DR, Schwab CW. Comorbidity in geriatric patients. Adv Trauma 1989; 29:541. 38. Ritter-Sterr C, Janssen I, List M et al. Surgery in the elderly cancer patient: a descriptive analysis of patient characteristics, comorbidities and psychosocial variables. Proc Am Soc Clin Oncol 1993; 12: A1559. 39. Merli GJ. Prophylaxis for deep vein thrombosis and pulmonary embolism in the geriatric patient undergoing surgery. Clin Geriatr Med 1990; 6:531–42. 40. Palmberg S, Hirsjarvi E. Mortality in geriatric surgery. With special reference to the type of surgery, anaesthesia, complicating diseases, and prophylaxis of thrombosis. Gerontology 1979; 25:103–12. 41. Buzby GP. Perioperative total parenteral nutrition in surgical patients. N Engl J Med 1991; 325:525–32. 42. Department of Health and Social Security (UK). A nutrition survey of the elderly. Rep Health Soc Subj (Lond) 1979; 16:1–209. 43. Morley JE. Nutrition in the elderly. Ann Intern Med 1988; 109: 890–904. 44. Pinchcofsky-Devin GD, Kaminski MV. Incidence of protein calorie malnutrition in the nursing home population. J Am Coll Nutr 1987; 6:109–12. 45. Rudman D, Feller AG, Nagruj HS et al. Relation of serum albumin concentration to death rate in nursing home men. J Parenter Enter Nutr 1987; 11:360–3. 46. Shizgal HM, Martin MF, Gimmon Z. The effect of age on the caloric requirement of malnourished and individuals. Am J Clin Nutr 1992; 55:783–9. 47. Gavin LA. Management of diabetes mellitus during surgery. West J Med 1989; 151:525–9. 48. Cohen CB, Cohen PJ. Do not resuscitate orders in the operating room. N Engl J Med 1992; 325:1879–82; 1991; letter 326:1571–2. 49. Cohen MM. Perioperative responsibilities of the surgeon. Clin Geriatr Med 1990; 6:459–67. 50. Lockwood M. Ethical dilemmas in surgery: some philosophical reflections. J Med Ethics 1980; 6:82 4. 51. Reiss R. Moral and ethical issues in geriatric surgery. J Med Ethics 1980; 6:71–7, 180. 52. Choudry NK, Choudhry S, Singer PA. CPR for patients labeled DNR: the role of limited aggressive therapy order. Ann Intern Med 2003; 138:65–8. 53. Walker RM. DNR in the OR. Resuscitation as an operative risk. JAMA 1991; 266:2407. 54. Champion HR, Copes WS, Buyer D et al. Major trauma in geriatric patients. Am J Public Health 1989; 79:1278. 55. Demarest GB, Turner MO, Clevenger FW. Injuries in the elderly: evaluation and initial response. Geriatrics 1990; 45:36. 56. Finelli FC, Jonsson J, Champion HR et al. A case control study for major trauma in geriatric patients. J Trauma 1989 29:541–8. 57. Grisso JA, Schwarz DF, Wishner AR et al. Injuries in an elderly inner-city population. J Am Geriatr Soc 1990; 38:1326–31. 58. Horst HM, Obeid FN, Sorensen VJ, Bivins BA. Factors influencing survival of elderly trauma patients. Crit Care Med 1986; 14:681–4. 59. Lehman LB. Head trauma in the elderly. Postgrad Med 1988; 83: 140–2; 145–7. 60. Luna GK, Carrico CJ. Trauma in the elderly. In: Surgical Care ofthe Elderly (Meakins JL, McClaran JC, eds). Chicago: Year Book Medical Publishers, 1988:473–84.

Surgical approaches to the older patient with cancer

713

61. McCoy GF, Johnstone BA, Duthie RB. Injury to the elderly in road traffic accidents. J Trauma 1989; 29:494–7. 62. Osler T, Hales K, Baack B et al. Trauma in the elderly. Am J Surg 1988; 156:537. 63. Deitch EA, Clothier J. Burns in the elderly: an early surgical approach. J Trauma 1983; 23:891. 64. Hunt JL, Purdue GF. The elderly burn patient. Am J Surg 1992; 164:472. 65. Kara M, Peters WJ, Douglas LG et al. An early surgical approach to burns in the elderly. J Trauma 1990; 30:430. 66. Gee MH, Gottlieb JE, Albertine KH et al. Physiology of aging related to outcome in the adult respiratory distress syndrome. J Appl Physiol 1990; 69:822–829. 67. McClish DK, Powell SH, Montenegro H, Nochomovitz M. The impact of age on the utilization of intensive care resources. J Am Geriatr Soc 1987; 35:983–8. 68. Mayer-Oakes SA, Oye RK, Leake B. Predictors of mortality in older patients following medical intensive care—the importance of functional status. J Am Geriatr Soc 1991; 39:862–8. 69. Craig DB. Postoperative recovery of pulmonary function. Anesth Analg 1981; 60:46. 70. Heuser MD, Case LD, Ettinger WH. Mortality in intensive care patients with respiratory disease—Is age important? Arch Intern Med 1992; 152:1683–8. 71. Kass JE, Castriotta RJ, Malakoff T. Intensive care unit outcome in the very elderly. Crit Care Med 1992; 20:1666. 72. Margulies DR, Lekawa ME, Bjerke S et al. Surgical intensive care in the nonagenarian. No basis for age discrimination. Arch Surg 1993; 128:753–8. 73. Nicholas F, LeGall Jr, Alperovitch A et al. Influence of patient’s age on survival, level of therapy and length of stay in intensive care units. Intens Care Unit 1982; 13:9–13. 74. Rockwood K, Noseworthy TW, Gibney RTN et al. One-year outcome of elderly and young patients admitted to intensive care units. Crit Care Med 1993; 21:687–91. 75. Worthley L, Holt A. Percutaneous tracheostomy. Intens Care World. 1992; 9:187–92. 76. Bowser-Wallace BH, Cone JB, Caldwell FT. Hypertonic lactated saline resuscitation of severely burned patients over 60 years of age. J Trauma 1985; 25:22. 77. Schneider EL. Infectious diseases in the elderly. Ann Intern Med 1983; 98:395–400. 78. Madden JW, Croker JR, Beynon GPJ. Septicemia in the elderly. Postgrad Med J 1981; 57:502. 79. Yoshikawa TT. Antimicrobial therapy for the elderly patient. J Am Geriatr Soc 1990; 38:1353– 72. 80. Leiber CP, Seinige UL, Sataloff DM. Choosing the site of surgery. An overview of ambulatory surgery in geriatric patients. Clin Geriatr Med 1990; 6:493–7. 81. Larach SW, Salomon MC, Williamson PR et al. Laparoscopic assisted abdominoperineal resection. Surg Laparosc Endosc 1993; 3:115–18. 82. Quattlebaum JK Jr, Flanders HD, Usher CH III. Laparoscopic assisted colectomy. Surg Laparosc Endosc 1993; 3:81–7. 83. Shimi S, Nathanson LK, Cuschieri A. Laparoscopic cardiomyotomy for achalasia. J R Coll Surg Edin 1969; 36:152–4. 84. Dvorak HF. Tumors: wounds do not heal. N Engl J Med 1986; 315: 1650–9. 85. Falcone RE, Nappa JF. Chemotherapy and wound healing. Surg Clin North Am 1984; 64:779– 94. 86. Nicaise J, Jonckers J, Smeis P et al. Social rehabilitation of the elderly after surgical intervention. Acta Chir Belg 1993; 93:122–5. 87. Clark GS, Murray PK. Rehabilitation of the geriatric patient. In: Practices and Principles of Rehabilitation Medicine (DeLisa JA, ed). Philadelphia: JB Lippincott, 1988:410. 88. Delisa JA, Miller RM, Melnick RR et al. Rehabilitation of the cancer patient. In: Cancer: Principles and Practices of Oncology, 2nd edn (DeVita VTG, Hellman S, Rosenberg J, eds). Philadelphia: JB Lippincott, 1989:2333. 89. Felsenthal G. Rehabilitating older patients: primary care evaluation, treatment, and resources. Geriatrics 1989; 44:89–90.

Comprehensive Geriatric Oncology

714

90. Harris KA, van Schie L, Carrole SE et al. Rehabilitation potential of elderly patients with major amputations. J Cardiovasc Surg 1991; 32:463. 91. Reyes RL, Leahey EB, Leahey EB Jr. Elderly patients with lower extremity amputations: three year study in a rehabilitation setting. Arch Phys Med Rehabil 1977; 58:116. 92. DeVivo MJ, Kartus PL, Rutt RD et al. The influence of age at time of spinal cord injury on rehabilitation outcome. Arch Neurol 1990; 47:687. 93. Emanuel LL, Barry MJ, Stoeckle JD et al. Advance directives for medical care: A case for greater use. N Engl J Med 1991; 324:889. 94. Ewen EF Jr, Keating HL 3rd. Alternatives to major surgery in the high-risk elderly. Clin Geriatr Med 1990; 6:481–92. 95. Fried TR, Gillick MR. Medical decision-making in the last six months of life: choices about limitation of care. J Am Geriatr Soc 1994; 42:303–7. 96. Society of Critical Care Medicine Ethics Task Force. Consensus report on the ethics of foregoing life-sustaining treatments in the critically ill. Crit Care Med 1990; 18:1435. 97. Faber-Langendoen K, Bartels DM. Process of forgoing life-sustaining treatment in a University hospital: An empirical study. Crit Care Med 1992; 20:570. 98. Smedira NG, Evans BH, Grais LH et al. Withholding and withdrawal of support from the critically ill. N Engl J Med 1990; 322:309.

34 Advances in geriatric surgery Peter J Fabri Introduction As a greater proportion of the population lives into their 80s or 90s or above, the likelihood of encountering malignancy likewise increases. Accordingly, the incidence of most malignancies increases in the elderly. At the same time, improvements in anesthetic technique, patient preparation, and management of coexistent medical conditions now allow surgical procedures in the older cancer patient that previously might not have been considered. Concurrently, changes in the healthcare environment are necessitating shorter hospital stays, increasing the use of ambulatory surgery and a burgeoning use of ‘minimally invasive’ surgical procedures, such as laparoscopy, thoracoscopy, interventional endoscopy, and interventional radiology.1 The surgical treatment of malignancies in elderly patients may translate into improved outcome,2–4 but also increases the risk for surgical complications, lengthy hospitalizations and dramatic costs. In the past, upper abdominal operations were often considered too risky in elderly patients,5–7 and in many institutions age limits were established for high-risk procedures such as pancreaticoduodenectomies and tri-segmentectomies of the liver. Recent studies, however, suggest8–11 that the outcome of major surgery is comparable in the elderly if careful patient selection and appropriate attention to detail is exercised.12–14 In very highrisk elderly patients, the choice of a surgical procedures for specific diseases may need to be modified.15 Attention to cardiac and pulmonary risk factors in the elderly is essential,16 and the influence of coexisting disease must be anticipated.17 A careful social and functional history, in addition to past and current illnesses, is essential. If these factors have been considered, it should be possible to offer appropriate and effective surgical therapy for many malignancies in elderly patients. Surgical oncology in the elderly does not require alteration in the technical performance of a given operation; therefore, we shall not reiterate traditional surgical atlases.18 Rather, surgical oncology in the elderly is a matter of decision-making and patient management. Esophageal disease Cancer of the esophagus often presents in an advanced stage. Even when it appears localized, however, submucosal spread and lymph node involvement are common. Consequently, because of the very poor response of this cancer to resection, many surgeons have been reluctant to operate on elderly patients with malignancies of the esophagus. Therefore, medical evaluation and treatment of esophageal symptoms,

Comprehensive Geriatric Oncology

716

endoscopic stenting and dilation,19 and endoscopic laser therapy20 have been offered as alternatives. It has been demonstrated, however, that esophageal resection can be performed safely in the elderly21–23 and with quite acceptable long-term survival.24 We are faced with the situation of a high-risk operation and a patient population with multiple associated diseases. Therefore, a very careful selection process to define the optimum candidates based on each of these two groups of risk factors is essential. Patients whose risk is too high might be offered chemotherapy, radiation, and palliative laser treatment with stent placement. Chosen surgical patients, however, should undergo resection, since this is the only therapeutic modality that currently offers the possibility of cure. Blunt esophagectomy, using a transhiatal approach, has been recommended25 as having fewer complications. While the evidence of complications has been argued, it appears clear that an anastomotic leak from a cervical esophagogastrostomy is better tolerated than a similar leak in an intrathoracic location. This favors the transhiatal approach with cervical reconstruction. The risk of reflux and aspiration as well as postoperative complications must, however, be considered. Applying accumulated experience in blunt dissection of the lower esophagus, it has often become possible to resect lesions of the distal esophagus using a smaller, abdominal, procedure, and a primary transhiatal anastomosis constructed using a circular stapling device (EEA) through the abdomen. This approach avoids the need for thoracotomy, with its attendant pulmonary complications, postoperative discomfort, and delayed recovery. Similarly, the introduction of thoracoscopic surgery has allowed careful dissection of the esophagus under direct vision with wide margins, with subsequent performance of a ‘controlled blunt esophagectomy’ through a cervical and abdominal approach and the same cervical anastomosis, for which complications appear to be fewer. Stomach and duodenum Even as the incidence of peptic ulcer disease has decreased in the USA, the incidence of gastric malignancy appears to be increasing. Similarly, there is a change in histology of distal esophageal lesions, with a decreasing proportion of squamous carcinoma and an increasing incidence of adenocarcinoma. In a sense, gastric cancer is ‘migrating’ proximally into the gastric fundus and esophagogastric junction. Meanwhile, antral carcinoma, previously the most common gastric location, is clearly decreasing. Upper gastric lesions are more undifferentiated and less radioresponsive. Consequently, most of the surgical attention to esophageal and gastric neoplasms is now focused on the esophagogastric junction. It is probably not critical to distinguish between an adenocarcinoma that originates in the distal esophagus and migrates caudad versus a carcinoma in the proximal stomach that extends proximally into the esophagus. The surgical approach and the expected outcome are probably similar in both cases. In many countries, carcinoma of the body of the stomach has been treated aggressively in elderly patients. Experience gained in the treatment of benign diseases of the stomach in the elderly26–31 has allowed transfer of these skills to more aggressive gastric resections for malignancy.32–39 An unusual variant of gastric carcinoma is that occurring following a previous procedure for peptic ulcer disease. Recent data would suggest that a period of

Advances in geriatric surgery

717

approximately 25 years is required for the development of gastric malignancy following antral resection. Although there is continued debate about whether the incidence of cancer in this setting is actually increased, it is clear that the entity exists and should be suspected in patients with upper gastrointestinal symptoms and a remote history of gastric resection.40,41 Aggressive surgical treatment of these patients is justifiable even in advanced stages, as long as appropriate patient selection and management of associated conditions are undertaken. Endocrine tumors The use of screening both by imaging and by biochemical assays has identified elderly patients with previously unrecognized mass lesions in the thyroid (thyroid scans, thyroid ultrasound, etc.), parathyroids (hypercalcemia), and adrenals (abdominal computed tomography (CT) and magnetic resonance imaging (MRI)). Management of these asymptomatic ‘tumors’ is controversial, since they are usually benign. Most authors would recommend that careful selection of patients for surgical treatment will result in better surgical results. Older patients tolerate total thyroidectomy or wide parathyroid exploration without much difficulty, regardless of chronological age.42,43 Many patients in this age group present with vague neuromuscular symptoms and are subsequently found to be hypercalcemic by laboratory screening.44 If patients are selected because of acceptable risk, expectation of improvement can be anticipated. In a review of asymptomatic hyperparathyroidism, Clark demonstrated that virtually all patients actually have significant preoperative symptoms that are not realized until after they have been eliminated by parathyroidectomy. Introduction of a laparoscopic approach to the adrenal gland may be a major advance in managing patients with adrenal mass lesions identified on CT scan that are smaller than 6 cm in size. Additionally, pheochromocytoma has required laparotomy and bilateral adrenal exploration. Currently, MRI can identify pheochromocytoma with a high degree of accuracy, confirming whether it is unilateral and thus allowing even a pheochromocytoma to be approached laparoscopically when the opposite adrenal gland is normal on MRI. In the case of endocrine disease of the elderly, it is more important than ever to establish an accurate diagnosis and to avoid aggressive treatment in ‘incidental’ disease. Examples are lesions in the thyroid that are cystic or multilobar, which are very unlikely to be malignant. Similarly, hypercalcemia should be evaluated thoroughly to exclude metastatic carcinoma, hypercalcemia associated with medical diseases such as sarcoidosis, and multiple myeloma, as should incidental adrenal lesions on CT scan. This latter group has been most puzzling. Recent data from many centers suggest that patients without evidence of endocrinopathy (no high blood pressure, hypokalemia, or cushingoid symptoms) and with lesions less than 4–5 cm can be observed with serial CT scans. Patients with lesions over 6 cm regardless of symptoms should undergo surgical exploration. The upper size limit for safe removal laparoscopically is probably about 6 cm, so that all lesions over 6 cm should probably be approached through an open surgical incision. Malignancy of the adrenal carries a very high mortality, since it is identified late. Yet most small adrenal lesions are not malignant. A very cautious approach to large lesions in the elderly is suggested because of the poor prognosis.

Comprehensive Geriatric Oncology

718

Breast cancer The incidence of breast cancer continues to increase throughout life, with the highest frequency in the oldest patients. As lifespan increases, an increasing number of patients in the latter years of life will develop breast tumors. Particularly with the increased use of screening mammography,45 many breast lesions in the elderly are being found that perhaps might not have been found before. The traditional approach to breast cancer in older women is to perform mastectomy routinely with the thought that breast conservation and cosmesis are not particularly important in the elderly female. More recent studies, however, suggest that cosmesis and sense of self-image are probably quite important in the elderly and should be considered in the treatment planning. It is uncertain whether age affects breast cancer favorably or unfavorably, since studies have been contradictory.46–49 Most authors would suggest that actuarial survival of breast cancer patients is probably not influenced by age at diagnosis. Since survival data appear to be favorable, women with small lesions can safely undergo lumpectomy with axillary dissection and radiation. If the size of the tumor relative to the breast would preclude an acceptable cosmetic result, mastectomy is probably warranted. Several centers are evaluating or using tamoxifen alone in the elderly patient with breast cancer, demonstrating good short-term results. Long-term results, however, are not yet available. Studies to date would suggest, however, that recurrence after tamoxifen therapy can still be treated surgically without apparent compromise in staging or curability of the disease. The use of chemotherapy in this age group is extremely controversial. Most studies do not show a distinct survival advantage of adjuvant use, although there may be a delay in the time to recurrence of disease. Tamoxifen has been the mainstay of treatment in this age group both in the adjuvant and the therapeutic setting. Hospital stays are becoming shorter and shorter, with many breast procedures being performed on an outpatient basis. Elderly patients tolerate this outpatient management well, as long as appropriate preoperative and psychosocial evaluations have been undertaken. Colorectal cancer Malignancies of the colon and rectum are among the more common lesions to be treated in the elderly. Several authors have reviewed their experience in the management of these lesions,50–59 and studies generally suggest that appropriately selected patients can be managed using techniques traditionally used in younger patients. Several authors suggest modified surgical approaches such as perineal rectosigmoidectomy,60 subtotal colectomy with primary ileocolonic anastomosis for obstructing carcinoma,61 laparoscopy-assisted resection,62 or conservative treatment with local excision.63 Patients seem to tolerate major surgical resections of the colon and rectum well, but do not tolerate the infectious complications and wound problems that may result. Careful attention to preoperative bowel preparation, both mechanical and antibiotic, is essential. Careful evaluation of the heart and lungs with preoperative correction of abnormalities to minimize the impact of comorbid illness is also important. Sphincter-sparing operations, which avoid the need for a permanent colostomy, appear to be well tolerated in the elderly, although they often result in an increased frequency of

Advances in geriatric surgery

719

bowel movements and/or incontinence. Overall, patients appear to tolerate large procedures on the colon quite well—the traditional concept that elderly patients should all have a colostomy to avoid the risks of surgical anastomosis do not appear to be warranted. Traditional abdominoperineal resection can be avoided in most cases by the performance of low anterior resection or coloanal pull-through. Elderly patients do not tolerate coloanal pull-through procedures as well as younger patients, however, and are frequently troubled by excessive diarrhea. Careful patient selection is therefore essential. Preoperative, sandwiched radiotherapy may simplify the removal of long lesions from the rectum, and certainly appears to reduce the incidence of local recurrence. Neoadjuvant chemotherapy is probably of benefit in patients with large lesions, and the addition of combined radiation and chemotherapy is currently being studied and also seems likely to be beneficial in appropriately selected patients. Recent experience confirms that local excision of rectal lesions is adequate therapy in selected patients. With or without adjuvant therapy, local recurrence rates are low, and survival appears comparable to that of larger operations. Careful evaluation of the surgical specimen for level of penetration and lymphatic involvement is important if such minimal excision is to be recommended. Pancreas Many surgeons have recommended that pancreatic resection should not be performed in patients over 65 because of the high operative risk and low survival yield. It has been shown, however, that pancreatic resection in the elderly patient is both possible and effective.64–66 Endoscopic treatment of pancreatic cancer for palliation67 is effective, but requires frequent (every 6–12 weeks) replacement via endoscopic retrograde cholangiopancreatography (ERCP). Renewed enthusiasm for resection of the pancreas (Whipple procedure) is found in the markedly increased operative mortality following pancreaticoduodenectomy at Johns Hopkins.68 Pylorus preservation in this operation has rapidly become the treatment of choice, because it minimizes gastric emptying disorders and does not appear to be associated with a significant incidence of marginal ulceration. The use of octreotide in an adjuvant setting to decrease the incidence and severity of pancreatic anastomotic dehiscence appears to be justified. Postoperative recovery times and tolerance of major surgery appear to be normal in elderly patients, and the stress of the initial procedure is not nearly as disadvantageous as major surgical complications. Accordingly, the intent should be to perform the ideal operation at the first setting with perfect anastomoses and attention to all necessaiy details.69 Localized excision of lesions of the ampulla and duodenum may be quite suitable in elderly patients, particularly if comorbid illness necessitates a rapid operation. Liver Hepatic and biliary resections have also been considered to be high-risk procedures and therefore not appropriate for the elderly. In recent years, however, aggressive resections

Comprehensive Geriatric Oncology

720

both in the USA and abroad70–74 have confirmed that operation does appear to be possible for primary liver tumors as well as for metastatic disease from the colon. Primary liver tumors should probably be resected if they are small, are not associated with advanced cirrhosis, and do not involve major vascular structures such as the vena cava. CT scans and MRI have reached a level of sophistication that allows appropriate evaluation of the suitability of patients for resection and avoids the need for unnecessary preresection abdominal exploration. Many studies suggest that anatomic resection of segments of the liver is preferable to wide local excision in many cases. Patients appear to tolerate hepatic resection well if they are appropriately screened preoperatively and if particular attention is paid to preservation of a sufficient proportion of the liver to assure adequate liver function.22 Biliary tract tumors similarly can be resected with very acceptable results75 in appropriately selected patients. Where preoperative imaging indicates unresectability due to anatomic factors or metastases, patients with advanced disease can be treated with endoscopic endoprosthesis.76 Patients who present acutely with obstruction due to malignant disease may derive benefit from temporary decompression via endoscopically placed biliary stents or by either percutaneous cholecystostomy or percutaneous transhepatic catheterization when endoscopic approaches are unsuccessful. Long-term palliation with stents77 is certainly possible; the average ‘survival’ of a stent is about 3 months before replacement is necessary, and therefore treatment should be carefully matched to the expected survival of the patient. Gallbladder cancer has posed a difficult problem because of its very poor prognosis. Several studies have demonstrated a place for aggressive surgical excision.78,79 Controversy continues about the role of extended surgical resection with portal lymph node dissection. At present, extended resection and lymph node dissections of the porta hepatis should be reserved for centers that are actively studying this problem and perform the operations frequently. Approaches to bypass both gallbladder and bile duct tumors by use of hepaticojejunostomy using segments III or IV of the liver have proven useful.70,80 Prostate The incidence of prostate cancer increases linearly with age81 and should perhaps be considered almost a routine diagnosis in the octogenarian. Treatment of this condition has been difficult because many patients appear to do quite well with no treatment at all. Nevertheless, many patients have a rapidly progressive and fatal course, and therefore serious consideration of appropriate diagnosis, staging, and management is essential. The symptoms of urinary obstruction can now be relieved endoscopically with the use of an endoprosthesis,82 followed by laser treatment of obstructing prostatic lesions.83 Some authors recommend deferring treatment in the elderly for low-grade stage T3 tumors without metastasis.84 Others, citing the excellent results of prostatectomy, recommend radical surgical excision in the elderly.85 Balducci et al86 and Gibbons87 discuss the relative roles of the various treatment modalities in this disease. The difficulty in interpreting the literature for prostate cancer is the difference between treating an individual and a population. The results from large population studies employing radical resection suggest a benefit, although clearly not a large one. In younger, healthy patients,

Advances in geriatric surgery

721

the risks of nervesparing prostatectomy appear justified. In the older patient, careful decision-making is essential, since many of these patients will never have clinical progression of disease. Accordingly, many authors would recommend expectant management for lesions in elderly patients, or perhaps radiation. Additional studies are required to clarify the optimum way to treat prostate cancer in the elderly. Bladder cancer Carcinoma of the bladder in the elderly patient can be managed easily by repeated transurethral resection of bladder tumors, with careful restaging of the depth of penetration of the tumor at each excision. However, many of these patients will require more aggressive therapy. Even in the elderly patient, radical cystectomy appears to be a well-accepted and tolerated procedure if it can be performed with minimal associated morbidity.88–92 Although a radical procedure may appear difficult, the mechanisms of urinary reconstruction have now been sufficiently evaluated to allow even elderly patients to undergo a minimal-risk procedure with suitable long-term results. Urinary incontinence can be a difficult problem in this age group,93 but resection to control local disease outweighs the need to treat hemorrhage, obstruction, and necrosis at a later time. When patients present with obstruction of the urinary tract due to cancers impinging on the ureter or ureteral orifices, percutaneous nephrostomy is a safe and effective measure for restoring excretion.94 Urologic procedures can often be performed through the tract of the percutaneous nephrostomy, utilizing laser technology and flexible scopes. Gynecologic malignancies Gynecologic malignancies are often considered to be diseases of middle-aged women. As with most malignancies, however, the actual incidence in elderly women is substantial and increases over time. Cancer in particular may be identified in elderly women long after their repro- ductive years.95 Radical resection of the uterus carries an increased risk in the elderly patient, but this again can be managed quite suitably if associated underlying diseases can be effectively controlled.96 Elderly patients with gynecologic malignancy undergo non-operative staging including CT scan and possible laparoscopy. In patients with a minimal number of risk factors and suitable perioperative staging and preparation, radical surgery should be recommended. Surgical stays are decreasing in length, and the elderly appear to tolerate this change well. In resection of the ovaries, hormonal replacement is probably justified, although debate continues about its sideeffects. Currently, replacement therapy for symptomatic females is being recommended as being of more benefit than risk. In the elderly woman, however, risk-benefit is an important consideration, since replacement therapy may increase the risk of coronary disease, may decrease that of osteoporosis, and probably increases that of endometrial cancer. Although some clinicians feel strongly about the cardiac risk—and there is some evidence of an increased incidence of cardiovascular disease—this appears to be minimal if patients are chosen appropriately and the hormone dose minimized to that necessary to control symptoms.

Comprehensive Geriatric Oncology

722

Thoracic tumors Although the incidence of smoking is decreasing, its long-term effects still result in a high frequency of lung cancer in elderly patients.97,98 Over the years, the relative benefit of pulmonary resection has been questioned. Recently, however, optimism regarding the use of chemotherapy and radiation alone has been tempered by a realization that surgical excision is still the best treatment for long-term control of symptoms as well as having the potential for cure. Pulmonary disease often has significant under-lying cardiac disease, which must be identified and treated. If patients’ underlying diseases can be adequately managed, pulmonary resection in the elderly patient appears to be a reasonable approach.99–105 Patients often present with a large apical mass, may have a histologic diagnosis of adenocarcinoma on percutaneous biopsy, and may not have any evidence of metastatic disease.106,107 These patients are ideal candidates for resection if their surgical risk is otherwise reasonable. Preoperative thoracoscopy may be indicated in marginal patients to assure that a lesion is resectable prior to making a commitment to a thoracotomy.108 Follow-up of patients with non-small cell lung carcinoma appears to be favorable in the elderly.109–111 Head and neck surgery Incidences of carcinomas of the larynx, the base of the tongue, and the palate increase with duration of smoking and exposure to other risk factors.112 Accordingly, elderly patients are not spared from these diseases. Since radiation therapy, chemotherapy, and surgical resection each have a role to play in treatment, planning the management of these patients requires a multimodality approach that includes head and neck surgery, radiation oncology, and medical oncology. Careful staging, including triple-endoscopy and thin-section CT scans, is essential to appropriately stage the tumor before a definition of therapy is considered. Many favorable patients will benefit from a multimodality approach. Other patients with substantial risk factors may benefit from radiation alone with regular follow-up. If such patients develop recurrence, salvage with surgery and/or chemotherapy is possible. If surgical resection is chosen, careful attention to identification of risk factors allows an appropriate planned approach.113–128 Many patients will present with significant malnutrition. Studies evaluating preoperative nutritional support have not shown improvement, and this should be reserved for patients with marked malnutrition. Rather, consideration of nutritional requirements should include establishment of a suitable route for continued enteral nutrition in the postoperative period. Many institutions have placed percutaneous endoscopic gastrostomy tubes at the time of initial diagnosis to allow continued use of the gastrointestinal tract throughout the remainder of staging, adjuvant therapy, and postoperative recovery. Elderly patients tolerate large, radical head and neck operations as well as multimodality therapy well if underlying associated illnesses are identified and treated. Accordingly, aggressive pursuit of nutritional maintenance is essential for the healing of flaps, stomas, and suture lines in radiated tissue. In many cases, hemilaryngectomy can be accomplished, which preserves the voice, and tracheostomy may also be avoided.

Advances in geriatric surgery

723

Neurosurgery Many studies of benign and malignant disease have shown that elderly patients tolerate neurosurgical procedures quite well.128–132 Debulking tumor burden for malignant tumors in elderly patients may have a very limited role to play, and therefore appropriate patient selection is warranted. In particular, removal of metastatic lesions to the brain should be limited to situations where a solitary lesion from a responsive tumor is identified on staging in a symptomatic patient whose symptoms are expected to be improved by resection.133 As more lesions are identified in patients of advanced age who have imaging studies (particularly MRI),134–136 more difficult decisions will have to be made about the appropriate surgical therapy. In particular, silent lesions in the elderly may not benefit from aggressive therapy. Again, very careful selection of patients is essential. Less invasive approaches, such as stereotactic surgery,137 laparoscopic surgery via small ventriculostomy, gamma-knife, and neutron-beam radiation, may be suitable modalities in patients at higher risk. Meningiomas and acoustic neuromas appear to be identified with increasing frequency in this age group as the use of imaging modalities increases. Very careful consideration of possible benefit should be included in the preoperative evaluation of these patients, since many of them are asymptomatic or minimally symptomatic, and are unlikely to derive substantial benefit from surgery. On the other hand, patients with substantial symptoms that limit their ability to function can be expected to derive comparable benefits to younger patients if their associated illnesses are appropriately treated.138–141 Skin tumors After many years of sun exposure, elderly patients are at high risk of developing skin cancer.142 Similarly, both unusual and common malignancies143 occur with increased frequency. Melanoma is common, can usually be treated with local excision, and follows an unpredictable course just as in younger patients. In most cases, 2 cm margins seem to be adequate. Age is probably not a negative factor in the treatment of these lesions. Careful consideration of the total body skin coverage, however, should also be made at the time that a single lesion is excised. Careful documentation of coexistent premalignant lesions, small malignant lesions in critical areas, etc., which may alter the outcome, is important before embarking on surgical intervention. Wide excision should be limited in magnitude, particularly on the face, but function is clearly the most important factor to consider, and particular attention should be paid to eye closure. Recent studies using radiolabelled vital dyes (injected around the tumor) have suggested that patients can be treated adequately without associated morbidity by undergoing only excision of the ‘sentinel node’. Most data have been accumulated in patients with melanoma, but recent studies have also shown an advance in breast carcinoma. Although short-term data and their actuarial evaluation are too new, evaluation of these data suggests that comparable staging can be accomplished and formal lymph node dissection of the axilla groin and neck can be avoided without apparent adverse reaction.

Comprehensive Geriatric Oncology

724

Orthopedics The elderly are still at risk of developing common orthopedic problems, the most frequent of which is fracture secondary to falls.144 Patients do not tolerate prolonged hospitalization, and so prompt medical evaluation and preparation for surgery is indicated. Although recent larger procedures, including total hip replacement, have received favorable support, it may be more prudent in elderly patients, particularly if their mobility is already severely restricted, to use limited procedures, including pinning. Patients who are at extremely high risk or have underlying terminal conditions may benefit from in-line traction in bed and control of pain. With appropriate patient selection, surgical repair or replacement in patients with acute fracture can be accomplished with very acceptable morbidity and mortality. A common problem in the elderly oncology patient is lytic lesions of bone leading to instability. Successful techniques for bone repair using prosthetic devices and radiotherapy have shown improved clinical response and, more importantly, symptomatic improvement. This procedure does not lead to a large number of cures, but does allow patients to become ambulatory. Summary While surgical techniques remain much as they are described in atlases, the philosophy of surgery for cancer in the elderly has evolved in recent years in ways that influence the preparation of the patient for the surgical procedure itself: • Increasingly, patients are being treated in an ambulatory setting, regardless of age. • Increased use of minimally invasive surgical procedures allows more rapid mobilization and return to normal activity, and therefore better functional results. • Patients are being treated concurrently for other medical problems, which are often factors in management decisions. For particular tumors, the following limited surgical procedures may be acceptable: • breast: lumpectomy with axillary dissection • carcinoma of the rectum: transanal resection • carcinoma of the lung: thoracoscopic wide excision (VATS).

References 1. Adkins RB, Scott HW Jr. Surgical procedures in patients aged 90 years and older. South Med J 1984; 77:1357. 2. Baranofsky A, Myers M. Cancer incidence and survival in patients 65 years of age and older. Cancer 1986; 36:27–41. 3. Becker TM, Goodwin JS, Hunt WC et al. Survival after cancer surgery of elderly patients in New Mexico. 1969–1982. J Am Geriatr Soc 1989; 37:155–9. 4. Boring C, Squires T, Tong T. Cancer statistics, 1991. Cancer 1991; 47:28.

Advances in geriatric surgery

725

5. Alexander HR, Turnbull AD, Salamone J et al. Upper abdominal cancer surgery in the very elderly. J Surg Oncol 1991; 47:82–6. 6. Burns GP, Parikh SR. Abdominal surgery in the elderly patient. Clin Geriatr Med 1990; 6:589– 607. 7. Fenyo G. Acute abdominal disease in the elderly. Am J Surg 1982; 143:751. 8. Donegan WL. Operative treatment of cancer in the older person by general surgeons. In: Comprehensive Geriatric Oncology (Balducci L, Lyman GH, Ershler WB, eds). Philadelphia: JB Lippincott, 1992: 151–9. 9. Hoskin MP, Warner MA, Lobdell CM et al. Outcomes of surgery in patients 90 years of age and older JAMA 1989; 261:1909–15. 10. Koruda MJ, Sheldon GF. Surgery in the aged. Adv Surg 1991; 24: 293–331. 11. Morel PH, Egeli RA, Wachtl S, Rohner A. Results of operative treatment of gastrointestinal tract tumors in patients over 80 years of age. Arch Surg 1989; 124:662–4. 12. Patterson WB. Surgical issues in geriatric oncology. Semin Oncol 1989; 16:57–65. 13. Keating HJ 3rd, Lubin MF. Perioperative responsibilities of the physician/geriatrician. Clin Geriatr Med 1990; 6:459–67. 14. Reiss R, Deutsch AA, Eliashiv A. Decision-making process in abdominal surgery in the geriatric patient. World J Surg 1983; 7:522–6. 15. Samet JM, Hunt WC, Key CR et al. Choice of cancer therapy varies with age of patient. JAMA 1986; 255:3385–90. 16. Ziffren SE. Comparison of mortality rates for various surgical operations according to age groups, 1951 to 1977. J Am Geriatr Soc 1979; 27:433. 17. Weitz HH. Noncardiac surgery in the elderly patient with cardiovascular disease. Clin Geriatr Med 1990; 6:511–29. 18. Zollinger RM, Zollinger RM Jr. Atlas of Surgical Operations, 6th edn. New York: MacMillan, 1988. 19. Castell DO. Esophageal disorders in the elderly. Gastroenterol Clin North Am 19:1990; 235– 54. 20. Siegel HI, Laskin KJ, Dabezaies MA et al. The effect of endoscopic laser therapy on survival in patients with squamous-cell carcinoma of the esophagus: further experience. J Clin Gastroenterol 1991; 13: 142–6. 21. Keeling P, Gillen P, Hennessy TP. Oesophageal resection in the elderly. Ann R Coll Surg Engl 1988; 71:34–6. 22. Karl R, Smith S, Fabri P. Validity of major cancer operations in elderly patients. Ann Surg Oncol 1995; 2:107–13. 23. Muechrcke DD, Kaplan DK, Connelly RJ. Oesophagogastrectomy in patients over 70. Thorax 1989; 44:141–5. 24. Sugirnachi K, Matsuzaki K, Kuwano H et al. Evaluation of surgical treatment of carcinoma of the esophagus: 20 years’ experience. Br J Surg 1985; 72:28–30. 25. Orringer MB, Stirling MC. Transhiatal esophagectomy for benign and malignant disease. J Thorac Cardiovasc Surg 1993; 105:265. 26. Feliciano DV, Bitondo CG, Burch JM et al. Emergency management of perforated peptic ulcers in the elderly patient. Am J Surg 1984; 148:764. 27. Fiser WP, Wellborn JC, Thompson BW et al. Age and morbidity of vagotomy with antrectomy or pyloroplasty. Am J Surg 1982; 144:694. 28. Kane E, Fried G, McSherry CK. Perforated peptic ulcer in the elderly. J Am Geriatr Soc 1981; 29:224. 29. McGee GS, Sawyers JL. Perforated gastric ulcers. Arch Surg 1987; 122: 555. 30. Nussbaum MS, Schusterman MA. Management of giant duodenal ulcer. Am J Surg 1985; 149:357. 31. Permutt RP, Cello JP. Duodenal ulcer disease in the hospitalized elderly patient. Dig Dis Sci 1982; 27:1.

Comprehensive Geriatric Oncology

726

32. Bandoh T, Isoyama T, Toyoshima H. Total gastrectomy for gastric cancer in the elderly. Surgery 1991; 109:136–42. 33. Coluccia C, Ricci EB, Marzola GG et al. Gastric cancer in the elderly: Results of surgical treatment. Int Surg 1987; 72:4–10. 34. Edelman DS, Russin DJ, Wallack MK. Gastric cancer in the elderly. Am Surgeon 1987; 53:170–173. 35. Habu H, Endo M. Gastric cancer in elderly patients—results of surgical treatment. HepatoGastroenterol 1989; 36:71–4. 36. Saario I, Salo J, Lempinen M et al. Total and near-total gastrectomy for gastric cancer in patients over 70 years of age. Am J Surg 1987; 154:269. 37. Svartholm E, Larsson SA, Haglund U. Total gastrectomy in the elderly patient. Acta Chir Scand 1987; 153:677–80. 38. Takeda J, Hashimoto K, Tanaka T et al. Gastric cancer surgery in the elderly. Kurume Med J 1992; 39:89–94. 39. Teixeira CR, Haruma K, Teshima H et al. Comparative report on endoscopic and surgical treatment for early gastric cancer in elderly patients. Arquiv Gastroenterol 1992; 29:75–9. 40. Northfield TC, Hall CN. Carcinoma of the gastric stump: risks and pathogenesis. Gut 1990; 31:1217. 41. Toftsgard C. Gastric cancer after peptic ulcer surgery. Ann Surg 1989; 220:159. 42. Whitman ED, Norton JA. Endocrine surgical diseases of elderly patients. Surg Clin North Am 1994; 74:127–44. 43. Miccoli P, Iacconi P, Cecchini GM et al. Thyroid surgery in patients aged over 80 years. Acta Chir Belg 1994; 94:222–3. 44. Delbridge LW, Marshman D, Reeve TS et al. Neuromuscular symptoms in elderly patients with hyperparathyroidism: improvement with parathyroid surgery. Med J Aust 1988; 149:74. 45. Mandelblatt J, Wheat M, Monane M et al. Breast cancer screening for elderly women with and without co-morbid conditions. Ann Intern Med 1992; 116:722–30. 46. Adami H, Malker B, Holmberg L et al. The relation between survival and age at diagnosis in breast cancer. N Engl J Med 1986; 315: 559–63. 47. Adami H, Malker B, Meirik O et al. Age as a prognostic factor in breast cancer. Cancer 1985; 56:898–902. 48. Bergman L, Dekker G, Van Leeuwen F et al. The effect of age on treatment choice and survival in elderly breast cancer patients. Cancer 1991; 67:2227–34. 49. Hunt K, Fry D, Bland K. Breast carcinoma in the elderly patient: an assessment of operative risk, morbidity, and mortality. Am J Surg 1980; 140:339–42. 50. Armaud JP, Schloegel M, Ollier JC et al. Colorectal cancer in patients over 80 years of age. Dis Colon Rectum 1991; 34:896–8. 51. Fitzgerald SD, Longo WE, Daniel GL, Vernava AM. Advanced colorectal neoplasia in the high-risk elderly patient: Is surgical resection justified? Dis Colon Rectum 1993; 36:161–6. 52. Hesterberg R, Schmidt WU, Ohmann C et al. Risk of elective surgery of colorectal carcinoma in the elderly. Dig Surg 1991; 8:22–7. 53. Hobler KE. Colon surgery for cancer in the very elderly. Cost and 3-year survival. Ann Surg 1986; 203:129–31. 54. Lewis AAM, Khoury GA. Resection for colorectal cancer in the very old: Are the risks too high? BMJ 1988; 296:459–61. 55. Payne JE, Chapuis PH, Pheils MT. Surgery for large bowel cancer in people aged 75 years and older. Dis Colon Rectum 1986; 29:733–7. 56. Richards PC. Colorectal cancer in the elderly. Front Radiat Ther Oncol 1986; 20:139–42. 57. Tomoda H, Tsujitani S, Furusawa M. Surgery for colorectal cancer in elderly patients—A comparison with younger adult patients. Jpn J Surg 1988; 18:397–402. 58. Vivi AA, Lopes A, Cavalcanti S de F et al. Surgical treatment of colon and rectum adenocarcinoma in elderly patients. J Surg Oncol 1992; 51:203–6.

Advances in geriatric surgery

727

59. Whittle J, Steinberg EP, Anderson GF, Herbert R. Results of colectomy in elderly patients with colon cancer, based on Medicare claims data. Am J Surg 1992; 163:572–6. 60. Johansen OB, Wexler SD, Daniel N et al. Perineal rectosigmoidectomy in the elderly. Dis Colon Rectum 1993; 36:767–72. 61. Kluger Y, Shiloni E, Jurim O et al. Subtotal colectomy with primary ileocolonic anastomosis for obstructing carcinoma of the left colon: valid option for elderly high risk patients. Israel J Med Sci 1993; 29: 726–30. 62. Vara-Thorbeck C, Garcia-Caballero M, Salvi M et al. Indications and advantages of laparoscopy-assisted colon resection for carcinoma in elderly patients. Surg Laparoscopy Endoscopy 1994; 4:110–8. 63. Rouanet P, Saint Aubert B, Fabre JM et al. Conservative treatment for low rectal carcinoma by local excision with or without radiotherapy. Brit J Surg 1993; 80:1452–6. 64. Connolly MM, Dawson PJ, Michelassi F et al. Survival in 1001 patients with carcinoma of the pancreas. Ann Surg 1987; 206:366–73. 65. Hannoun L, Christophe M, Ribeiro J et al. A report of forty-four instances of pancreaticoduodenal resection in patients more than seventy years of age. Surg Gynecol Obstet 1993; 177:556–60. 66. Sciannameo F, Ronca P, Alberti D, Uccellini R. Therapeutic strategies in the surgical management of pancreatic neoplasms in the elderly. Panminerva Medica 1993; 35:93–5. 67. Huibregtse K, Katon RM, Coene PP, Tytgat GN. Endoscopic palliative treatment in pancreatic cancer. Gastrointest Endosc 1986; 32:334. 68. Yeo CJ, Cameron JL, Maher MM et al. A prospective randomized trial of pancreaticogastrostomy versus pancreaticojejunostomy after pancreaticoduodenectomy. Ann Surg 1995; 222:580–92. 69. Gadzijev E, Pegan V. Extended excision of the ampulla of Vater—a new operative technique for elderly patients. Hepato-Gastroenterol-ogy 1992; 39:475–7. 70. Bismuth H, Castaing D, Traynor O. Resection or palliation: priority of surgery in the treatment of hilar cancer. World J Surg 1988; 12: 39. 71. Ezaki T, Yukaya H, Ogawa Y. Evaluation of hepatic resection for hepatocellular carcinoma of the elderly. Br J Surg 1987; 74:471. 72. Mentha G, Huber O, Robert J et al. Elective hepatic resection in the elderly. Br J Surg 1992; 79:557–9. 73. Nagasue N, Chang YC, Takemoto Y et al. Liver resection in the aged (seventy years or older) with hepatocellular carcinoma. Surgery 1993; 113:148–54. 74. Takenaka K, Shimada M, Higashi H et al. Liver resection for hepato-cellular carcinoma in the elderly. Arch Surg 1994; 129:8:846–50. 75. Saunders K, Tompkins R, Longmire W Jr, Roslyn J. Bile duct carcinoma in the elderly. A rationale for surgical management. Arch Surg 1991; 126:1186–90; discussion 1190–1. 76. Shepherd HA, Royle G, Ross AP et al. Endoscopic biliary endoprosthesis in the palliation of malignant obstruction of the distal common bile duct: a randomized trial. Br J Surg 1988; 75:1166. 77. Speer AG, Cotton PB, Russell RCG et al. Randomized trial of endoscopic versus percutaneous stent insertion in malignant obstructive jaundice. Lancet 1987; 2:57. 78. Nakamura S, Sakaguchi S et al. Aggressive surgery for carcinoma of the gallbladder. Surgery 1989; 106:467. 79. Silk YN, Douglass HO Jr, Nava HR et al. Carcinoma of the gallbladder. The Roswell Park experience. Ann Surg 1989; 210: 751–7. 80. Blumgart LH, Thompson JN. The management of malignant strictures of the bile duct: tumors of the biliary and intrahepatic bile ducts. Curr Prob Surg 1987; 24:81. 81. Stamey TA, McNeal JE. Adenocarcinoma of the prostate. In: Campbell’s Urology, 6th edn (Walsh PC, Retik AB, Stamey TA et al, eds). Philadelphia: WB Saunders, 1992:2829.

Comprehensive Geriatric Oncology

728

82. Adam A, Jager R, McLoughlin J et al. Wall stent endoprosthesis for the relief of prostatic urethral obstruction in high risk patients. Clin Radiol 1990; 42:228–32. 83. Kabalin JN. Urolase laser prostatectomy. Monogr Urol 1993; 14: 23–36. 84. Adolfsson J. Deferred treatment of low grade stage T3 prostate cancer without distant metastases. J Urol 1993; 149:326. 85. Kerr LA, Zincke H. Radical retropubic prostatectomy for prostate cancer in the elderly and the young: complications and prognosis. Eur Urol 1994; 25:305–11; discussion 311–2. 86. Balducci L, Trotti A, Pow-Sang J. Advances and controversies in the prevention and treatment of prostate cancer. Annee Gerontol 1992; 2:97–110. 87. Gibbons RP. Localized prostate carcinoma. Surgical management. Cancer 1993; 72:2865–12. 88. Kursh ED, Rabin R, Persky L. Is cystectomy a safe procedure in the elderly patients with carcinoma of the bladder? J Urol 1977; 118: 40. 89. Skinner EC, Lieskovsky G, Skinner DG. Radical cystectomy in the elderly patient. J Urol 1984; 131:1065. 90. Tachibana M, Deguchi N, Jitsukawa S et al. One-state total cystectomy and ileal loop diversion in patients over eighty years old with bladder carcinoma. Urology 1983; 22:512. 91. Wood DP, Montie JE, Maatman TJ et al. Radical cystectomy for carcinoma of the bladder in the elderly patient. J Urol 1987; 46: 138. 92. Zincke H. Cystectomy and urinary diversion in patients eighty years or older. Urology 1982; 19:139. 93. Rousseau P, Fuentevilla-Clifton A. Urinary incontinence in the aged. Part 2: Management strategies. Geriatrics 1992 47:37–40, 45, 48 [Erratum: 1992; 47:87]. 94. Segura JW. Percutaneous nephrostomy: technique, indications and complications. AUA Update Series, 1993; 12: Lesson 20. 95. McGonigle KF, Lagasse LD, Karlan BY. Ovarian, uterine, and cervical cancer in the elderly woman. Clin Geriatr Med 1993; 9:115–30. 96. Fuchtner C, Manetta A, Walker JL et al. Radical hysterectomy in the elderly patient: analysis of morbidity. Am J Obstet Gynecol 1992; 166:593–7. 97. Ershler WB, Socinski MA, Greene CJ. Bronchogenic carcinoma, metastases, and aging. J Am Geriatr Soc 1983; 31:673–6. 98. O’Rourke MA, Feussner JR, Fiegl P, Laszlo J. Age trends of lung cancer stage at diagnosis. JAMA 1987; 258:921–6. 99. Brucke P. Is lung cancer resection justified in patients aged beyond 70 years? Eur J Cardiothorac Surg 1993; 7:336. 100. Osaki T, Shirakusa T, Kodate M et al. Surgical treatment of lung cancer in the octogenarian. Ann Thorac Surg 1994; 57:188–92, discussion 192–3. 101. Plotrlikov VI, Kulish VL, Malaev SG. Surgery for elderly patients with cancer of the cardia. Semin Surg Oncol 1992; 8:41–5. 102. Roxburgh JC, Thompson J, Goldstraw P. Hospital mortality and long term survival after pulmonary resection in the elderly. Ann Thorac Surg 1991; 51:800–3. 103. Sherman S, Guidot CE. The feasibility of thoracotomy for lung cancer in the elderly. JAMA 1987; 258:927–30. 104. Shiracusa T, Tsutsui M, Iriki N et al. Results of resections for bronchogenic carcinoma in patients over the age of 80. Thorax 1989; 44:189–91. 105. Thomas P, Sielezneff I, Ragni J et al. Is lung cancer resection justified in patients aged over 70 years? Eur J Cardiothorac Surg 1993; 7:246–50; discussion 250–1. 106. DeMaria LC, Cohen HJ. Characteristics of lung cancer in elderly patients. J Gerontol 1987; 42:540–5. 107. Teeter SM, Holmes FF, MacFarlane MJ. Lung cancer in the elderly population. Influence of histology on the inverse relationship of stage to age. Cancer 1987; 60:1331–6. 108. Reilly JJ Jr, Mentzer SJ, Sugarbaker DJ. Preoperative assessment of patients undergoing pulmonary resection. Chest 1993; 103(4 Suppl):342S–5S.

Advances in geriatric surgery

729

109. Gebitekin C, Gupta NK, Martin PG et al. Long-term results in the elderly following pulmonary resection for non-small cell lung carcinoma. Eur J Cardiothorac Surg 1993; 7:653– 6. 110. Ishida T, Yokoyama H, Kaneko S et al. Long term results of operation for non-small cell lung cancer in the elderly. Ann Thorac Surg 1990; 50:919–22. 111. Whittel J, Steinberg EP, Anderson GF, Herbert R. Use of Medicare claims data to evaluate outcomes in elderly patients undergoing lung resection for lung cancer. Chest 1991; 100:729– 34. 112. Barzan L, Veronesi A, Caruso G et al. Head and neck cancer and aging: a retrospective study in 438 patients. J Laryngol Otol 1990; 104:634–40. 113. McGuirt WF, Loevy S, McCabe BF et al. The risks of head and neck surgery in the aged population. Laryngoscope 1977; 87:1378–82. 114. Harries M, Lund VJ. Head and neck surgery in the elderly: a maturing problem. J Laryngol Otol 1989; 103:306–9. 115. John AC, Vaughan ED. Laryngeal resection in patients of seventy years and older. J Otol 1980; 94:629–35. 116. Johnson JT, Rabuzzi D, Tucker HM. Composite resection in the elderly: a well tolerated procedure. Laryngoscope 1977; 87: 1509–15. 117. Jun MY, Strong EW, Saltzman EI et al. Head and neck cancer in the elderly. Head Neck Surg 1983; 5:376–82. 118. Kowalski LP, Alcantara PS, Magrin J et al. A case-control study on complications and survival in elderly patients undergoing major head and neck surgery. Am J Surg 1994; 168:485– 90. 119. Linn BS, Robinson DS, Klimas NG. Effects of age and nutritional status on surgical outcomes in head and neck cancer. Ann Surg 1988; 207:267–73. 120. Loewy A, Huttner DJ. Head and neck surgery in patients past 70. Arch Otol 1984; 84:523–6. 121. Martin H, Rasmussen LH, Perras C. Head and neck surgery in patients of the older group. Cancer 1955; 8:707–11. 122. McGuirt WF, Davis SP rd: Demographic portrayal and outcome analysis of head and neck cancer surgery in the elderly. Arch Otolaryngol—Head Neck Surg 1995; 121:150–4. 123. Morgan RF, Hirata RM, Jacques DA et al. Head and neck surgery in the aged. Am J Surg 1982; 144:449–51. 124. Morton RP, Benjamin CS. Elderly patients with head-and-neck cancer. Lancet 1990; 335:1597. 125. Robinson DS. Head and neck considerations in the elderly patient. Surg Clin North Am 1994; 74:431–9. 126. Sanders AD, Blom ED, Singer MI et al. Reconstructive and rehabilitative aspects of head and neck cancer in the elderly. Otol Clin North Am 1990; 23:1141–56. 127. Tucker HM. Conservation laryngeal surgery in the elderly patient. Laryngoscope 1977; 87:1995–99. 128. Amacher AL, Bybee DE. Toleration of head injury by the elderly. Neurosurgery 1987; 20:954. 129. Caruso R, Salvati M, Cervoni L. Primary intracranial arachnoid cyst in the elderly. Neurosurg Rev 1994; 17:195–8. 130. Gijtenbeek JM, Hop WC, Braakman R, Avezaat CJ. Surgery for intracranial meningiomas in elderly patients. Clin Neurol Neurosurg 1993; 95:291–5. 131. Howard MA, Gross AS, Dacey RG et al. Acute subdural hematomas: an age-dependent clinical entity. J Neurosurg1989; 71:858. 132. Jamjoom A, Nelson R, Stranjalis G et al. Outcome following surgical evaluation of traumatic intracranial hematomas in the elderly. Br J Neurosurg 1992; 6:27. 133. Kelly PJ, Hunt C. The limited value of cytoreductive surgery in elderly patients with malignant gliomas. Neurosurgery 1994; 34: 62–6; discussion 66–7.

Comprehensive Geriatric Oncology

730

134. Maurice-Williams RS, Kitchen ND. Intracranial tumors in the elderly: the effect of age on the outcome of first time surgery for meningiomas. Br J Neurosurg 1992; 6:131–7. 135. Maurice-Williams RS, Kitchen N. The scope of neurosurgery for elderly people. Age Ageing 1993; 22:337–42. 136. Nishizaki T, Kamiryo T, Fujisawa H et al. Prognostic implications of meningiomas in the elderly (over 70 years old) in the era of magnetic resonance imaging. Acta Neurochir 1994; 126:59–62. 137. Popovic EA, Kelly PJ. Stereotactic procedures for lesions of the pineal region. Mayo Clin Proc 1993; 68:965–70. 138. Ramsay HA, Luxford WM. Treatment of acoustic tumors in elderly patients: Is surgery warranted? J Laryngol Otol 1993; 107:295–7. 139. Rubin G, Ben David U, Gornish M, Rappaport ZH. Meningiomas of the anterior cranial fossa floor. Acta Neurochir 1994; 129:26–30. 140. Samii M, Tatgiba M, Matthies C. Acoustic neurinoma in the elderly: factors predictive of postoperative outcome. Neurosurgery 1992; 31:615–9; discussion 619–20. 141. Umansky F, Ashkenazi E, Gertel M, Shalit MN. Surgical outcome in an elderly population with intracranial meningioma. J Neurol Neurosurg Psychiatry 1992; 55:481–5. 142. Jones EW. Some special skin tumors in the elderly. Br J Dermatol 1990; 122(Suppl 35):71–5. 143. Ries WR, Aly A, Vrabec J. Common skin lesions of the elderly. Otol Clin North Am 1990; 23:1121–39. 144. Perez ED. Hip fracture: physicians take more active role in patient care. Geriatrics 1994; 49:31–7.

35 Perioperative considerations in the geriatric oncology patient Rafael Miguel, Hector Vila Introduction Setting arbitrary age limits for the geriatric patient population is somewhat difficult. These limits are arbitrary in that change in the age that classifies a patient ‘geriatric’ is continual. For example, in the early 20th century, surgery on patients above the age of 50 was considered dangerous and not recommended.1 Indeed, in 1927, Alton Ochsner2 suggested that ‘an elective operation for inguinal hernia in a patient older than 50 years is not justified’. This impression has certainly changed. By 1985, Catlic3 reported six patients over the age of 100 who underwent anesthesia and surgery. His impression at the time reflected the changing mood in society and medicine. He stated that ‘elective surgery should not be deferred nor emergency surgery denied, even for centenarians, on the basis of chronologic age’. Data from the US Census Bureau have shown changing demographics of the population (Figure 35.1). Furthermore, as the population ages, this will have a significant impact on those patients going to surgery. Since patients going to surgery tend to be older rather than young, a greater portion of patients of any hospital’s operating rooms will be occupied by geriatric patients. Common knowledge would dictate that

Figure 35.1 US demographics.

Comprehensive Geriatric Oncology

732

older patients have a markedly higher incidence of perioperative complications, even death, when compared with their younger counterparts. However, little information is available that implicates age per se as a risk factor. The most important consideration in the elderly is to search for and identify associated abnormalities. These may occur secondary to the natural decline of basic organ function due to the aging process. For this reason, a basic understanding of the physiologic changes of aging that impact perioperative management is useful, whether a patient undergoes an inpatient or an outpatient operation.4 The latter is important since more mandates are being received from Medicare and third-party payors for outpatient and same-day-admit procedures as greater emphasis is being placed on decreasing costs. This emphasis needs to be directed to preoperative evaluation during clinic visits, so that associated abnormalities may be identified and optimized, if present. It is hoped that a thorough understanding of the physiologic changes commonly found in the elderly, and tailoring their anesthetic technique and perioperative management, will lead to improved outcomes. Physiologic changes of aging and their anesthetic implications General considerations There is a significant decrease in body mass with aging, which is due to a decrease in the number of functioning parenchymal cells and an increase in interstitial substances. This accounts for a generally accepted decrease in basal metabolic rate (BMR) of 1% per year after the age of 30. There is a significant change in the composition of body fluids. Total body water decreases by 10–15%. This change leads to a drop from 60% total body water in younger patients to 45% in the elderly. Since the extracellular body fluid volume remains the same, the

Figure 35.2 Age and intraoperative rectal temperature.

Perioperative considerations in the geriatric oncology patient

733

drop is primarily due to a decrease in intracellular fluid. Total plasma proteins remain unchanged, although the relative proportions of different proteins change significantly. Albumin concentration decreases, while globulin concentration increases. Regulation of temperature becomes more difficult, since there is a decrease in the number of skin capillaries. This causes a decreased capacity for vasoconstriction and vasodilatation. Sweat gland atrophy contributes to a decrease in the capacity to sweat and release heat. These changes in the elderly render them unable to adapt to ambient temperature changes, making them especially susceptible to hypo- and hyperthermia. Decreases in body temperature are routine in the anesthetized surgical patient, but that drop is accentuated in the elderly (Figure 35.2). It has been shown that improvements in morbidity can be achieved by decreasing perioperative hypothermic events. Kurz et al5 found a decrease in surgical wound infections and shorter hospitalizations by maintaining normothermia perioperatively. Frank et al6 demonstrated that in patients with cardiac risk factors, maintenance of perioperative normothermia was associated with a lower incidence of morbid cardiac events (i.e. unstable angina/ischemia, cardiac arrest, or myocardial infarction) as well as ventricular tachycardia when compared with hypothermic patients. Particular attention needs to be paid to perioperative temperature monitoring and to actively warming and cooling patients as necessary. Structural characteristics The musculoskeletal system undergoes dramatic changes in the elderly. Some of the structural changes and their management are listed in Table 35.1. The elderly patient generally adopts a posture of generalized flexion. The thoracic spine becomes kyphotic secondary to degenerative changes in the vertebral column, intravertebral discs, and paraspinal tendons and muscles. The amount of osteoporosis seen is progressive and is of staggering importance. Females older than 45 demonstrate osteoporosis, and it is estimated that by the age of 65, 33% of all females have vertebral fractures and by the age of 81, one-third of all women and one-sixth of all men will have had a hip fracture.7 Osteoporosis becomes a problem in males above the age of 55. While the bone is qualitatively normal, whatever bone there is, is less dense and there is less of it. The patient is more susceptible to bony fractures with otherwise-negligible trauma. At present, it is unknown whether this is part of the natural aging process or a disease entity in and of itself. Osteoarthritic changes are seen throughout the body and joint changes are universal with increased aging. There is thinning of joint cartilage, a loss of joint fluid, and hardening of joint capsules with proliferation of adjacent bones. This leads to osteophyte formation. Skeletal muscle wasting is seen secondary to a decrease in the number and size of individual muscle fibers. Encouraging results, however, came from a study in which it was pointed out that nonagenarians could significantly increase strength and endurance by progressive weight training.8 There is degradation of motor endplates. The generalized wasting with loss of skin elasticity, vascularity, and tensile strength is accompanied by a decrease in subcutaneous fat. This decrease is accentuated with age. This makes the patient particularly vulnerable to even minor trauma. Because of this loss of support structures and subcutaneous tissue, great attention should be paid to

Comprehensive Geriatric Oncology

734

Table 35.1 General and structural changes in the elderly Changes

Implications

Management

Loss of functioning parenchymal cells; decreased number of skin capillaries; sweat gland atrophy

10–15% drop in basal metabolic rate (BMR); decreased ability to vasoconstrict or vasodilate

Actively warm or cool as necessary

Osteoarthritis

Decreased mobility of joints, neck, and mouth

Position while awake, evaluate airway access

Loss of muscle and subcutaneous fat; bony resorption

Ease of developing pressure trauma; facial anatomy changes

Pad pressure points; dentures/oral packs may help airway support

pressure points in the perioperative period. Padding with sheepskin, foam, or other suitable materials is indicated. Many elderly patients with fragile bones and a limited range of motion should be positioned awake to avoid skeletal injury.9 Skin and muscular atrophy lead to problems with cannulation of veins, which are more fragile and mobile. Changes in orofacial structures contribute to a loss of elasticity and tone over the mouth muscles. There is significant resorption of alveolar bone and weakening of support for dental structures. This is commonly accompanied by lost or loose teeth. The anesthetic implications of these structural changes are many. Airway management is primarily affected by loss of orofacial support. Difficulty in maintaining a patient’s airway can be encountered. The question remains whether dentures should be left in or out. While dentures are commonly removed prior to anesthesia for fear of losing them or causing airway obstruction under anesthesia, they may improve the ability to maintain a good seal while performing bag-mask ventilation. It may be advantageous to leave dentures in place. Similarly, since elderly patients have significant resorption of their facial structures, gauze may be used under the lips to increase facial bulk and facilitate a tight-fitting seal around the mask and face. Close examination of the oral cavity needs to be done to identify loose teeth and to remove any dislodged teeth. Neck and jaw mobility are restricted in the elderly, and should be evaluated preoperatively. This evaluation is important, since many patients will report pain on positioning, which would otherwise appear to be appropriate and indeed may reveal the presence of vascular abnormalities, such as carotid stenosis. This may manifest as lightheadedness, dizziness, or even fainting when changing head position in the awake patient. Waiting until the patient is asleep to assess the position for operation will obviously fail to reveal problems. This evaluation becomes even more important when one considers the degree of cervical osteoarthritis seen in the elderly. This results in a decrease in size of transverse process canals through which the vertebral artery passes. It can be easily understood how manipulation of the head can further impair flow, leading to vertebrobasilar insufficiency and global cerebral ischemia.

Perioperative considerations in the geriatric oncology patient

735

Cardiovascular system The cardiovascular system presents the most important age-related physiologic changes that affect anesthetic management. While once thought to be part of the natural aging process, many of the changes seen in the cardiovascular system are now considered to be related to preexisting diseases in the patient and lifestyle changes associated with prolonged deconditioning.10 The heart demonstrates increased amounts of subpericardial fat. There are patches of fat in the endocardium and capillary muscles, with increased fibrotic thickening and rigidity of all valves. There is left atrial enlargement, an increase in left ventricular (LV) wall thickness, and a decrease in LV cavity size (Table 35.2). The ventricular conduction system is invaded by fibrosis, which causes an increased frequency of arrhythmias. Vessel walls are less resilient, so there is a lower capacity to accommodate for

Table 35.2 Cardiorespiratory changes in the elderly Changes

Implications

Management

Fibrosis of sinoatrial node; ventricular conduction

Arrhythmias; decreased heart rate

Continual ECG monitoring

Atherosclerotic vessel walls

Decreased BP accommodation; compensatory LVH

Avoid rapid changes in blood volume

Myocardial fiber atrophy; Decrease in CO; increased decrease in LV cavity; circulation time; decreased ejection valvular calcification fraction

Afterload reduction, avoid cardiodepressant medication; titrate medications

Calcific, arthritic thoracic Inefficient expiration; RV increases joints, bronchi, and chest by 50%; VC/IC decreases; dead wall space ventilation increases

Maximize preoperative pulmonary function; support ventilation postoperatively

CV increases; MVV mismatch, resting decreases; chemoreceptor Increased P O lower; less ventilatory reserve; a 2 response decreases response to PaCO2 increase/PaO2 decrease blunted

Supplemental O2; monitor ETC02/SPO2; always R/O in postoperative delirium, light sedation/narcosis

Abbreviations: ECG, electrocardiogram; BP, blood pressure; LVH, left ventricular hypertrophy; LV, left ventricle; CO, cardiac output; RV, residual volume; VC/IC, vital capacity/inspiratory capacity; CV, closing volume; MVV, maximum voluntary ventilation; , ventilation/perfusion; PaO2, partial pressure of oxygen in arterial blood; PaCO2, partial pressure of carbon dioxide in arterial blood; ETCO2/SPO2, endotracheal carbon dioxide concentration/blood oxygen saturation.

wide changes in arterial pressure. While cardiac output (CO) averages approximately 6.5 l/min at age 25, there is a progressive decrease to 50% of that value by age 80.11 This is primarily due to a decrease in stroke volume and heart rate. There is increasing evidence that this decrease may occur only in patients who have adopted a sedentary lifestyle or are affected by disease.12 Circulation time is increased by 33%, which facilitates patient

Comprehensive Geriatric Oncology

736

overdosing, especially when considered in combination with a decrease in blood flow to metabolic end-organs. There is a decrease in systolic blood pressure, with an increase in diastolic pressure. Longstanding disease, such as hyper-tension or congestive heart failure, will greatly exacerbate all of the aforementioned cardiovascular changes. Therefore, maintaining near-normal vital signs, maintaining satisfactory oxygenation, and producing a favorable myocardial O2 supply-to-demand ratio are of utmost importance. Pulmonary system The pulmonary system is important in anesthesia because of the increased need for homeostasis and gas exchange and the involvement of the lung with uptake and elimination of anesthetic gases. Alveoli are affected by the aging process, and septal membranes weaken and are often disrupted. This causes a significant coalescence (i.e. an increase in size with a decrease in number) of alveoli in the elderly. Calcific and arthritic changes are seen in the cartilage and joints of the thorax and bronchi. Ventilatory muscles become weaker, and therefore there is increased rigidity of lung parenchyma, tracheobrochial tree, and thorax (Table 35.2). Inspiration becomes more inefficient; there is a decrease in chest wall mobility and muscle strength. Expiration becomes more inefficient because of a decrease in elastic recoil. All of these changes significantly affect lung volumes. Total lung capacity decreases by approximately 10%. Residual volume (RV) increases by approximately 50% at the expense of vital capacity (VC) and inspiratory capacity (IC). These decrease by 30% and 70%, respectively. Anatomic dead space increases with age. At age 20, approximately 20% dead space ventilation is seen. This doubles by the time the patient is 60. There is a decrease in tidal volume and minute ventilation, and the ventilatory response to a CO2 challenge is impaired. The closing volume (CV), the volume of lung in which airways collapse, increases.13 This may be the most important change in the pulmonary system. When the CV is greater than the functional residual capacity, the CV will be within normal tidal volumes, so some airways will be collapsed until inspiration. At approximately 36 years of age, the CV is greater than the functional residual capacity in the supine patient. At age 60, this occurs in the sitting position. Obviously, this will include essentially all positions, which will lead to an

Perioperative considerations in the geriatric oncology patient

737

Figure 35.3 Age related decrease in the partial pressure of oxygen in arterial blood (PaO2). (FiO2, fractional concentration of inspired oxygen.) increase in ventilation perfusion ( ) mismatch units and decreased partial pressure of oxygen in arterial blood (PaO2) (Figure 35.3). The ideal PaO2 value can be calculated by the following formula: PaO2=109 mmHg–(0.43×age in years) The anesthetic implication of these changes in the pulmonary system is evidenced by the increase in pulmonary problems seen perioperatively in elderly patients. While the operative mortality rate for lobectomy in younger patients is 2–4%, and that for pneumonectomy is up to 10%, in the elderly patient with poor lung function these operative mortality rates may exceed 15 and 30%, respectively.14 Lower postoperative PaO2 values are seen in these patients. In addition to all of these changes in the ventilatory system, the effects of positive-pressure ventilation, endotracheal intubation, decrease in mucociliary transport, central respiratory depression, and residual neuromuscular blockade have to be considered. Particularly important to the respiratory system are the influence that the latter two have perioperatively. The use of perioperative opioids would be expected to have a significantly more intense and long-lasting effect in elderly patients. Scott and Stanski15 have found dose requirements of fentanyl and alfentanil to decrease by 50% from the age of 20 to 85. Nervous system The weight of the brain decreases to 80% of peak weight secondary to neuron loss in the cerebellum, cerebral cortex, and thalamus. The most rapid reduction in gray matter tissue mass and the most rapid increase in compensatory cerebrospinal fluid occurs after the

Comprehensive Geriatric Oncology

738

sixth decade. The most metabolically active cells (those producing neurotransmitters) decrease by the greatest amount, with up to 50% disappearing. This results in chemical alterations that contribute to the decrease in central nervous system (CNS) function. These include a decrease in the rate of conversion of tyrosine and dopa. The activities of monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) are increased.16 In combination, these contribute to an overall decrease in catecholamines. Serotonin synthesis is decreased and its catabolism is increased. Cholinesterase and acetylcholine activity is decreased. With this overall decrease in CNS activity, there is a corresponding decrease in anesthetic requirements. For example, greater pain relief may be achieved from a given dose of agent and the patient will be able to tolerate a less than perfect regional anesthetic. Fear of the development of significant confusion with supplemental sedation may steer many anesthesiologists away from regional anesthetics. The well-described ‘sundowner syndrome’, which occurs when sedating elderly patients and maintaining them in poorly lit areas leading to hallucinations, is a real concern. Two avenues may be taken in treating this syndrome: heavily sedate the patient or withdraw all sedative medications. The present author favors the latter. However, one must never lose sight of supplying pain relief during the immediate postoperative period despite the desire to enhance mental clarity. Genitourinary system Morphologic changes are seen in the genitourinary system after the age of 40. A progressive decrease in renal mass is observed, with a great loss of cortex and medulla. There are intrarenal vascular changes. There is a decrease in cortical blood flow, and in the medulla there is a progressive shunt contributing to a more non-perfused medulla. After 40, there is a 10% per decade decrease in renal blood flow. Primarily, glomerular filtration decreases progressively to 90% to 50% of what it was at age 20. Blood urea nitrogen (BUN) also increases in a linear fashion. At age 20, 30, and 40, it is 10, 13, and 20mg/100ml, respectively. Creatinine clearance decreases by 50% in patients above the age of 65, but is matched by a decrease in creatinine production, and thus serum creatinine remains un-changed.17 Concentrating capacity decreases, and so the capacity to conserve sodium and excrete acid is diminished.18 There is difficulty compensating for acute acidosis, be it respiratory or metabolic. The anesthetic considerations of these renal changes are that the renal excretion of medications administered perioperatively is decreased. This is another reason to decrease anesthetic medication doses. Furthermore, while renal function is generally maintained to prevent uremia, the reserve capacity to compensate for fluid overload or dehydration, congestive heart failure, or sodium loads is impaired and can easily lead to acute renal failure. The direct effect of general anesthesia on the kidneys is relatively small when compared with the combined effect that general anesthesia and surgery have in decreasing renal blood flow and glomerular filtration rate (GFR) through the reninangiotensin system.19,20 The decreases in renal blood flow and GFR depend on the type of anesthesia, being greatest for inhalational anesthetics (e.g. nitrous oxide), less so for narcotic techniques, and less so still for regional anesthetics. Oliguria is the rule rather than the exception during anesthesia and surgery, and does not necessarily imply that

Perioperative considerations in the geriatric oncology patient

739

renal damage is occurring, although it should not be ignored. It is imperative that brisk urine output be maintained perioperatively. Maintenance of a urine flow of at least 0.5ml/kg is mandatory. Postoperative confusion and lethargy may be related to medication or hypoxemia, but could also be secondary to water intoxication, and this should always be included in the differential diagnosis. Acute renal failure accounts for 20% of perioperative deaths among elderly surgical patients.21 Gastrointestinal system With aging, there is significant atrophy in the stomach, accompanied by a decrease in acid secretion. The rate of gastric emptying decreases. There is progressive salivary gland atrophy. While there is no specific age-attributable deterioration in liver function, there is some deterioration secondary to decrease in cardiac output. Additionally, CNS disease such as stroke, Parkinson’s disease, dementia, and medications can cause swallowing dysfunctions that increase mortality and morbidity.22 The implications of these changes for anesthesia are important. Since there is a significant decrease in gastric emptying, there is an increase in gastric residual volume in the elderly. This emphasizes the need for more consideration regarding the time from last oral intake. It is not uncommon to have regurgitation and subclinical aspiration occur while mask ventilation is done in the elderly. A decrease in gastroesophageal sphincter tone accompanies the aging process, and may contribute to this complication. The elderly patient essentially survives with a chronic xerostomia. Therefore, drying agents to decrease saliva production are much less indicated in the elderly than in their younger counterparts. Endocrine system There is a 25% decrease in the weight of the pituitary gland by the age of 80, but no significant alterations of secretion is attributable to age. The adrenocorticotropic hormone (ACTH) response relative to stress is not affected. Adrenal function and circadian rhythm are maintained well. Thyroid function is decreased, but does not appear to require treatment. Myxedema is probably the most common thyroid disease of the elderly, but is often confused with the aging process per se. Hyperthyroid disease is uncommon in the elderly, but accounts for 10–17% of all patients with thyrotoxicosis. Parathyroid function remains normal. Deterioration in oarian function is probably the most significant endocrine function change seen in females. Estrogen concentration is one-third to onehalf of that in women in their 20s. Testosterone levels fall and decreased spermatogenic activity is seen in men above the age of 65. The endocrine pancreas is significantly affected. This is manifested by the fact that diabetes mellitus is present in 10% of all patients above the age of 65. The urinary threshold for glucose increases, and so urinary glucose testing is not reliable. It correlates with much higher serum glucose levels then the 160mg/dl concentration seen in younger patients.

Comprehensive Geriatric Oncology

740

Pharmacologic changes in the elderly Perioperatively, a multitude of medications are given, so knowledge of the differences in behavior of commonly used drugs is indicated. Furthermore, the elderly comprise approximately 12% of the general population, yet they receive 30% of all prescriptions. Over-the-counter medications are used by almost 70% of the elderly, compared with 10% of the general adult population.23 Understanding the need for a specialized prescription and differences in behavior of medications is essential for successful perioperative management. Distribution phase There is a decrease in total body weight and skeletal muscle mass in the elderly (Table 35.3). A dose regimen based on a per-kilogram basis will result in higher and more prolonged blood tissue levels, since most medications are distributed over lean body mass. For example, diazepam has a half-life of 20 hours at 20 years of age. By the time the patient is 80, this is increased to 90 hours. This accounts for an increased depressant effect for days after a single dose of diazepam. In addition to the more prolonged effects, a more intense effect from a given dose can be expected. Bell et al24 found that the dose of midazolam required to induce ptosis in a 20-year-old patient was 10mg, yet the same effect was attained with 2mg in patients aged 85. The relative increase in total body fat will result in accumulation and prolongation of fat-soluble medications and inhaled anesthetic agents. All highly protein-bound medications (e.g. sodium thiopental and meperidine) will exhibit higher free-drug concentrations secondary to a decrease in serum albumin, which is compounded by the smaller initial volume of distribution seen in the elderly. The decrease in cardiac output will delay delivery of drug to end-organs. This effect will also decrease the removal of medications, increasing the possibility of overdosing and prolongation of effects. Biotransformation The capacity to change lipid-soluble medications to water-soluble forms is diminished as liver mass and liver blood flow decreases, and so excretion will be slower. Esterase activity is lower, and so there is an increased duration of succinylcholine and ester local anesthetics (e.g. tetracaine and 2-chloroprocaine). There is a decrease in the number of receptors, as well as changes in receptor states, which leads to a decreased responsiveness to agents such as atropine, which produces a lower tachycardic response. The need for muscle relaxation in many operations makes the choice of the appropriate agent an important consideration. There is a small decrease in succinylcholine requirements secondary to a decrease in plasma cholinesterase level and a decrease in the number of peripheral nerve axons.25 Vecuronium, atracurium, mivacurium, rocuronium, and cisatracurium are less affected by the aging process. The initial dose remains unchanged, and a decrease in distribution in the elderly

Perioperative considerations in the geriatric oncology patient

741

Table 35.3 Pharmacologic changes in the elderly Changes

Implications

Management

Decreases in total body water and muscle mass

Higher, more prolonged blood/tissue levels

Decrease doses of medications greater than a function of body weight

Decreases in liver parenchyma and blood flow

Conversion of fat-soluble to watersoluble forms impaired

Some decrease in dose; caution with prolonged effects

Increase in total body fat; decrease in serum albumin

Greater accumulation of fat-soluble medications; higher protein-bound free-drug concentration; more prolonged effects

Decrease doses of fat-soluble (e.g. fentanyl and inhaled agents) and highly protein-bound (e.g. thiopental and morphine medications)

offsets the decrease in clearance rate, and so their half-life is virtually unchanged or moderately increased. Anesthetic management Premedication The more elderly and ill the patient, the less sedation is necessary. Often, the elderly patient will have a slightly clouded mental status, which would be sufficient for preoperative sedation. This should not be further jeopardized by adding sedative or narcotic medications. Consideration should be given to the fact that elderly patients tolerate hospital experiences much better than their younger counterparts. They are accustomed to hospital visits and tend to be more tolerant of invasive procedures than younger patients. A small dose of a short-acting anxiolytic (e.g. midazolam 1–2 mg intravenously) can produce adequate sedation and amnesia for a longer period than in younger patients (Figure 35.4). Midazolam may occasionally precipitate hostility instead of tranquility. One study reported an incidence of paradoxical events of 10.2%, with the only independent predictor being an age older than that of the entire study group. Flumazenil 0.2–0.3 mg (range 0.1–0.5 mg) effectively stopped the midazolam-induced paradoxical activity within 30 seconds.26 Preoperative opioids should be reserved for those patients undergoing potentially painfiil procedures before induction (central venous pressure (CVP)/Swan-Ganz line insertion, epidural catheter placement, etc.). In-depth inquiry should be made of the elderly patient regarding drug use—both prescription and over-the-counter. Most drugs will be continued throughout the perioperative period. In general, all cardiovascular

Comprehensive Geriatric Oncology

742

Figure 35.4 Aging and pharmacokinetics of midazolam. Table 35.4 Perioperative diabetic management • At home (or in hospital) on the morning of surgery –

Glass of juice

–

NPO for solids/milk products

–

No regular insulin

–

50% long-acting insulin

–

Carry hard candy

• Preoperative holding area –

Start i.v. and piggyback glucose at 5–10 g/h

–

Measure blood glucose, K+, urine glucose/ketones

• Intraoperative –

Draw periodic glucose (q2–4h)

–

Treat hyperglycemia with i.v. regular

• Postoperative

Perioperative considerations in the geriatric oncology patient

–

Draw PACU blood glucose, K+, urine glucose/ketones

–

‘Sliding scale’

743

medications except diuretics should be continued through surgery. The elderly commonly suffer from diabetes and perioperative management of their disease begins prior to arrival at the hospital (Table 35.4). While most patients receive ‘routine’ NPO (‘nil per os’) orders, these may not be appropriate in the diabetic. A glass of juice (e.g. apple or pulpfree orange) is necessary alimentation in a modified fasting preoperative state. Insulin dose is reduced. No regular insulin is given on the morning of surgery, and 50% of the long-acting dose is given. A supplemental D5W infusion is started at 50–75 ml/hour. Serial blood sugars should be checked and treated with intravenous regular insulin aliquots as necessary. While there has been much discussion regarding the long duration of some of the oral hypoglycemics and the expectation that the patient will be eating soon, it is more prudent that oral hypoglycemics be withheld. Induction agents Sodium thiopental requirements are decreased by 25–75%. There is an increase in onset time secondary to a decrease in cardiac output and an increase in circulation time. There is an initial higher serum concentration secondary to a decrease in the volume of distribution. The elimination half-life is dramatically prolonged from 6–12 hours to 13– 25 hours. Etomidate is a hemodynamically stable induction drug. Its clearance depends on hepatic blood flow, which may result in an increase in its elimination half-life. While a single induction dose of sodium thiopental may have prolonged effects in the elderly, more efficient short-acting alternatives are available. Propofol has the most rapid recovery profile of the induction agents, with few side-effects. The dose needs to be decreased, or significant cardiovascular depression will be seen. The drop in blood pressure may be greater than what is seen with sodium thiopental secondary to the absence of a reflex tachycardia. The drop in blood pressure is primarily due to a negative inotropic effect with little change in systemic vascular resistance. Narcotics play an important role in anesthetic and postoperative pain management. Elderly postoperative patients have an increased duration of analgesia and an increase in sensitivity as the drug free-fraction (i.e. non-protein-bound) is increased. This allows a significant reduction in narcotic dose. Significant pharmacokinetic changes have been shown with fentanyl.27 Beta half-lives for fentanyl and its analogues (i.e. alfentanil and sufentanil) are significantly prolonged. The 50% decrease in age-related requirements is also due to increased brain sensitivity.28 Attention should be paid to cardiovascular responses to intubation. Elevation of heart rate and left ventricular end-diastolic pressure are two major determinants of myocardial oxygen consumption, and should be avoided if possible. The addition of a small amounts of opioids decreases the dose of the induction drug, and will decrease the hypertensive and tachycardic response seen with laryngoscopy and endotracheal intubation. Other agents, such as esmolol and nitroglycerin, have been used for the same effect with some success. Muscular atrophy leads to a decrease by 33% in the dose of muscle relaxants that needs to be used. Similarly, any residual neuromuscular blockade is more significant,

Comprehensive Geriatric Oncology

744

since the remaining end-plates cannot increase whatever function needs to be compensated. Anesthetic technique No specific technique has been documented to demonstrate significant superiority over another. Every technique should be considered dangerous and can be misused. Cohen et al29 found that advanced age, male sex, large operations, preoperative condition, intraoperative complications, and emergency surgery were major determinants of morbidity and mortality. They found that narcotic-based anesthetics seemed to be associated with higher mortality; however, this may be due to a narcotic technique being a more popular choice in higher-risk patients. Other multicenter studies have yielded similar results.30 Induction and maintenance doses of all analgesic and anesthetic medications should be significantly decreased in the elderly. Elderly patients tend to drop their blood pressure more on induction and increase it more on skin incision than their younger counterparts. This increased hemodynamic instability is secondary to decreases in blood volume and blood vessel reactivity. The decreased efficiency of the baroflex response and increased adrenergic hormonal response to stimulation make the availability of more rapid and shorter-acting agents more useful in medication titration. Of all the anesthetic techniques, local anesthetic infiltration with a field block is the safest. Unfortunately, it is useful in very few instances. The inhalational anesthetic requirement, defined by the minimum alveolar concentration (MAC), is affected by the aging process, and is decreased by 25–75%.31 For example, the isoflurane MAC in the newborn is 1.3%, whereas in the 70-year-old patient it is 0.9%. Desflurane, a recent introduction to the inhalation armamentarium, has the lowest metabolization (0.02%) of all of the inhaled anesthetic agents. Since it undergoes less degradation than any of the other inhaled agents, produces less cardiac depression, and offers a more rapid recovery profile due to its insolubility, it is an attractive choice in the elderly. The bispectral index (BIS) monitor measures the sedative component of the anesthetic state and can be particularly useful in guiding titration of drugs in the elderly. Age-related electroencephalogram differences exist in the normal population, but have been found not to affect the BIS, which correlates with depth of sedation independently of age.32 General versus regional anesthesia: Is outcome changed? In 1984, Shulman et al33 demonstrated improvement in pulmonary function testing after thoracotomy utilizing epidural anesthesia with postoperative epidural opioids, as compared with a narcotic-based general anesthetic and intravenous opioids postoperatively. This study raised the possibility that a regional anesthetic may have advantages over a general anesthetic, and may possibly influence outcomes. This was studied in 1987 by Yeager et al34 in high-risk surgical patients. They found that a variety of endpoints such as heart failure, respiratory failure, infections, intubation time, hospital cost, physician cost, and, most importantly, mortality were improved when utilizing a regional anesthetic with postoperative spinally administered opioids. Unfortunately,

Perioperative considerations in the geriatric oncology patient

745

Yeager et al terminated their study early since they saw a change in mortality and felt that they could not ethically continue. Why these differences were seen is still left open to question. Part of the reason may be the effect of epidural opioids in blunting the adrenergic stress hormone response to surgery. Breslow et al35 at Johns Hopkins published a report demonstrating that epidural morphine decreases postoperative hypertension by attenuating sympathetic nervous system hyperactivity. They found decreases in plasma cortisol and norepinephrine (noradrenaline) levels when utilizing epidural morphine, but not when using intravenous opioids. These studies in the late 1980s opened the way for a variety of studies in the 1990s to evaluate the influences of regional versus general anesthesia on postoperative outcome. Some studies caused great excitement, describing a potential, previously unrecognized beneficial effect of local anesthetics.36–38 By interfering with the coagulation cascade, a decreased re-operation rate of lower extremity revascularization procedures was seen with the use of epidurally administered local anesthetics. Unfortunately, no differences in outcome parameters such as angina, myocardial infarction or mortality were seen. A large-scale study was undertaken by Bode et al39 to determine whether the use of a regional or a general anesthetic influenced cardiac outcome after peripheral vascular surgery—a group of patients likely to have coronary artery disease. After evaluating 423 randomized patients receiving general, epidural, or spinal anesthetics for femoral-to-distal artery bypass surgery, it appeared that choice of anesthesia did not significantly influence cardiac morbidity and overall mortality. A recent series of studies has demonstrated the benefit of thoracic epidural analgesia for thoracic surgery. Benefits include a reduction in the incidence of supraventricular tachyarrhythmias and improved oxygenation and hemodynamic stability during general anesthesia.40,41 A third study confirmed that even in patients with end-stage chronic obstructive pulmonary disease, epidural analgesia with bupivacaine did not impair ventilatory mechanics.42 In summary, although some early studies indicated that differences in outcome may have existed between general and regional anesthetics in high-risk patients, more recent randomized trials aimed at identifying differences in cardiac outcome have not been able to demonstrate that these differences were due solely to the technique employed. A reasonable argument for differences found between the techniques in some studies is the change in overall perioperative management, as put forth by Sharrock et al.43 They found differences in mortality when comparing elderly patients receiving total hip and/or knee arthroplasty in the period from 1981 to 1985 as compared with those patients from 1987 to 1991 (0.39% versus 0.10%; p=0.0003). Differences in management included almostexclusive use of epidural anesthesia, decreased duration of surgery, decreased blood loss/intravenous fluid administration, and increased intraarterial/CVP/ Swan-Ganz line use. Non-anesthetic factors that should be considered are the introduction of new medications (e.g. antibiotics, ACE inhibitors and β/Ca2+-channel blockers), use of autologous blood, improved prophylaxis/surveillance of deep vein thrombosis, and improved perioperative nursing. Cognitive function postoperatively and long-term is a concern in older patients undergoing surgery and anesthesia. A large-scale study44 has evaluated whether differences in these parameters existed between regional and general anesthetics in older patients. Ten tests of memory, psychomotor, and language skills showed no differences 1

Comprehensive Geriatric Oncology

746

week and 6 months postoperatively in 262 patients with a median age of 69 (86% of all patients studied were older than 60) undergoing orthopedic operations. While there was no difference between the types of anesthetic utilized with respect to delirium, those patients who developed postoperative delirium fared worse in one test of psychomotor function 1 week and 6 months postoperatively (p<0.003). Perioperative management of cancer patients The cancer patient presents several specific conditions that affect anesthetic management. These include anatomic and physiologic changes resulting from the cancer itself or treatments such as chemotherapy and radiation. Anatomic changes Head and neck tumors and airway management may present the most difficult anesthetic challenge. Preoperative airway evaluation is essential. Oral examination will reveal obvious masses obstructing the airway; however, additional information such as fiberoptic laryngeal evaluation and computed tomography (CT) scans to exclude tracheal compression should be performed.45 Awake fiberoptic intubation or tracheostomy under sedation should be considered on patients with obstructing tumors. Dexamethasone can be used perioperatively to decrease edema. Mediastinal masses, usually lymphomas or metastatic tumors, can cause complete airway obstruction or cardio-vascular arrest during induction of anesthesia. Preoperative evaluation must include a CT scan of the chest, pulmonary function testing with flow volume loops, and echocardiography to rule out vessel or cardiac compression.46 Management should include positioning to decrease compression, awake intubation, spontaneous ventilation throughout the procedure, and (in some cases) standing cardiopulmonary bypass for treatment of cardio-vascular collapse. Pericardial metastasis commonly causes effusions and possible tamponade. Symptoms include dyspnea, chest pain, and abdominal pain. Jugular venous distention, diminished heart sounds, and EEG with decreased voltage are common findings. Echocardiography should be obtained on any patient with suspected effusion. In severe tamponade, subxyphoid pericardiocentesis under local anesthesia should be performed. For surgical pericardiectomy, anesthetic management should include arterial catheter, large-bore venous access, and use of ketamine or etomidate for induction. Chemotherapy Since the modern age of chemotherapy was instituted in the early 1940s with mechlorethamine (nitrogen mustard), significant developments in antineoplastic agents have been achieved. Unfortunately, some agents are associated with serious side-effects that occur more frequently and at lower doses in the elderly. There is increasing popularity of multidose regimens that work synergistically to combat cancer. This synergism also increases the capacity to induce side-effects. While a more complete review of these agents is not appropriate for this chapter, basic knowledge of the

Perioperative considerations in the geriatric oncology patient

747

complications associated with chemotherapy administration, and considerations in the surgical patient, is essential. For a more detailed discussion of chemotherapy in the elderly cancer patient, see Chapter 39 of this volume.47 Pulmonary system Bleomycin and nitrosoureas are associated with the development of progressive pulmonary fibrosis. The threshold dose for pulmonary fibrosis after bleomycin is of the order of 450–500 mg/m2. That toxic threshold is reduced in patients above the age of 65, in patients with pre-existing pulmonary disease, and in patients who receive adjuvant thoracic radiotherapy. Use of combination chemotherapy, especially involving cyclophosphamide, further decreases the toxic threshold.48 Of perioperative significance is the controversy surrounding oxygen administration and bleomycin-induced pulmonary fibrosis (Table 35.5). While it is commonly recommended that oxygen administration be restricted in these patients,49 since it has been implicated in the development of postoperative pulmonary failure

Table 35.5 Perioperative management of patients with pulmonary fibrosis • Preoperative pulmonary optimization –

Steroids

–

Antibiotics as indicated

–

Smoking cessation

–

Light or no sedation

• Intraoperative –

Low FiO2 (maintain SPO2 >90%)

–

Limit crystalloids to maintenance and fasting deficit replacement

–

Consider central hemodynamic monitoring

• Postoperative –

Aggressive pulmonary toilet

–

Bronchodilators as necessary

–

Bronchodilators as indicated

Abbreviations: FiO2, fractional concentration of inspired oxygen; SPO2, blood oxygen saturation.

and exacerbation of pulmonary fibrosis,50 at least one study has found no difference with its use.51 Present available information warrants caution with oxygen administration and careful titration of the lowest amount of oxygen to maintain a blood oxygen saturation (SpO2) over 90% by pulse oximetry appears to be appropriate in any patient with a prior history of bleomycin therapy.

Comprehensive Geriatric Oncology

748

Another perioperative problem seen with pulmonary fibrosis is fluid overload (Table 35.5). The lungs can increase lymph drainage up to 20-fold in response to fluid overload. However, patients with pulmonary fibrosis lose lymphatics and are extremely sensitive to crystalloid administration. Strict limitation of crystalloids to replace fasting and maintenance fluid deficits is mandatory. Colloid agents (e.g. hydroxyethyl starch and albumin) are preferred for volume replacement owing to their greater intravascular duration. A CVP or pulmonary artery catheter are useful to titrate fluids and guide therapy to maintain hemodynamic stability. Cardiovascular system Elderly patients with malignancies may already have a compromised cardiovascular system. A detailed history and physical examination are essential, with attention being directed to the patient’s exercise tolerance and change in exercise pattern. Unfortunately, in many patients, deterioration may be seen that is not solely attributable to a decrease in cardiac function but also to a generalized weakened state. Chemotherapeutic agents may contribute to this cardiac deterioration. The major drugs implicated in cardiac toxicity are doxorubicin, daunorubicin, cyclophosphamide, methotrexate, and cisplatin. All are cardiotoxic in a dose-related fashion. Paclitaxel has also been found to cause cardiovascular/ECG disturbances, but without a relation to dose. The toxic threshold for doxorubicin is 500mg/m2, and that for daunorubicin is 900mg/m2. Cardiac toxicity, both acute and chronic, may limit effectiveness and dosing. Acute cardiac toxicity may manifest during or shortly after an intravenous infusion. Acute toxicity does not appear to be dose-related and does not predict who will develop a more serious cardiomyopathy. It is commonly associated with ECG changes, such as ventricular tachycardia, heart block, supraventricular arrhythmias, premature atrial contractions/premature ventricular contractions, sinus tachycardia, low ECG voltage and non-specific ST-T wave changes. At low doses, a left ventricular dysfunction syndrome may occur, which may not be clinically evident if the patient does not have pre-existing decreased cardiac reserve. These patients are particularly sensitive to cardiac effects of inhalation agents and dysrhythmic effects of catecholamines. Therefore, close observation in those patients who have received cardiotoxic agents over the 2 weeks previous to operation is warranted. A preoperative ECG is mandatory, and a preoperative echocardiogram, searching for evidence of cardiomyopathy, is strongly recommended. Clinical signs are not sufficient for diagnosis, since a low-level asymptomatic cardiac dysfunction syndrome may exist, which may become manifest when periods of stress are encountered, such as those seen during operation. Obviously, if the patient demonstrates any sign of cardiac decompensation, such as shortness of breath, jugular venous pulse, or S3, then a full cardiac evaluation is indicated. Chronic toxicity is infrequent in young healthy patients below cumulative levels under 500mg/m2 of doxorubicin; however, 50% of all patients will have left ventricular dysfunction and weakness reaching 500mg/m2, regardless of risk factors. The presence of risk factors (i.e. age over 60, cardiac irradiation, underlying valvular or coronary artery disease, history of hypertension, administration of single doses of doxorubicin of more than 50mg/m2, co-administration of mitomycin C, and systemic disease that can decrease myocardial reserve, such as diabetes mellitus) should all be considered when approaching the threshold. At a dose of

Perioperative considerations in the geriatric oncology patient

749

over 600mg/m2 in patients receiving doxorubicin, overt cardiomyopathy is seen in more than 40% of patients. Morphologic changes increase linearly between 100 and 600mg/m2; this can be seen early with electron microscopy. While endomyocardial biopsy is a sensitive method to track the progression of disease, a continuous decline in cardiac function can be followed by ejection fraction measurements with radionuclide angiography.52 MUGA is much more sensitive than clinical findings. All patients should be followed by MUGA regardless of how long ago cardiotoxic chemotherapy agents were received. Symptoms can occur weeks to years after the last dose, and present clinically as congestive heart failure. Therapy would include avoiding further clinical injury by eliminating cardiotoxic medications, maintaining contractility, and reducing afterload. As these patients may pose significant challenges in the operating room, a risk-benefit ratio needs to be established to determine the appropriate anesthetic technique and degree of invasive monitoring. A short superficial, non-bloodletting procedure in a patient with a history of mild to moderate cardiac dysfunction may be satisfactorily managed with noninvasive monitors. However, a patient undergoing a larger operation with significant fluid shifts and a potential for blood loss merits invasive monitoring, such as intra-arterial blood pressure monitoring and Swan-Ganz catheter placement or transesophageal echocardiography to accurately determine fluid requirements and optimize cardiovascular conditions. Summary As we have seen, the elderly posses organic and functional differences that must be taken into consideration when developing a perioperative plan. It is well established that age is not the major consideration in assessing risk. The single most important risk factor evidence of deterioration is organ function. Organ systems must be evaluated preoperatively and an anesthetic plan formulated that will provide accordingly for any dysfunction. The elderly not only may possess more organ dysfunction than their younger counterparts, but they also have a greater potential for significant drug interaction. They are much more likely to be taking prescription and over-the-counter medications than their younger counterparts. How these medications interact with the multitude of pharmacologic agents given perioperatively is imperative. While average life-expectancy continues to increase, the species-specific lifespan value continues unchanged at 115–120 years. Continued improvement in maintaining the biological machinery by leading healthier lifestyles (e.g. non-smoking, aerobic exercise, and dietary intake) allows greater numbers to approach maximal lifespan values. Where once they were rarely seen, octa- and nonagenarians are successfully undergoing surgery and anesthesia with increasing regularity. This trend is certain to continue. ‘The straw that breaks the camel’s back may be a small one, when the camel is near the end of his journey’ HAROLD GRIFFITHS, MD

Comprehensive Geriatric Oncology

750

References 1. Smith OC. Advanced age as a contraindication to operation. Med Rec (NY) 1907; 72:642. 2. Ochsner A. Is risk of operation to great in the elderly? Geriatrics 1927; 22:121. 3. Catlic MR. Surgery in centenarians, JAMA 1985; 253:31–9. 4. Muravchick S. Preoperative assessment of the elderly patient: Anesthesiol Clin North Am 2000; 18:71–9. 5. Kurz A, Sessler DI, Lenhardt R, for the Study of Wound Infection and Temperature Group. Perioperative normothermia to reduce the incidence of surgical wound infection and shorten hospitalization. N Engl J Med 1996; 334:1209–15. 6. Frank SM, Fleisher LA, Breslow MJ et al. Perioperative maintenance of normothermia reduces the incidence of morbid cardiac events. JAMA 1997; 277:1127–34. 7. McClesky CH. Anesthesia for the geriatric patient. In: Clinical Anesthesia, 2nd edn (Barash PG, Cullen BF, Stoelting RK, eds). Philadelphia: JB Lippincott, 1992:1353–87. 8. Fiatarone MA, Marks EC, Ryan ND et al. High-intensity strength training in nonagenarians: effects on skeletal muscle. JAMA 1990; 263:3029–34. 9. Martin JT. Positioning aged patients. Anesthesiol Clin North Ama 2000; 18:105–21. 10. Lakatta EG, Fleg JL. Aging of the adult cardiovascular system. In:; Geriatric Anesthesia: Principles and Practices (Steven CR, Assaf RAE, eds). Boston: Butterworths, 1986. 11. Brandfonbrener M, Landowne M, Shock NW. Changes in cardiac output with age. Circulation 1955; 69:557–66. 12. Rodeheffer RJ, Gerstenblith G, Becker LC et al. Exercise cardiac output is maintained with advancing age in healthy human subjects: cardiac dilatation and increased stroke volume compensate for a diminished heart rate. Circulation 1984; 69:203–13. 13. Smith TC. Respiratory effects of aging. Semin Anesthesiol 1986; 5:14. 14. Pontoppidan H, Geffin D, Lowenstein E. Acute respiratory failure in the adult. N Engl J Med 1982; 287:690–7. 15. Scott JC, Stanski DR. Decreased fentanyl and alfentanil dose requirements with age. A simultaneous pharmacokinetic and pharmodynamic evaluation. J Pharmacol Exp Ther 1987; 240:159–66. 16. McGeer EG, McGeer PL. Age changes in the human for some enzymes associated with metabolism of catecholamines, GABA, and acetylcholine. Adv Behav Biol 1975; 16:287. 17. Rowe JW, Andres R, Tobin JD et al. The effect of age of creatinine clearance in man: a cross sectional and longitudinal study. J Gerontol 1976; 31:155–63. 18. Mirenda JV, Grissom TE. Anesthetic implications of the renin-angiotensin system and angiotensin-converting enzyme inhibitors. Anesth Analg 1991; 72:667–83. 19. Miller ED, Longnecker DE, Peach MJ. The regulatory function of the renin-angiotensin system during general anesthesia. Anesthesiol 1978; 48:399–403. 20. Sweny P. Is postoperative oliguria avoidable? Br J Anaesth. 1991; 67: 137–45. 21. Muravchik S. Anesthesia for the Elderly. In: Anesthesia, 3rd edn (Miller RD, ed). Edinburgh: Churchill Livingstone, 1990. 22. Lieu PK, Chong MS, Seshadri R. The impact of swallowing disorders in the elderly. Ann Acad Med Singapore 2001; 30:148–54. 23. Stewart RB, Cooper JW. Polypharmacy in the aged. Practical solutions. Drugs Aging 1994; 4:449–61. 24. Bell GD, Spichett GP, Reeve PA et al. Intravenous midazolam for upper gastrointestinal endoscopy: a study of 800 consecutive cases relating dose to age and sex of patient. Br J Clin Pharmacol 1991; 23: 241–3, 187. 25. Shanor SP, Van Hees GR, Baart N et al. The influence of age and sex on human plasma and red cell cholinesterase. Am J Med Sci 1961; 242:357.

Perioperative considerations in the geriatric oncology patient

751

26. Weinbroum AA, Szold O, Ogorek D, Flaishon R. The midazolaminduced paradox phenomenon is reversible by flumazenil. Epidemiology, patient characteristics and review of the literature. Eur J Anaesthesiol 2001; 18:789–97. 27. Bently JB, Borel JE, Nenad RE, Gillespie TJ. Influence of age on the pharmacokinetics of fentanyl. Anesth Analg 971, 1982; 61:968. 28. Scott JC, Stanski DR. Decreased fentanyl and alfentanil dose requirements with age. A simultaneous pharmacokinetic and pharmacodynamic evaluation. J Pharmacol Exp Ther 1987; 240:159–66. 29. Cohen MM, Duncan PG, Tate RB. Does anesthesia contribute to operative mortality? JAMA 1988; 260:2859–63. 30. Forrest JB, Rehder K, Cahalan MK, Goldsmith CH. Multicenter study of general anesthesia: III. Predictors of severe perioperative adverse outcomes. Anesthesiology 1992; 76:3–15. 31. Munson ES, Hoffman JC, Eger EI. Use of cyclopropane to test generality of anesthetic requirement in the elderly. Anesth Analg 1984; 63: 998–1000. 32. Renna M, Venturi R. Bispectral index and anaesthesia in the elderly. Minerva Anesthesiol 2000; 66:398–402. 33. Shulman M, Sandler AN, Bradley JW et al. Postthoracotomy pain and pulmonary function following epidural and systemic morphine. Anesthesiol 1984; 61:569–75. 34. Yeager MP, Glass DD, Neff RK, Brinck-Johnsen FT. Epidural anesthesia and analgesia in high risk surgical patients. Anesthesiol 1987; 66:729–36. 35. Breslow MJ, Jordan DA, Christopherson R et al. Epidural morphine decreases postoperative hypertension by attenuating sympathetic nervous system hyperactivity. JAMA 1989; 261:3577– 81. 36. Cook PT, Davies MJ, Cronin KD, Moran T. A postoperative, randomized trial comparing spinal anesthesia using hyperbaric cinchocaine with general anesthesia for lower limb vascular surgery. Anaesth Intens Care 1986; 14:373–80. 37. Tuman KJ, McCarthy RJ, March RJ et al. The effects of anesthesia and analgesia on coagulation and outcome after major vascular surgery. Anesth Analg 1991; 73:696–704. 38. Christopherson R, Beattie C, Frank SM et al. Perioperative morbidity in patients randomized to epidural or general anesthesia for lower extremity vascular surgery. Perioperative Ischemia Randomized Anesthesia Trial Study Group. Anesthesiol 1993; 79:422–34. 39. Bode RH Jr, Lewis KP, Zarich SW et al. Cardiac outcome after peripheral vascular surgery: comparison of general and regional anesthesia. Anesthesiol 1996; 84:3–13. 40. Von Dossow V, Welte M, Zaune U et al. Thoracic epidural anesthesia combined with general anesthesia: the preferred anesthetic technique for thoracic surgery. Anesth Analg 2001; 92:848– 54. 41. Oka T, Ozawa Y, Ohkubo Y. Thoracic epidural bupivacaine attenuates supraventricular tachyarrhythmias after pulmonary resection. Anesth Analg 2001; 93:253–9. 42. Gruber EM, Tschernko EM, Kritzinger M et al. The effects of thoracic epidural analgesia with bupivacaine 0.25% on ventilatory mechanics in patients with severe chronic obstructive pulmonary disease. Anesth Analg 2001; 92:1015–9. 43. Sharrock NE, Cazan MG, Hargett MJL et al. Changes in mortality after total hip and knee arthroplast over a ten-year period. Anesth Analg 1995; 80:242–8. 44. Williams-Russo P, Sharrock NE, Mattis S et al. Cognitive effects after epidural versus general anesthesia in older adults. JAMA 1995; 274: 44–50. 45. Lefor AT. Perioperative management of the patient with cancer. Chest 1999; 115:165S–71S. 46. Mathes DD, Bogdenoff DL. Preoperative evaluation of the cancer patient. In: Surgical Problems Affecting the Patient with Cancer (Lefor AT, ed). Philadelphia: Lippencott-Raven, 1996:273–304. 47. Cova D, Balducci L. Cancer chemotherapy in the older patient. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:463–88.

Comprehensive Geriatric Oncology

752

48. Cooper JA, White DA, Matthay RA. Drug-induced pulmonary disease. Am Rev Resp Dis 1986; 133:321–40. 49. Waid-Jones MI, Coursin DB. Perioperative considerations for patients treated with bleomycin. Chest 1991; 99:993–9. 50. Goldiner PL, Carlon GC, Cvitkovic E et al. Factors influencing postoperative morbidity and mortality in patients treated with bleomycin. BMJ 1978; i:1664–7. 51. LaMantia KR, Glick JH, Marshall BE. Supplemental oxygen does not cause respiratory failure in bleomycin-treated surgical patients. Anesthesiol 1984; 60:65–7. 52. Gottdiener JS, Mathisen DJ, Borer JS et al. Doxorubicin cardiotoxicity: assessment of late left ventricular dysfunction by radionuclide cineangiography. Ann Intern Med 1981; 94:430–5.

36 Hematopoiesis and aging Lynn C Moscinski Introduction The aging process is characterized by alterations in the functions of many organ systems. Changes occur in the cardiovascular, endocrine and immune systems, and have been studied extensively. Changes in bone marrow function are also evident, but the physiologic basis for these alterations is less well understood. Clearly, the bone marrow plays an important role in normal homeostasis, producing cells responsible for maintenance of oxygen delivery, hemostasis, and host defense against infection. The bulk of evidence favors preservation of normal homeostatic bone marrow function with aging in healthy individuals, although functional deficits are apparent under conditions of hematopoietic stress. The question of which of these observed cellular alterations are normal physiologic responses and which are consequences of coexistent disease processes remains under debate. In order to place published experimental data in perspective, an understanding of the regulation of normal hematopoiesis is essential. Normal bone marrow function The production of mature peripheral blood cells from primitive precursors within the marrow results from a complex interaction between primitive hematopoietic stem cells, the stromal microenvironment, and a set of soluble regulatory cytokines produced locally. The orderly development of the hematopoietic system requires that a strict balance be maintained between cell self-renewal, cell differentiation, and cell death. Continued production of terminally differentiated peripheral blood cells occurs, while a balance is maintained between amplification of immature precursors and maturation with transit into the peripheral blood compartment. Most immature precursors go unrecognized by traditional light-microscopic examination. The earliest morphologically recognizable myeloid, erythroid, and megakaryocytic precursors are actually relatively mature progeny of a cell found at low numbers within the marrow. This self-renewing cell is referred to as the primitive hematopoietic stem cell (Figure 36.1). The concept of a primitive hematopoietic stem cell was introduced by Till and McCulloch1 in the early 1960s. They analyzed the number and nature of cells giving rise to trilineal spleen colonies in an irradiated mouse model, and noted that each colony was derived from a single

Comprehensive Geriatric Oncology

754

Figure 36.1 Early hematopoietic stem cells have a high proliferative potential, with more limited differentiation kinetics. Their progeny, the late stem cells, undergo preferential differentiation to form stem cells committed to the various hematopoietic lineages. These undergo terminal maturation to form the recognizable peripheral blood and lymph node elements. Each stage of

Hematopoiesis and aging

755

stem cell differentiation is antigenically characterized by a constellation of surface antigens which can be readily measured by flow cytometry. CFU-S, colony-forming unit-spleen; CFU-GM, colony-forming unit-granulocyte/macrophage.

Figure 36.2 Primitive hematopoietic stem cells are defined by their maximal differentiating and repopulating abilities, as measured by a technique called ‘competitive repopulation’.

Comprehensive Geriatric Oncology

756

Donor and competitor cells are chosen from mouse strains to express different surface allelic markers. The mature progeny are assayed for the proportion of cells expressing each marker, and this value is used to estimate the stem cell number (relative to a standard dose of competitor cells) and to evaluate for stem cell enrichment efficiency. In this example, the ‘enriched’ donor sample is three times as efficient as the original sample, and therefore reflects an increased proportion of functional stem cells. RBC, red blood cells. clonogenic precursor. Furthermore, these precursors were capable of continuous repopulating ability.2,3 The cell type giving rise to the spleen colonies was termed a colony-forming unit-spleen (CFU-S). This same cell was later shown to also be capable of giving rise to peripheral blood and thymic lymphocytes,4,5 and thus became the prime candidate for the then-elusive pluripotent stem cell. Since this initial description, a series of cell types has been characterized, and both early and late stages of stem cell differentiation are identified. It is now known that pluripotent stem cells are short-lived,6,7 and represent only a small fraction of cells within the bone marrow and fetal liver. They can be defined by their maximum differentiating and repopulating ability as measured by ‘competitive repopulation’ assays.8,9 Such assays measure the long-term functional ability of stem cells (Figure 36.2). Using this methodology, competitor and donor hematopoietic populations are derived from mice that carry allelic variants of genes specifying quantifiable cellular markers. One population, termed the competitor, is an aliquot of fresh bone marrow cells that serves as an internal standard for repopulating potential. In each experiment, different donor populations containing unknown stem cell contents are measured relative to the repopulating ability of the internal standard competitor pool. Thus, various donor cell populations and bone marrow fractions can be compared.10 Hematopoietic stem cells have been subfractionated based on size, density, and the expression of cell surface molecules.5,11,12 There is a general consensus that most human stem cells are contained within the cell population expressing surface CD34 (where ‘CD’ refers to the international nomenclature for antigens, the so-called ‘clusters of differentiation’). CD34-positive (CD34+) stem cells represent a spectrum of stages of differentiation and lineage commitment, with variable functional properties, in vitro laboratory properties, and surface antigen expression (Table 36.1). The majority of CD34+ bone marrow cells are ‘late stem cells’, already committed to either the hematopoietic or stromal cell lineages.13,14 The most immature progenitors within the CD34+ population are further fractionated by the differential expression of CD38, CD45RA, CD71, CDw90 (Thy-1), and HLA-DR.15–20 A newly identified population of stem cells in both mice and humans has been characterized as CD34−, but capable of

Hematopoiesis and aging

757

multilineage repopulation in experimental models. The precise relationship between these CD34− stem cells and traditional CD34+ stem cells is not well understood.21 The establishment of hematopoiesis during embryonic development, as well as the continued maturation and differentiation of bone marrow precursors in vivo, requires an interaction with both cellular and soluble factors. Observed changes in stem cell numbers coincide with alterations in the stromal cell content of yolk sac, liver, spleen, and bone marrow when these sites become active in hematopoiesis.22,23 In liver, spleen and bone marrow, increased numbers of fibroblastoid colony-forming units (CFU-f) precede the onset of hematopoiesis.24 When recultured in vitro, CFU-f are capable of maintaining hematopoiesis in both human and mouse long-term marrow cultures.25,26 This suggests a close inter-action between stem cell proliferation/maintenance and stromal cell support. CFU-f are primarily fibroblastoid stromal cell types, and are assayed by plating bone marrow in soft agar in vitro. However, normal hematopoietic stroma in vivo is heterogeneous, and, in addition to CFU-f, is composed of macrophages, endothe-

Table 36.1 Definition of hematopoietic stem cells Properties Early stem cells (pre CFU-S)

Late stem Lineage-committed cells (CFU-S) stem cells

Functional

Self-renewal; long-term radioprotection of the host

Production of myeloid, erythroid and lymphoid elements

Laboratory

CFU-S formation in secondary transplantation into lethally irradiated mice (long-term repopulation)

Antigenic

Mouse: Sca-1 (stem cell antigen) positive, Thy-1.1 weakly positive, Lin (lineage markers) negative, KDR receptor (vascular endothelial growth factor receptor II) positive

Secondary Methylcellulose colony spleen colony formation for multiassays (CFU-S) potential lineage growth Long-term liquid Dexter

Human: CD34 positive, Rh123 (rhodamine dye) weakly positive, CD38 negative, CD71 (transferrin receptor) negative, HLA-DR negative, c-Kit receptor positive, CD45RO positive, CD45RA weakly positive, CDw90 (Thy1) weakly positive

Radioprotection of the host

Human: CD34 positive, RH123 (rhodamine dye) strongly positive May express variable CD33 (myeloid), CD10/CD19 (Blymphoid), CD38 and HLA-DR

lial cells, and fibroblast (reticular) cells, with many of the fibroblasts converting to adipocytes over time.27–32 The mechanism for stem cell dependence on stromal cell layers is most likely an interaction of stem cell membrane proteins with adhesion molecules present on the

Comprehensive Geriatric Oncology

758

surface of stromal cells (Figure 36.3). Such adhesion is postulated to ‘activate’ the stromal cell components, with resultant production of cytokines.33–39 The most primitive pluripotent stem cells do not appear to respond to any one cytokine given alone. Colony growth in soft agar can be seen when these cells are incubated with interleukin-3 (IL-3) in combination with a variety of other growth factors.40 Response of committed myelomonocytic precursors and lymphoid progenitors has been demonstrated to the early-acting growth factors stem cell factor (SCF, also known as c-Kit ligand and Steel factor), Flt-3/Flt-2 ligand, thrombopoietin (TPO), and IL-1, as well as IL-6, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GMCSF), and macrophage CSF (M-CSF), IL-7, and IL-5, IL-11, IL-12, and leukemia inhibitory factor (LIF).41 Commitment to the erythroid lineage requires both early-acting growth factors and erythropoietin (EPO). Megakaryocytic differentiation is less well understood, but requires many of the same early-acting growth factors. TPO42,43 induces differentiation in vitro, and ex vivo megakaryocytic expansion is now possible.44

Figure 36.3 Binding of hematopoietic stem cells to stroma via surface adhesion molecules results in the release of multiple cytokines by the now-‘activated’ stromal cells. The relative levels of these cytokines and the efficiency with which they can bind to receptors on the stem cell

Hematopoiesis and aging

759

allows for a balance between stem cell replication and differentiation. SCF, stem cell factor (c-Kit ligand, Steel factor); IL, interleukin; GM-CSF, granulocyte-macrophage colonystimulating factor; G-CSF, granulocyte CSF; M-CSF, macrophage CSF. The effect of aging on bone marrow function A multitude of alterations in hematopoiesis have been ascribed to the aging process, when studied in mice (Table 36.2). No major changes in basal hematopoiesis, however, are noted with aging.45,46 The aging process is typically characterized by a reduction in functional reserve capacity. Thus, while basal function is normal, the ability to respond to increasing demand and infectious or inflammatory stress is compromised. This compromise may involve all lineages within the bone marrow, and is the most frequently cited mechanism for the anemia of aging. Older mice and humans recover hemoglobin values more slowly after phlebotomy than do their younger counter-parts,47 and a less than optimum increase in hemoglobin level is noted during transitions to high altitude.48 The fragility of the aging hematopoietic system is further highlighted by studies of mice approaching their maximal life-expectancy.49 The median lifespan of the experimental mouse line C57BL/6 is 24 months and the maximum reported lifeexpectancy is 48 months. Mice at 48 months of age have been used in experiments in which they are housed either individually or in groups of five or more animals. Under experimental conditions where crowding occurs, a significant alteration in bone marrow function results, and the majority of animals become anemic. Examination of their bone marrow shows decreases in the number of countable stem cells and morphologically recognizable mature progeny. Therefore, when viewed globally, these experiments support the clinical impression that minor stresses that may not affect hematopoiesis in younger individuals can cause significant abnormalities in aged animals. Since no abnormalities in basal hematopoiesis can be detected, it is probable that

Table 36.2 The physiologic basis of ‘aging’ in the hematopoietic system of mice Observed ‘aging’ phenomenon

Probable physiologic mechanism

Myeloid abnormalities Increased proliferative capacity of late stem cells (CFU-S)

Unknown

Increased differentiative capacity of late stem cells (CFU-S), with production of more committed

Altered stromal cell regulation and increased demand for mature cells

Comprehensive Geriatric Oncology

760

stem cells Decreased resynthesis of cytokine substances in bone marrow

Altered stromal cell regulation, with increased fibroblast content of bone marrow

Decreased ability of early stem cells to repopulate the bone marrow of lethally irradiated mice

Decreased marrow graft content of ‘activated’ stromal cell components capable of cytokine secretion and initiation of hematopoietic reconstitution

Decreased in vitro CFU-GM colony formation

Decreased sensitivity of CFU-GM to exogenous IL-3, G-CSF, and GM-CSF

Reduction in hematopoietic reserve Blunted proliferative response to stress, most likely secondary to abnormal cytokine regulation Reduced cycling of committed stem cells (CFU-GM)

Increased demand for mature cells and increased complement of CFU-GM

Increased spontaneous chromosomal abnormalities

Decreased DNA repair mechanisms; altered telomerase activity (?)

T-lymphoid abnormalities Blunted T-cell proliferative response to mitogens

Increased content of mature T cells in bone marrow, with shortened duration of response to cell activation accompanied by a decrease in bone marrow-derived thymocyte progenitors; decreased local cytokine production by macrophages and stromal cells

Increased T-cell content of bone marrow

Compensatory increase in infiltrating effector T cells secondary to blunted T-cell proliferative response

B-lymphoid abnormalities Increased auto-antibody production Cytokine dysregulation, most notably increased IL-6; restricted VH gene usage Decreased production of normal immunoglobulin-producing cells

Cytokine dysregulation, most notably IL-7 and IL-4; abnormal T-cell regulation; decreased B-progenitor content of bone marrow

Restricted VH gene usage

Decreased B-cell precursors and increased peripheral selection; progressive decline in RAG-1 gene activity

IL, interleukin; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage CSF; RAG-1, recombination-activating gene 1.

these clinically apparent effects are secondary to blunting or suppression of cell proliferation and function during inflammatory or other physiologic stresses. This is most probably a consequence of cytokine mediation. There is general consensus that aging causes decrements in the proliferative potential of some cell types.50–52 There may be blunting of the proliferative response of normal marrow hematopoietic cells, resulting in inadequate amplification of myelopoiesis. This could potentially lead to neutropenia53,54 or could be manifested as a slow recovery from myelotoxic chemotherapy.55 Age-related deficits in compensatory myelopoiesis have also been ascribed to changes in the number of bone marrow progenitors, alterations in the

Hematopoiesis and aging

761

responsiveness of these progenitors to regulatory cytokines,56 decreased production of cytokines,57–59 or defects in the bone marrow microenvironment.60 The majority of studies to delineate the effects of aging on hematopoietic cell proliferation have been performed in rodents, predominantly mice or senescenceaccelerated strains of mice. Contradictory studies exist, and alterations in the function of the hematopoietic system during the aging process are not universally accepted. It is likely that some of the confusion results from differences in experimental procedures, differences between strains of laboratory mice, or inherent differences between rodent models and normal human physiology. For example, bone marrow cellularity in rodents increases with increasing age, while cellularity in humans decreases. Such basic differences in physiology may impact significantly on the extrapolation of results from experimental animal studies. However, despite some limitations, many lessons can be learned from in vitro evaluations. In the following sections, the specific effects of aging on each stage of normal stem cell differentiation will be discussed. As will become obvious, a multitude of laboratory abnormalities are found. Most of these are minor alterations or are poorly reproducible. No consistent patterns have been found, and the effect of aging on stem cell function remains a debated topic. The effect of aging on pluripotent stem cells (pre CFU-S and CFU-S) It appears curtain that pluripotent stem cells have a finite replicative capacity.61 Nonetheless, it is evident that stem cells can function far longer than the lifespan of the host, such that the physiologic consequences of this finding are unclear. In serial transplantation studies in W/W-anemic recipient mice, stem cells from healthy C57BL/6(B6) donors generated normal hematopoiesis for at least 100 months, which is 3–4 times the lifespan of normal mice.62 In human allogeneic bone marrow recipients, hematopoiesis is sustained for at least 20–30 years after transplantation. Evidence exists, however, that stem cells are heterogeneous in self-renewal capacity; young CFU-S (pre CFU-S) show a high self-renewal capacity and give rise to older CFU-S with diminishing self-renewal and increasing differentiation potential.63,64 During the aging process in mice,65 hematopoietic stem cells appear to accumulate. These repopulating cells retain their self-renewal potential, but develop a more restricted myeloid differentiation preference and less lymphoid differentiation potential. This anomaly has been postulated to result from repeated hematopoietic stem cell self-renewal and symmetric division, which may gradually produce intrinsically defective stem cells. In addition to defects in lymphoid lineage commitment, functional efficiency in homing and engraftment is also affected.66 Basal hematopoiesis shows no significant change, yet a significantly reduced reserve capacity is evident during stress or intercurrent illness. In order to understand why elderly people appear to possess less hematopoietic reserve than their youthful counterparts, early stem cell function has been evaluated in aging mice. Several studies have attempted to quantitate the number of pluripotent stem cells in the bone marrow.67,68 In the majority of cases, no differences could be detected in the absolute number of late stem cells (CFUS) or committed multilineage stem cells (CFU-mix) when comparing bone marrows obtained from young and old mice. Marginal differences in proliferative potential, however, have been found.67 There is a suggestion that cells originating from older bone

Comprehensive Geriatric Oncology

762

marrows proliferate to a greater extent and produce more committed stem cells than those from younger donors. This leads to a three- to fourfold increase in the relative and absolute numbers of the most primitive stem cell subsets. It has been proposed that these precursor cells proliferate in the older animal to compensate for their age-specific functional abnormalities.69 This finding appears to be somewhat confusing, and its relevance to physiologic stem cell functioning during aging is uncertain. A direct relationship between increased stem cell pool and murine strain-specific lifespan has been suggested. The basic mechanism for this observation clearly involves many factors extrinsic to the stem cell itself and appears to be a result of stromal cell dysregulation. It is generally accepted68 that the function of marrow stem cells, when these cells are transplanted into other animals or studied in culture, does not change significantly with age, although alterations in accessory cells occur. Resynthesis of cytokines appears to be slower in older mice, suggesting abnormalities in cytokine regulation or stromal cell function. However, while stromal cell dysfunction and abnormalities of stem cell proliferation can be demonstrated in vitro, these abnormalities do not appear capable of resulting in a significant decrement in stem cell function in vivo. As an exception to these findings, a single study70 identified a decrease in absolute CFU-S number using a novel chronobiological approach. The authors suggested that both circadian and seasonal variations in stem cell number exist. Using a calculation of mean CFU-S number, as identified by day-8 spleen colony assays, older mice appeared to have a slight decrement in absolute stem cell number. They also demonstrated less variability by season and time of day than younger littermates. The magnitude of this change, however, was quite small. It is probable that normal physiologic variations in stem cell number contributed to the difficulty in interpreting these data. Applying these findings to elderly human patients is problematic. Whether or not small changes in in vitro stem cell number leads to in vivo abnormalities is unclear. In order to answer this question, functional studies are needed. Using serial transplantation into lethally irradiated mice, stem cells show a gradual loss of self-replicative ability.64 While early evidence suggested that CFU-S from young donors were better able to repopulate the marrow of irradiated mice than stem cells obtained from older donors, this difference was probably related to stromal cell content and induced cytokine secretion. There is evidence suggesting that many of the early published serial transplant studies had significant methodologic artifacts.71,72 Furthermore, as noted above, any defect in stem cell number or function is marginal. Therefore, in summary, it appears that the CFU-S have sufficient reserve capacity to produce adequate numbers of hematopoietic cells for periods that far exceed the maximum life-expectancy of the host.73 Furthermore, although functional defects are evident, most observed abnormalities of stem cell function are likely secondary to alterations in stromal cells or stem cell/stromal cell interactions. The effect of aging on committed hematopoietic precursors Studies have examined the effect of aging on the number of both committed hematopoietic stem cells (CFU-granulocyte/macrophage (CFU-GM), CFU-erythroid (CFU-E), burst-forming units-erythroid (BFU-E), etc.) and differentiated bone marrow cells.49 In mice, the results are similar for late and early stem cells. Most studies show no

Hematopoiesis and aging

763

age-related reduction in the number of erythroid (BFU-E and CFU-E) or granulocyte/macrophage (CFU-GM) progenitor cells. Furthermore,74 there appear to be no age-related differences in the proportion of CD34+ marrow cells or of more mature CD34+ subsets, defined as CD34+/CD33+ cells. Maximum colony formation by primitive CD34+ cells stimulated with combinations of cytokines, including G-CSF, GM-CSF, and IL-3, is also similar in young and old subjects. However, an inverse correlation between the number of CD34+ stem cells isolated from peripheral blood and age has been documented.75 It is possible that this results from a similar functional homing defect as described for early stem cells, although this hypothesis has not yet been tested directly. Also, similar to early stem cells, the kinetics of the proliferative response may be altered, although no consistent pattern of abnormalities is found. Alterations appear to be growth factor-specific, and thus do not represent a generalized stem cell defect. For example, dose-response studies have identified a decrement in the sensitivity of cells obtained from elderly subjects to G-CSF, but not to IL-3 or GM-CSF. Similarly, the ability of early erythroidcommitted progenitors (CFU-E) to respond to EPO and IL-376 is unchanged. When using a similar strategy to evaluate the mature progeny of committed stem cells,77 no significant decrement in mature peripheral blood neutrophils, erythroid cells, or platelets can be identified. The effect of aging on progenitor cell cycle kinetics Another explanation for changes in marrow reserve during aging is an abnormality in the ability of stem cells to maintain proliferation, either temporally or in response to a stimulus. Several subtle abnormalities in both early and committed stem cell proliferation have already been discussed. Interestingly, it has been shown that the bone marrows of aged mice accumulate stem cells, and that these mice contain stem cells that are abnormal in cycle.69 They replicate on addition of cytokines, but maintenance of the cycling rate of CFU-GM, as measured using the thymidine suicide technique,78 is lower in elderly than in young adult mice.79,80 Data suggest that the reduced cycling of CFU-GM in older mice may be due to a constant demand for mature cells and an increased complement of CFUGM modulated by stromal regulation.81 The effect of aging on stem cell integrity The proliferative lifespan of the stem cells that sustain hematopoiesis throughout life is not clearly delineated. It has been proposed that the sequential loss of telomeric DNA from the ends of human chromosomes during cell division eventually reaches a critical point that triggers cellular senescence.82 This occurs because of the absolute requirement for DNA synthesis to begin at the binding site for the DNA replicative enzyme DNA polymerase (a process called ‘priming’), and the fact that this enzyme causes unidirectional DNA synthesis only. This unidirectional process results in incomplete replication of the terminal ends of the linear chromosomes distal to the DNA polymerasebinding site.83,84 In order to compensate for this replicative defect, eukaryotes have evolved a

Comprehensive Geriatric Oncology

764

Figure 36.4 Linear chromosomal DNA cannot be fully replicated by DNA polymerase. Therefore, special DNA sequences, called telomeres, have evolved at the ends of human chromosomes. A special enzyme called telomerase contains an integral RNA template. It is capable of adding nucleotides to the replicating (leading) end of the chromosome in an attempt to extend its 3′ end, allowing replication to be completed. DNA polymerase presumably fills in the

Hematopoiesis and aging

765

adjacent (lagging) strand, but uses telomeric DNA as a site of initiation of synthesis (primer). If telomerase is not present, the chromosomal ends become progressively shortened until chromosomal replication can no longer proceed. specialized rescue mechanism involving both chromosomal nucleoprotein modifications and a novel enzyme known as telomerase (Figure 36.4). Eukaryotic chromosomes end in specialized nucleoprotein structures called telomeres, which in humans contain tandem repeats of the nucleotides TTAGGG. Telomeres are critical for chromosome stability and function, and the loss of telomeres signals cell cycle arrest and chromosomal loss in yeast.85 Shortening of telomeres during mammalian aging in vivo has been observed in dermal and epidermal cells,86 peripheral blood leukocytes,87 and colonic epithelium,88 but not in sperm DNA.86 There is evidence suggesting that early (pre CFU-S) human stem cells (CD34+/CD38dim/−) from bone marrows of adult donors have shorter telomeres than similar cells obtained from fetal liver or umbilical cord blood.82 This finding suggests that the proliferative potential of hematopoietic stem cells may indeed be limited. To support this contention, telomeric shortening has been studied in stem cells after they have been induced to undergo excessive replication cycles. Shortened telomeres are well described in peripheral blood leukocytes following allogeneic bone marrow transplantation, in some bone marrow failure syndromes, and following some cytotoxic chemotherapy regimens.89 The telomeric shortening after bone marrow transplantation corresponds to approximately 15 years of aging, yet acquired bone marrow failure has not been described. Thus, telomeric shortening as a cause of suboptimal marrow responsiveness to proliferative stimuli or altered hematopoiesis appears unlikely. Stem cell utilization, as measured by X-chromosome inactivation, also appears to be independent of telomere length. It has been known for some time that clonality assays in healthy elderly women can be unreliable owing to an acquired progressive skewing of Xchromosome inactivation.90 It was postulated that this could be the result of a decreased stem cell pool, and telomeric senescence was implicated as the primary cause. However, it has become clear that factors other than telomeric senescence (random stem cell loss or X-allelic exclusion) are important in altering hematopoiesis with aging. Evidence in laboratory-bred safari cats91 suggests that this skewing is a result of inherited genetic factors that cause a selective advantage to certain cells carrying one or the other X chromosome. Thus, hemizygous selection appears to be the cause of the age-dependent skewed hematopoiesis that characterizes the bone marrows of elderly individuals. The process of aging is also associated with a general loss in the biologic competence of both single cells and the individual as a whole. At the cellular level, this loss is seen as a decrease in the ability of proliferating cells to replicate and of postmitotic cells to function effectively. When cytogenetic analysis was performed on the dividing bone marrow of rats,92 the incidence of chromosomal abnormalities (predominantly hypodiploidy) increased gradually with aging. Other abnormalities, such as polyploidy or changes in mitotic index, were not significant. The overall DNA content remains constant

Comprehensive Geriatric Oncology

766

owing to the small number of hypodiploid cells present (6.57% in males and 5.99% in females). When other tissues outside of bone marrow are examined for similar abnormalities, an increase in univalency and non-disjunction are found in the ovaries of females.93 No significant alterations in sperm chromosome number or structure could be identified in even the very oldest males, although the division frequency did decline sharply at the extremes of aging.92 Evidence for possible abnormalities of DNA repair and chromosomal dysregulation during aging was found in studies in which cytogenetic alterations were examined following exposure to mutagens.94 Older animals developed a higher frequency of micronuclei, reduced metaphase indices, and lower sister chromatid exchange per cell when compared with younger counterparts. Treatment with mutagens will significantly increase micronuclei and sister chromatid exchange in most strains of mice at all ages. The important point to note, however, is that the magnitude of this change increases significantly in older animals. When strain-dependent genetic predispositions are taken into account, sensitivity to mutagens and a decreased ability to repair abnormalities appear to characterize the aging animal. The effect of aging on bone marrow stroma Age-related variations in hematopoiesis are well documented, but, as noted previously, it is sometimes difficult to distinguish between the influence of extrinsic (marrow microenvironment) and intrinsic (genetic or stem cell) factors. Bone marrow stroma is an important source of extrinsic signals necessary for maintenance of both in vitro and in vivo hematopoiesis. Direct contact signaling between stem cells and stromal cells via adhesion receptors and secretion of cytokines has been documented.33,39 Serial transplantation studies in aging mice have suggested that defective secretion of cytokines and decreases in the ability of bone marrow stroma to maintain stem cell replication are the major factors responsible for the decreased cell proliferation that characterizes aging. This deficiency has been further evaluated in other experimental models,95 where a variety of latent deficiencies of the hematopoietic microenvironment have been documented. No change in the capacity of stromal cells to bind stem cells has been identified. However, when colony formation in culture is studied during aging,96 an increase in the bone marrow content of stromal precursor cells forming fibroblast colonies (CFU-f) is noted. This increase in bone marrow stroma is not associated with changes in bone marrow stem cell content, although a relationship between stromal cell number and bone marrow cellularity is apparent. The changes in stromal cell content, cell number, and cellular organization97–99 point to an age-related reorganization of the bone marrow microenvironment. How stromal cell reorganization influences stem cell physiology is not well understood. This most likely reflects a general paucity of experiments designed to evaluate the contribution of stroma to cell proliferation and function. The few functional studies in the literature are generally not well controlled. A single report suggests decreased neutrophil function when granulocytes are grown in long-term cultures of stroma from older as opposed to younger donors.100 In this study, neutrophil function following stimulation by the mitogen 4-phorbol-12-myristate-13-acetate (PMA) was

Hematopoiesis and aging

767

decreased in cultures initiated from the bone marrow stroma of older mice. However, neither cytokine production nor variability in culture conditions were evaluated. The effect of aging on cytokine production and release Although the steady-state blood cell levels are normal, many older persons appear to have an impaired ability to accelerate hematopoiesis in response to physiologic stress. This impairment, in large part, appears to be due to a disordered cytokine regulatory network. Abnormalities in both constitutive expression and induced expression have been described.101 The majority of evidence documents alterations in both cytokine secretion and cellular responses to cytokines in vitro, and few of these proteins have been measured directly in vivo (Table 36.3). No published studies have identified decreases in the serum levels of cytokines necessary for myeloid proliferation or differentiation.102 However, an age-related decline in secretion of human IL-3 and GM-CSF by phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells has been demonstrated in elderly persons and centenarians when compared with young adults.103 Furthermore, a paradoxical increase in serum SCF was noted, illustrating the complexity of this system, and suggesting the presence of an as-yet uncharacterized compensatory mechanism to maintain the stem cell pool. Of the cytokines studied in some detail in the literature, the most consistent results have been with measurements of IL-2, IL-6, and IL-7.104,105 Levels of IL-2 show a consistent decrease, likely contributing to abnormalities of T-cell function. Likewise, several studies106,107 have evaluated the contribution of decreased production of IL-7 on altered B-lymphoid differentiation during aging. IL-7 is produced by bone marrow stromal cells, and is required for pre-B-cell development.108 Whether alterations in cytokine secretion or production in vitro will translate into meaningful in vivo phenomena remains to be seen. Decreases in IL-2 and IL-7 production correlate with clinical data showing decreased immune function in elderly individuals. Perhaps the most important cytokine for gerontologists is IL-6.109 IL-6 is a multifunctional protein (Figure 36.5) produced by a wide variety of cells under varied conditions. It is the critical factor in the acute-phase inflammatory response, and appears to be involved in such diverse activities as induction of B-cell proliferation and maturation, regulation of protease inhibitors such as α1-antichymotrypsin and α2macroglobulin, and stimulation of bone resorption in vitro. Dysregulation of IL-6 expression has been implicated in the pathogenesis of a variety of neoplastic and nonneoplastic disorders, including multiple myeloma,110,111 non-Hodgkin lymphoma (NHL),112,113 rheumatoid arthritis,114,115 Castleman’s disease,116,117 and cardiac myxoma.118 The regulation of IL-6 gene expression is complex, with low to absent levels found in the serum of normal individuals. With aging, however, there is a gradual increase in

Table 36.3 A variety of cytokine abnormalities (in vivo and in vitro) that have been associated with aging. Mouse

Human

Comprehensive Geriatric Oncology

In vivo abnormalities

768

Decreased serum IL-3 Decreased serum IL-2 Increased serum IL-6

Increased serum IL-6 Increased serum SCF

In vitro abnormalities • Abnormalities in cytokine production and/or secretion

Decreased production of IL-1, IL-6 and TNF by LPSand thioglycolatestimulated peritoneal macrophages

Decreased production of IL-2 by anti-CD3-stimulated T cells

Decreased production of IL-7 by long-term bone marrow cultures

Decreased production of IL-4 and IFN-y by conA-stimulated mononuclear cells

Decreased production of IL-3 and GM-CSF by PHAstimulated PBMC

Increased production of IL-6 by PHA-stimulated lymphocytes • Abnormalities in cellular responses to cytokines

Decreased responsiveness of B precursors to IL-7

Decreased responsiveness of marrow progenitors to G-CSF

Decreased responsiveness of bone marrow stromal cells to PDGF and IGF-I

IL, interleukin; SCF, stem cell factor (c-Kit ligand, Steel factor); TNF, tumor necrosis factor; LPS, lipopolysaccharide; GM-CSF, granulocyte-macrophage colony-stimulating factor; PHA, phytohemagglutinin; PBMC, peripheral blood mononuclear cells; IFN-γ, interferon-γ; conA, concanavalin A; G-CSF, granulocyte colony-stimulating factor; PDGF, platelet-derived growth factor; IGF-I, insulin-like growth factor I.

Hematopoiesis and aging

769

Figure 36.5 Interleukin-6 (IL-6) exerts a number of important effects on many organ systems. Increases in IL-6 during normal aging are felt to contribute to the pathogenesis of several neoplastic and non-neoplastic (predominantly inflammatory) disorders. the level of measurable IL-6, even in the absence of documented inflammatory stimuli.119–121 It has been postulated that changes in IL-6 regulation may constitute one of the fundamental aging processes and could conceivably contribute to a broad spectrum of age-associated diseases.109 Because of the known effects on B-cell proliferation, dysregulation of IL-6 gene expression may well be related to the appearance of autoantibodies and perhaps the benign paraproteinemias that occur in aging mice.122,123 Furthermore, since α1-antichymotrypsin and α2-macroglobulin may adversely alter the breakdown of amyloid precursor proteins, IL-6-induced increases in these protease inhibitors may contribute to the pathogenesis of Alzheimer’s disease.124–126 When administration of recombinant human IL-6 was tested in vivo in Rhesus monkeys, a number of alterations in hematologic and immune parameters were observed.127 IL-6-treated animals lost an average of 10.9% of their body weight over a 28-day period of IL-6 administration. In addition to weight loss, there was a decrease in

Comprehensive Geriatric Oncology

770

hemoglobin and hematocrit without evidence of peripheral hemolysis or obvious bone marrow suppression. A transient leukocytosis, as well as a sustained thrombocytosis, were also noted. Decreases in natural killer (NK)cell activity and number were identified. Such changes are transient when normal young adult monkeys are studied, but are sustained in elderly animals. A similar dichotomy is noted when examining serum protein. In normal adult monkeys, total protein levels rise after administration of IL-6, secondary to increases in acute-phase reactants and the appearance of a hypergammaglobulinemia. However, unlike the young adult animals, older subjects show a fall in serum total protein, which remains depressed for up to 1 week after the administration of IL-6 is discontinued. Thus, IL-6 clearly has a multitude of diverse effects on metabolism and homeostasis, and these effects may be variable during aging. Perhaps the most extensively studied effect of IL-6 on aging is that related to osteoporosis. Osteoblasts are among the many cell types that secrete IL-6, and IL-6 stimulates bone resorption in vitro.128 Increasing levels of IL-6 with aging may contribute to postmenopausal osteoporosis.129 Decreasing estrogen levels result in a decrease in IL-6 gene expression,130 with increased bone resorption and osteoclast activation. The system is complex, however. In addition to IL-6, at least two other cytokines are implicated in the generation of osteoporosis. Both insulin-like growth factor I (IGF-I)131 and plateletderived growth factor (PDGF)132 have been identified as mitogens for marrow stromal cells. They enhance cell growth and bone turnover through their actions on bone formation and bone resorption, and appear to be less potent in older individuals. This lack of stimulation may result in decreased progenitor cell proliferation, and subsequently a diminished expansion of new osteoblasts. The effect of aging on immune function Bone marrow T cells The reported decline in immune responses during aging has been largely attributed to reduced functioning of the T-cell compartment (Figure 36.6).133 The majority of studies designed to investigate the biologic basis for the T-lymphocyte changes utilize mouse models. Sharp et al134 have shown an increase in the proportion of T lymphocytes in bone marrow with age. When these cells were sorted by flow cytometry and studied for proliferative response to mitogen (concanavalin A), T lymphocytes from bone marrow of older mice showed a significantly lower response than those obtained from younger donors. When adjusting the cultures for the presence of equal numbers of T lymphocytes, older bone marrows appeared to initially manifest a higher level of proliferation. However, the response was maintained for a shorter duration, suggesting a functional deficit. Thus, there are greater numbers of effector T lymphocytes in the bone marrow of older animals, but they show a proliferative response of shorter duration. Concomitant with the increase in mature T cells, Globerson et al135 have identified a decrease in the number of bone marrow-derived thymocyte progenitor cells with aging. It was suggested that this decrease may be a normal function of aging that accompanies involution of the thymus. The proportion of

Hematopoiesis and aging

771

Figure 36.6 A multitude of abnormalities in both T- and B-cell differentiation and proliferation have been ascribed to the aging process. These defects occur at all stages of Tand B-lymphocyte development. mature T cells (CD4+/CD8+ ratios) derived from bone marrow of both young and older individuals appears similar. Since these mature T cells are long-lived and can continue to

Comprehensive Geriatric Oncology

772

proliferate in response to immunogenic stimuli, the observed decrease in thymocyte progenitors may have little functional impact. Thymic involution, however, imparts additional functional abnormalities to Tlymphocyte proliferation and function during aging. Sustained cell production by the thymus depends on the continued migration of bone marrow thymocyte precursors to the thymus. As previously demonstrated,136 the ability of bone marrow-derived prothymocytes from aged individuals to migrate in response to thymic supernatants is grossly defective. Pre-incubation of these same bone marrow cells with neonatal thymic epithelium dramatically improves the ability of the aged bone marrow stem cells to migrate in vitro. Growth hormone and IGF-I stimulate thymopoiesis, and their levels decrease with age.137 It is apparent that thymic factors, hormone levels, and bone marrow cytokines are necessary for the function and differentiation of prothymocytes in the bone marrow, and alterations in either their levels or the cellular response influence T-cell production during aging. When bone marrow-derived T lymphocytes are studied by flow cytometry,138 the majority are CD3+ cells possessing a cytotoxic/suppressor phenotype (CD8+), although both CD8+ and CD4+ cells do increase numerically with aging. These T lymphocytes are thymic-derived, and are not biased for any usage of specific T-cell receptor (TCR) β chains. Their proportions differ from T-cell subsets within the spleen and peripheral blood, suggesting that this population of T lymphocytes preferentially proliferates in the bone marrow microenvironment. Their proliferation appears to be dependent on the surrounding bone marrow non-T-cell population.138 Direct contact between bone marrow T cells and non-T cells leads to inhibition of T-lymphocyte proliferation after addition of exogenous mitogen. Whether or not this inhibition prevents cytotoxic T cells from recognizing homologous bone marrow hematopoietic elements and proliferating (autoimmunity) is unknown at this time, but certainly appears feasible. Globerson139 has identified an additional mechanism responsible for abnormal T-cell differentiation and function in aging mice. Bone marrow cells from young and old mice were cocultured with lymphoiddepleted fetal thymic explants. Although the proportion of total T cells developing from older bone marrow donors was significantly lower than that of younger bone marrow donors, there was no difference in the ratio of T-cell subsets or reactivity to mitogen. Unlike previous studies, which implicated only thymic-derived defects, this study suggested an intrinsic lesion in the bone marrow-derived T-cell precursors. Whether this reflects abnormal differentiation or an increase in programmed cell death has not yet been established. It was noted that the frequency of thymocyte progenitors in older bone marrow donors is reduced by approximately 40% during aging. If the older cells were cultured in the presence of fetal thymic explants for 24 hours longer than those of younger donors, T-cell development was normalized. This suggests the possibility that bone marrow-derived T cells of older donors have a decreased affinity for thymic stroma. Thus, there are multiple defects that accumulate in the bone marrow T-cell compartment with aging. Decreased affinity for stroma, in addition to decreases in migratory activity and cell replication during aging, can be of major impact.

Hematopoiesis and aging

773

Bone marrow B cells B-lymphocyte development is modulated by a complex network of positively and negatively acting cytokines, as well as by cell-to-cell interactions. T-lymphocyte function appears to exert a major role in B-cell development. Few abnormalities of aging have been directly attributed to defects in B-cell development or function within the bone marrow (Figure 36.6). An age-related decrease in the number of pre-B lymphocytes in the bone marrow has been confirmed.140 These cells were identified by cell surface phenotyping as CD19+/CD10+ dual-positive cells. The decrease in early B-cell precursors is accompanied by a decreased capacity to generate surface immunoglobulin-positive mature B cells. Neither the presence of inhibitory factors nor increases in suppressor T cells could be identified as the cause of these effects. Development of B-cell precursors into mature immunoglobulin-bearing B cells depends on soluble factors such as IL-4 and IL-7, as well as cellular interactions provided by stromal cells and T cells.141 During the aging process in mice, stromal cell function appears to become altered. Release of IL-7 by stromal cells requires cell-to-cell contact with B-cell precursors. There is evidence suggesting that the secretion of IL-7 by aged stromal cells is delayed when compared with stromal cells from young donors.107 Since marrow stromal cells are the only local source of IL-7, this delayed secretion may have a profound effect on the generation of new B lymphocytes in the marrow. Furthermore, there may also be a decreased overall response to cytokine-induced proliferation. Johnsson and Phillips142 identified a two- to fivefold lower response to IL-7 in mice over 20 weeks of age when compared with younger animals. This decrease appeared to be secondary to a reduced frequency of IL-7-responsive pro/pre-B cells in the bone marrow of the older mice, and could not be overcome by the addition of large amounts of IL-7. Despite these intrinsic defects, most of the age-related changes in B lymphocytes appear to be reflective of aging T lymphocytes. There is a constant decrease in the amount and affinity of antibody produced by aged animals,143 accompanied by ageassociated increases in auto-antibody production.144 The decline in antigen responsiveness associated with aging has been characterized in both qualitative and quantitative terms.140,143 The magnitude of responses to both thymic-independent and thymic-dependent antigens are depressed. Furthermore, in the aged, the expressed antibody repertoire is principally composed of low-affinity antibodies with a decrease in, or absence of, medium- and high-affinity antibodies. Along with this lack of maturation in antigen affinity, there occurs a concomitant change in the expressed repertoire of antibodies to a given antigen. Auto-anti-idiotypic antibodies produced during the normal immune response of the aged animal are markedly enhanced when compared with those seen in the immune responses of younger adults. This abnormality is accompanied by a rise in titers of auto-antibodies and a gradual increase in total serum immunoglobulin concentration. Some of the molecular genetic abnormalities responsible for these alterations have also been described. Aging mice have been found to have higher frequencies of peripheral mature B cells utilizing restricted variable gene (VH) families. This suggests that older animals express less diversified antibody repertoires as a consequence of reduced B-cell precursors and increased peripheral selection.144 This restricted gene usage

Comprehensive Geriatric Oncology

774

may contribute to the increase in autoimmunoreactivity noted during aging. Although CD5+ B cells have been associated with immune-reactive populations, no significant differences in the frequency of CD5+ B cells have been observed during aging. A mechanism postulated for the decrease in VH gene usage is the progressive decline in expression of recombination-activating gene 1 (RAG-1). This gene is expressed in early pre-B lymphocytes, where it is involved in the process of recombination and rearrangement of immunoglobulin gene segments to produce mature immunoglobluin. RAG-1 messenger RNA is expressed by B-cell precursors, and in mouse bone marrow increases during the first 2 months of life to reach a maximum level at 2 months of age.145 This level is maintained until adulthood, where levels progressively decrease. A decrease in RAG-1 gene expression is directly correlated with a loss of antigen diversity within the immunoglobulin gene family.146 This may explain why, with increasing age, the antibody response becomes progressively more dominated by IgM and low-affinity antibody, with decreased immunoglobulin class switching and decreased somatic mutation. This abnormality also affects T-cell function, as shown by studies in nude mice.145 Transfer of young T cells is capable of restoring full antigen diversity and RAG-1 gene expression to bone marrow cells. Thus, both extrinsic and intrinsic changes in bone marrow B cells occur with aging. The number of B-cell progenitors is decreased. Changes in regulatory mechanisms, predominantly stromal cell and T-cell function, are the major factors responsible for the major decline in the B-cell immune response with age.147 The interactions of B-cell production and differentiation and thymic involution remain to be elucidated. Conclusions While many defects in hematopoiesis have been ascribed to the aging process, their specificity remains controversial. The difficulty in assessing functional abnormalities is in part related to the coexistence of other disease processes in the aging population. However, more importantly, it is the complex interactions between normal stem cells and their progenitors, the bone marrow stroma, and the immune system (both T and B lymphocytes), as well as the multitude of cytokines produced, which contribute to a vast interactive network. While multiple studies in mice and other rodents have attempted to dissect this complex process, human studies must confirm these findings. The importance of these studies cannot be underestimated, since an understanding of the physiology of hematopoiesis is paramount to the construction of less toxic and more effective therapies for the aging patient population. References 1. Till JE, McCulloch EA. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 1961; 14: 213–22. 2. Becker AJ, McCulloch EA, Till JE. Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature 1963; 197:452–4.

Hematopoiesis and aging

775

3. Wu AM, Till JE, Siminovitch L, McCulloch EA. Cytological evidence for a relationship between normal hematopoietic colony-forming cells and cells of the lymphoid system. J Exp Med 1968; 127:455–64. 4. Abramson S, Miller RG, Phillips RA. The identification in adult bone marrow of pluripotent and restricted stem cells of the myeloid and lymphoid systems. J Exp Med 1977; 145:1567–79. 5. Visser JWM, Van Bekkum DW. Purification of pluripotent hematopoietic stem cells. Exp Hematol 1990; 18:248–56. 6. Micklem HS, Lennon JE, Ansell JD, Gray RA. Numbers and dispersion of repopulating hematopoietic cell clones in radiation chimeras as functions of cell dose. Exp Hematol 1987; 15:251–7. 7. Harrison DE, Astle CM, Lerner C. Number and continuous proliferation pattern of transplanted primitive immunohematopoietic stem cells. Proc Natl Acad Sci USA 1988; 85:822–6. 8. Harrison DE. Competitive repopulation: a new assay for long-term stem cell functional capacity. Blood 1980; 55:77–81. 9. Harrison DE, Jordan CT, Zhong RK, Astle CM. Primitive hematopoietic stem cells: direct assay of most productive populations by competitive repopulation with simple binomial, correlation, and covariance calculations. Exp Hematol 1993; 21:206–19. 10. Jordan CT, Astle CM, Zawadzki J et al. Long-term repopulating abilities of enriched fetal liver stem cells measured by competitive repopulation. Exp Hematol 1995; 23:1011–15. 11. Lu L, Walker D, Broxmeyer HE et al. Characterization of adult human marrow hematopoietic progenitors highly enriched by two-color cell sorting with My10 and major histocompatibility class II monoclonal antibodies. J Immunol 1987; 139:1823–9. 12. Terstappen LWMM, Lund-Johansen F. Hematopoietic progenitors in fetal and adult tissue. Blood Cells 1994; 20:392–6. 13. Civin CI, Strauss LC, Brovall C et al. Antigenic analysis of hematopoiesis. III. A hematopoietic progenitor cell surface antigen defined by a monoclonal antibody raised against Kg-la cells. J Immunol 1984; 133:157–65. 14. Simmons PJ, Torok-Storb B. CD34 expression by stromal precursors in normal human adult bone marrow. Blood 1991; 78:2848–53. 15. Terstappen LWMM, Huang S, Safford M et al. Sequential generations of hematopoietic colonies derived from single non-lineage committed CD34+CD38− progenitor cells. Blood 1991; 77:1218–27. 16. Huang S, Terstappen LWMM. Lymphoid and myeloid differentiation of single human CD34+, HLA-DR+, CD38− hematopoietic stem cells. Blood 1994; 83:1515–26. 17. Baum CM, Weissman IL, Tsukamoto AS et al. Isolation of a candidate human hematopoietic stem-cell population. Proc Natl Acad Sci USA 1992; 89:2804–8. 18. Lansdorp PM, Sutherland HJ, Eaves CJ. Selective expression of CD45 isoforms on functional subpopulations of CD34+ hemopoietic cells from human bone marrow. J Exp Med 1990; 172:363–6. 19. Brandt J, Srour EF, Van Besien K et al. Cytokine-dependent long-term culture of highly enriched precursors of hematopoietic progenitor cells from human bone marrow. J Clin Invest 1990; 86:932–48. 20. Verfaillie CM, Blakholmer K, McGlave PB. Purified primitive human hematopoietic progenitors with long term in vitro repopulating capacity adhere selectively to irradiated bone marrow stroma. J Exp Med 1990; 172:509–20. 21. Bonnet D. Normal and leukemic CD34-negative human hematopoietic stem cells. Rev Clin Exp Hematol 2001; 5:42–61. 22. Klein AK, Dyck JA, Stitzel KA et al. Characterization of canine fetal lymphohematopoiesis: studies of CFU-GM, CFU-L and CFU-F. Exp Hematol 1983; 11:263–74. 23. Van Den Heuvel RL, Versele SRM, Schoeters GER, Vanderborght OLJ. Stromal stem cells (CFU-f) in yolk sac, liver, spleen and bone marrow of pre- and postnatal mice. Br J Haematol 1987; 66:15–20.

Comprehensive Geriatric Oncology

776

24. Van Den Heuvel R, Schoeters G, Leppens H, Vanderborght OLJ. Stromal cells in long-term cultures of liver, spleen, and bone marrow at different developmental ages have different capacities to maintain GM-CFC proliferation. Exp Hematol 1991; 19:115–21. 25. Van Den Heuvel RL, Schoeters GER, Vanderborght OLJ. Haemopoiesis in long-term cultures of liver, spleen and bone marrow of pre- and postnatal mice: CFU-GM production. Br J Haematol 1988; 70:273–7. 26. Cappellini MD, Potter CG, Wood WG. Long-term haemopoiesis in human fetal liver cell cultures. Br J Haematol 1984; 57:61–70. 27. Westen H, Bainton DF. Association of alkaline phosphatase-positive reticulum cells in bone marrow with granulocytic precursors. J Exp Med 1979; 150:919–37. 28. Allen TD. Haemopoietic microenvironments in vitro: ultra-structural aspects. Ciba Found Symp 1980; 84:38–67. 29. Tavassoli M, Friedenstein A. Hemopoietic stromal micro-environment. Am J Hematol 1983; 15:195–203. 30. Xu CX, Hendry JH, Testa NG, Allen TD. Stromal colonies from mouse marrow: characterization of cell types, optimization of plating efficiency and its effects on radiosensitivity. J Cell Sci 1983; 61: 453–66. 31. Laver J, Ebell W, Castro-Malaspina H. Radiobiological properties of the human hematopoietic microenvironment: contrasting sensitivities of proliferative capacity and hematopoietic function to in vitro irradiation. Blood 1986; 67:1090–7. 32. Wang Q-R, Wolf NS. Dissecting the hematopoietic micro-environment. VIII. Clonal isolation and identification of cell types in murine CFU-F colonies by limiting dilution. Exp Hematol 1990; 18:355–9. 33. Wolf NS, Bertoncello I, Jiang DZ, Priestley G. Developmental hematopoiesis from prenatal to young-adult life in the mouse model. Exp Hematol 1995; 23:142–6. 34. Wolf NS. Dissecting the hematopoietic microenvironment. III. Evidence for a positive short range stimulus for cellular proliferation. Cell Tissue Kinet 1978; 11:335–45. 35. Ploemacher RE, Moledijk WJ, Brons NHC, de Ruiter H. Defective support of Sl/Sld splenic stroma for humoral regulation of stem cell proliferation. Exp Hematol 1986; 14:9–15. 36. Zsebo K, Wypych J, McNiece I et al. Identification, purification, and biological characterization of hematopoietic stem cell factor from buffalo rat liver conditioned medium. Cell 1990; 63:195–201. 37. Anderson DM, Lyman SD, Baird A et al. Molecular cloning of mast cell growth factor, a hematopoietin that is active in both membrane bound and soluble forms. Cell 1990; 63:235–43. 38. Huang E, Nocka K, Beier DR et al. The hematopoietic growth factor KL is encoded by the Sl locus and is the ligand of the c-kit receptor, the gene product of the W locus. Cell 1990; 63:225– 33. 39. Williams DE, Eisenman J, Baird A et al. Identification of a ligand for the c-kit proto-oncogene. Cell 1990; 63:167–74. 40. Heimfeld S, Hudak S, Weissman IL, Rennick D. The in vitro response of phenotypically defined mouse stem cells and myeloerythroid progenitors to single or multiple growth factors. Proc Natl Acad Sd USA 1991; 88:9902–6. 41. Ogawa M, Matsunaga T. Humoral regulation of hematopoietic stem cells. Ann NY Acad Sci 1999; 872:17–23; discussion 23–4 42. Bartley TD, Bogenberger J, Hunt P et al. Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl. Cell 1994; 77:1117–24. 43. Kaushansky K, Lok S, Holly RD et al. Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin. Nature 1994; 369:568–71. 44. Maurer AM, Liu Y, Caen JP, Han ZC. Ex vivo expansion of megakaryocytic cells. Int J Hematol 2000; 71:203–10. 45. Everitt AV, Webb C. The blood picture of the aging male rat. J Gerontol 1958; 13:255–60.

Hematopoiesis and aging

777

46. Coggle JE, Proukakis C. The effect of age on the bone marrow cellularity of the mouse. Gerontologia 1970; 16:25–9. 47. Boggs DR, Patrene KD. Hematopoiesis and aging III: Anemia and a blunted erythropoietic response to hemorrhage in aged mice. Am J Hematol 1985; 19:327–38. 48. Udupa KB, Lipschitz DA. Erythropoiesis in the aged mouse. I. Response to stimulation in vivo. J Lab Clin Med 1984; 103:574–80. 49. Williams LH, Udupa KB, Lipschitz DA. Evaluation of the effect of age on hematopoiesis in the C57BL/6 mouse. Exp Hematol 1986; 14: 827–32. 50. Hayflick L. The cell biology of human aging. N Engl J Med 1976; 295: 1302–8. 51. Norwood TH, Smith JR, Stein GH. Aging at the cellular level: the human fibroblast like cell model. In: The Handbook of the Biology of Aging, 3rd edn (Schneider EL, Rowe JW, eds). San Diego: Academic Press, 1990:131–54. 52. Goldstein S. Replicative senescence: the human fibroblastcomes of age. Science 1990; 249:1129–31. 53. Finklestein M, Petkun W, Friedman M. Pneumococcal bacteremia in the elderly. J Am Geriatr Soc 1983; 31:19–27. 54. Weinstein M, Murphy J, Reller L. The clinical significance of positive blood cultures—500 episodes of bacteremia in adults. Rev Infect Dis 1983; 5:54–70. 55. Begg C, Carbone P. Clinical trials and drug toxicity in the elderly. The experience of the Eastern Cooperative Oncology Group. Cancer 1983; 52:1986–92. 56. Lipschitz D, Udupa K, Milton K, Thompson C. Effect of age on hematopoiesis in man. Blood 1984; 63:502–9. 57. Gillis S, Kozan R, Durante M, Weksler M. Decreased production of and response to T-cell growth factor by lymphocytes from aged humans. J Clin Invest 1981; 67:937–942. 58. Nagel J, Chopra R, Chrest F et al. Decreased proliferation, IL-2 synthesis, IL-2 receptor expression are accompanied by decreased mRNA expression in PHA stimulated cells from elderly donors. J Clin Invest 1988; 81:1096–102. 59. Buchanan J, Rothstein G. Deficient growth factor production as a cause of hematopoietic dysregulation in aged subjects. Clin Res 1989; 37:149A (abstr). 60. Lee M, Segal G, Bagby G. The hematopoietic microenvironment in the elderly: defects in IL-1 induced CSF expression in vitro. Exp Hematol 1989; 17:952–6. 61. Lipschitz DA, Udupa KB. Age and the hematopoietic system. J Am Geriatr Soc 1986; 34:448– 54. 62. Zaucha JM, Yu Cong, Mathioudakis G et al. Hematopoietic responses to stress conditions in young dogs compared with elderly dogs. Blood 2001; 98:322–7. 63. Schofield R, Lajtha LG. Effect of isopropyl methane sulphonate (IMS) on haemopoietic colony-forming cells. Br J Haematol 1973; 25:195–202. 64. Schofield R, Lord BI, Kyffm S, Gilbert CW. Self maintenance capacity of CFU-s. J Cell Physiol 1980; 103:355–62. 65. Sudo K, Ema H, Morita Y, Nakauchi H. Age-associated characteristics of murine hematopoietic stem cells. J Exp Med 2000; 192: 1273–80. 66. Morrison SJ, Wandyez AM, Akashi K et al. The aging of hematopoietic stem cells. Nat Med 1996; 2:1011–16. 67. Sharp A, Zipori D, Toledo J et al. Age related changes in hemopoietic capacity of bone marrow cells. Mech Ageing Dev 1989; 48:91–9. 68. Schofield R, Dexter TM, Lord BI, Testa NG. Comparison of haemopoiesis in young and old mice. Mech Ageing Dev 1986; 34: 1–12. 69. Globerson A. Hematopoietic stem cells and aging. Exp Gerontol 1999; 34:137–46. 70. Sletvold O, Laerum OD. Multipotent stem cell (CFU-S) numbers and circadian variations in aging mice. Eur J Haematol 1988; 41: 230–6. 71. Harrison DE, Astle CM, Delaittre JA. Loss of proliferative capacity in immunohemopoietic stem cells caused by serial transplantation rather than aging. J Exp Med 1978; 147:1526–31.

Comprehensive Geriatric Oncology

778

72. Ross EAM, Anderson H, Micklem HS. Serial depletion and regeneration of the murine hematopoietic system. Implication for hematopoietic organization and the study of cellular aging. J Exp Med 1982; 155:432–44. 73. Harrison DE. Normal production of erythrocytes by mouse marrow continuous for 73 months. Proc Natl Acad Sci USA 1972; 70: 3184–8. 74. Chatta GS, Andrews RG, Rodger E et al. Hematopoietic progenitors and aging: alterations in granulocytic precursors and responsiveness to recombinant human G-CSF, GM-CSF, and IL-3. J Gerontol 1993; 48: M207–12. 75. Egusa Y, Fujiwara Y, Syahruddin E et al. Effect of age on human peripheral blood stem cells. Oncol Rep 1998; 5:397–400. 76. Hirota Y, Okamura S, Kimura N et al. Haematopoiesis in the aged as studied by in vitro colony assay. Eur J Haematol 1988; 40:83–90. 77. Sletvold O, Laerum OD, Riise T. Rhythmic variations of different hemopoietic cell lines and maturation stages in aging mice. Mech Ageing Dev 1988; 42:91–104. 78. Lord BI, Schofield R. Haemopoietic spleen colony forming units. In: Cell Clones: Manual of Mammalian Cell Techniques (Potten CS, Hendry JH, eds). Edinburgh: Churchill-Livingstone, 1985:13. 79. Iscove NN, Till JE, McCulloch EA. The proliferative states of mouse granulopoietic progenitor cells. Proc Soc Exp Biol Med 1970; 134: 33–6. 80. Tejero C, Testa NG, Lord BI. The cellular specificity of haemopoietic stem cell proliferation regulators. Br J Cancer 1984; 50:335–41. 81. Tejero C, Testa NG, Hendry JH. Decline in cycling of granulocyte-macrophage colony-forming cells with increasing age in mice. Exp Hematol 1989; 17:66–7. 82. Vaziri H, Dragowska W, Allsopp RC et al. Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proc Natl Acad Sci USA 1994; 91:9857–60. 83. Olovnikov AM. A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J Theor Biol 1973; 41: 181–90. 84. Watson JD. Origin of concatemeric T7 DNA. Nat New Biol 1972; 239:197–201. 85. Lundblad V, Szostak JW. A mutant with a defect in telomere elongation leads to senescence in mice. Cell 1989; 57:633–43. 86. Allsopp RC, Vaziri H, Patterson C et al. Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci USA 1992; 89:10114–18. 87. Vaziri H, Schachter F, Uchida I et al. Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes. Am J Hum Genet 1993; 52:661–7. 88. Hastie ND, Dempster M, Dunlop MG et al. Telomere reduction in human colorectal carcinoma and with ageing. Nature 1990; 346: 866–8. 89. Robertson JD, Gale RE, Wynn RF et al. Dynamics of telomere shortening in neutrophils and T lymphocytes during ageing and the relationship to skewed X chromosome inactivation patterns. Br J Hematol 2000; 109:272–9. 90. Kassar NE, Hetet G, Briere J, Grandchamp B. X-chromosome inactivation in healthy females: incidence of excessive lyonization with age and comparison of assays involving DNA methylation and transcript polymorphism. Clin Chem 1998; 44:61–7. 91. Abkowitz JL, Taboada M, Shelton GH et al. An X chromosome gene regulates hematopoietic stem cell kinetics. Proc Natl Acad Sci USA 1998; 95:3862–6 92. Sen S, Talukder G, Sharma A. Chromosomal alterations and DNA content in rats during ageing. Genome 1989; 32:389–92. 93. De Boer P, van der Hoeven FA. The use of translocation derived marker bivalents for studying the origin of meiotic instability in female mice. Cytogenet Cell Genet 1980; 26:49–58. 94. Singh SM, Toles JF, Reaume J. Genotype- and age-associated in vivo cytogenetic alterations following mutagenic exposures in mice. Can J Genet Cytol 1986; 28:286–93.

Hematopoiesis and aging

779

95. Boggs SS, Patrene KD, Austin CA et al. Latent deficiency of the hematopoietic microenvironment of aged mice as revealed in W/Wv mice given +/+ cells. Exp Hematol 1991; 19:683–7. 96. Sidorenko AV, Andrianova LF, Macsyuk TV, Butenko GM. Stromal hemopoietic microenvironment in aging. Mech Ageing Dev 1990; 54:131–42. 97. Sidorenko AV. Stromal precursor cells of hemopoietic and lymphoid organs in aged mice. Arch Biol (Bruxelles) 1985; 96: 237–51. 98. Schofield R, Dexter TM, Lord BI, Testa NG. Comparison of hemopoiesis in young and old mice. Mech Ageing Dev 1986; 34: 1–12. 99. Sidorenko AV, Gubrii IB, Andrianova LF et al. Functional rearrangement of lymphohemopoietic system in heterochronically parabiosed mice. Mech Ageing Dev 1986; 36:41–56. 100. Udupa KB, Lipschitz DA. Effect of donor and culture age on the function of neutrophils harvested from long-term bone marrow culture. Exp Hematol 1987; 15:212–216. 101. Baraldi-Junkins CA, Beck AC, Rothstein G. Hematopoiesis and cytokines. Relevance to cancer and aging. Hematol Oncol Clin North Am 2000; 14:45–61. 102. Li DD, Chien YK, Gu MZ et al. The age-related decline in interleukin-3 expression in mice. Life Sci 1988; 43:1215–22. 103. Bagnara GP, Bonsi L, Strippoli P et al. Hemopoiesis in healthy old people and centenarians: well-maintained responsiveness of CD34+ cells to hemopoietic growth factors and remodeling of cytokine network. J Gerontol 2000; 55A:B61–6 104. Fong TC, Makinodan T. In situ hybridization analysis of age associated decline in IL-2 mRNA expressing murine T cells. Cell Immunol 1989; 118:199–207. 105. Holbrook NJ, Chopra RK, McCoy MT et al. Expression of interleukin 2 and the interleukin 2 receptor in aging rats. Cell Immunol 1989; 120:1–9. 106. Updyke LW, Cocke KS, Wierda D. Age-related changes in production of interleukin-7 (IL-7) by murine long-term bone marrow cultures (LTBMC). Mech Ageing Dev 1993; 69:109–17. 107. Stephan RP, Reilly CR, Witte PL. Impaired ability of bone marrow stromal cells to support Blymphopoiesis with age. Blood 1998; 91: 75–88. 108. Namen AE, Lupton S, Hjerrild K et al. Stimulation of B-cell progenitors by cloned murine interleukin-7. Nature 1988; 333: 571–3. 109. Ershler WB. Interleukin-6: A cytokine for gerontologists. J Am Geriatr Soc 1993; 41:176–81. 110. Kawano M, Hirano T, Matsuda T et al. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature 1988; 332:83–5. 111. Klein B, Zhang XG, Jourdan M et al. Paracrine rather than autocrine regulation of myelomacell growth and differentiation by IL-6. Blood 1989; 73:517–26. 112. Nachbaur DM, Herold M, Maneschg A, Huber H. Serum levels of interleukin-6 in multiple myeloma and other hematologic disorders: correlation with disease activity and other prognostic parameters. Ann Hematol 1991; 62:54–8. 113. Merz H, Fliedner A, Orscheschek K et al. Cytokine expression in T-cell lymphomas and Hodgkin’s disease. Its possible implication in autocrine or paracrine production as a potential basis for neoplastic growth. Am J Pathol 1991; 139:1173–80. 114. Ganter U, Arcone R, Toniatti C et al. Dual control of CRP gene expression by interleukin-1 and interleukin-6. EMBO J 1989; 8: 3773–9. 115. Garman RD, Jacobs KA, Clark SC, Raulet DH. B cell stimulatory factor 2 (β2-interferon) functions as a second signal for interleukin-2 production by mature murine T cells. Proc Natl Acad Sci USA 1987; 84:7629–33. 116. Brandt SJ, Bodine DM, Dunbar CE, Nienhuis AW. Dysregulated interleukin-6 expression produces a syndrome resembling Castle-man’s disease in mice. J Clin Invest 1990; 86:592–9. 117. Yoshizaki K, Matsuda T, Nishimoto N et al. Pathogenic significance of interleukin-6 (IL6/BSF-2) in Castleman’s disease. Blood 1989; 74:1360–7.

Comprehensive Geriatric Oncology

780

118. Jourdan M, Bataille R, Seguin J et al. Constitutive production of interleukin-6 and immunologic features in cardiac myxoma. Arthritis Rheum 1990; 33:398–403. 119. Daynes RA, Araneo BA, Ershler WB et al. Altered regulation of IL-6 production with normal aging: possible linkage to the age-associated decline in dehydroepiandrosterone (DHEA) and its sulfated derivative. J Immunol 1993; 150:5219–30. 120. Tang B, Matsuda T, Akria S et al. Age-associated increase in interleukin-6 in MRL/lpr mice. Int Immunol 1991; 3:273–8. 121. Foster KD, Conn CA, Kluger MJ. Fever, tumor necrosis factor and interleukin-6 in young, mature and aged Fischer 344 rats. Am J Physiol 1992; 262: R211. 122. Radl J. Age-related monoclonal gammopathies: clinical lessons from the aging C57BL mouse. Immunol Today 1990; 11:234–6. 123. Radl J, Sepers JM, Skvaril F et al. Immunoglobulin patterns in humans over 95 years of age. Clin Exp Immunol 1975; 22:84–90. 124. Abraham CR, Shirahama T, Potter H. α1-Antichymotrypsin is associated solely with amyloid deposits containing the B-protein. Amyloid and cell localization of α1-antichymotrypsin. Neurobiol Aging 1990; 11:123–9. 125. Vandenabeele P, Fiers W. Is amyloidogenesis during Alzheimer’s disease due to an IL-1/IL-6mediated ‘acute phase response’ in the brain? Immunol Today 1991; 12:217–19. 126. Bauer J, Konig G, Strauss S et al. In vitro matured macrophages express Alzheimer’s βA4amyloid precursor protein indicating synthesis in microglial cells. FEBS Lett 1991; 282:335–40. 127. Sun WH, Binkley N, Bidwell DW, Ershler WB. The influence of recombinant human interleukin-6 on blood and immune parameters in middle-aged and old Rhesus monkeys. Lymphokine Cytokine Res 1993; 12:449–55. 128. Ishimi Y, Miyaura C, Jin CH et al. IL-6 is produced by osteoblasts and induces bone resorption. J Immunol 1990; 145:3297–303. 129. Roodman GD. Interleukin-6: an osteoporotic factor? J Bone Miner Res 1992; 7:475–8. 130. Girasole G, Jilka RL, Passeri G et al. 17β-Estradiol inhibits interleukin-6 production by bone marrow-derived stromal cells and osteoblasts in vitro: a potential mechanism for the antiosteoporotic effect of estrogens. J Clin Invest 1992; 89:883–91. 131. Tanaka H, Quarto R, Williams S et al. In vivo and in vitro effects of insulin-like growth factor-I (IGF-I) on femoral mRNA expression in old rats. Bone 1994; 15:647–53. 132. Tanaka H, Liang CT. Effect of platelet-derived growth factor on DNA synthesis and gene expression in bone marrow stromal cells derived from adult and old rats. J Cell Physiol 1995; 164:367–75. 133. Pawelec G, Effros RB, Caruso C et al. T cells and aging. Front Biosci 1999; 4:d216–69 134. Sharp A, Kukulansky T, Malkinson Y, Globerson A. The bone marrow as an effector T cell organ in aging. Mech Ageing Dev 1990; 52:219–33. 135. Globerson A, Sharp A, Fridkis-Hareli M et al. Aging in the T lymphocyte compartment. A developmental view. Ann NY Acad Sci 1992; 673:240–51. 136. McCormick KR, Haar JL. Bone marrow-thymus axis in senescence. Am J Anat 1991; 191:321–4. 137. Montecino-Rogriguez E, Clark R, Dorshkind K. Effects of insulinlike growth factor administration and bone marrow transplantation on thymopoiesis in aged mice. Endocrinology 1998; 139: 4120–6. 138. Hozumi K, Masuko T, Nishimura T et al. Characterization of the T cells in aged rat bone marrow. Immunol Lett 1993; 36:137–44. 139. Globerson A. Thymocyte progenitors in ageing. Immunol Lett 1994; 40:219–24. 140. Schulze DH, Goidl EA. Age-associated changes in antibodyforming cells (B cells). Proc Soc Exp Biol Med 1991; 196:253–9. 141. Kincade PW. Experimental models for understanding B lymphocyte formation. Adv Immunol 1987; 41:181–267.

Hematopoiesis and aging

781

142. Jonsson JI, Phillips RA. Interleukin-7 responsiveness of B220+ B cell precursors from bone marrow decreases in aging mice. Cell Immunol 1993; 147:267–78. 143. Price GB, Makinodan T. Immunologic deficiencies insenescence. I. Characterization of intrinsic deficiencies. J Immunol 1972; 108: 403–12. 144. Viale AC, Chies JAB, Huetz F et al. VH-gene family dominance in ageing mice. Scand J Immunol 1994; 39:184–8. 145. Ben-Yehuda A, Szabo P, Dyall R, Weksler ME. Bone marrow declines as a site of B-cell precursor differentiation with age: relationship to thymus involution. Proc Natl Acad Sci USA 1994; 91:11988–92. 146. Ben-Yehuda A, Szabo P, Weksler ME. Age-associated change in the B-cell repertoire: effect of age on RAG-1 gene expression in murine bone marrow. Immunol Lett 1994; 40:287–9. 147. Ghia P, Melchers F, Rolink AG. Age-dependent changes in B lymphocyte development in man and mouse. Exper Gerontol 2000; 35:159–165.

37 Anemia and aging: Relevance to the management of cancer Lodovico Balducci, Cheryl L Hardy Introduction Anemia has gained a prominent role in cancer management in recent years.1 The interest in anemia stems from a number of considerations, including the following: • Chemotherapy-induced myelotoxicity is enhanced by anemia, owing to restriction of the volume of distribution of water-soluble agents, and increased concentration of free drug in the circulation.2–6 • Anemia is associated with fatigue, which is the most common long-term side-effect of both cancer and chemotherapy.7–9 • The advent of recombinant erythropoietin (rhEPO) allows reversal of anemia for a prolonged period of time and without the risks of blood transfusions.10 In older cancer patients, the effects of anemia may be magnified, owing to reduced functional reserve of multiple organ systems (see Chapter 18 of this volume11); furthermore, anemia in older patients may have additional adverse effects, including decreased survival,12–16 functional dependence,17–18 and other iatrogenic complications, including delirium,19 congestive heart failure,20 death from coronary artery disease,21 and cognitive decline.22 As anemia is a prominent risk factor for chemotherapy-related toxicity, it deserves a special chapter in a textbook of geriatric oncology. The focus of this chapter will be the interaction of cancer, aging, and anemia. Definition of anemia According to the World Health Organization (WHO), anemia is defined as a hemoglobin value of less than 13 g/dl for men and less than 12 g/dl for women. Because this definition is generally accepted, we shall adopt it in the following review of the epidemiology of anemia and aging, but this definition may be obsolete in view of new findings. In favor of the WHO definition of anemia, the concentration of endogenous erythropoietin (EPO) in the circulation of younger adults starts to increase for hemoglobin values below 12 g/dl, indicating that hypoxia is present at these hemoglobin levels.23,24 New data indicate, however, that higher upper hemoglobin levels may be more appropriate to define anemia, at least in older individuals:

Anemia and aging: Relevance to the management of cancer

783

• The Woman’s Health Study, involving 1005 women aged 65 and older followed longitudinally for an average of 7 years, showed that hemoglobin below 13.4 g/dl was an independent risk factor for mortality.12 • Two studies exploring the relationship between hemoglobin and fatigue levels in cancer patients showed that the highest incremental improvement of fatigue was obtained for hemoglobin levels between 11 and 13 g/dl.25,26 • In some older individuals, the increment in the circulating levels of endogenous EPO is seen for hemoglobin levels higher than 12 g/dl;27–28 this finding suggests that, in the presence of peripheral vascular disease, tissue hypoxia may develop at higher hemoglobin levels. • The incidence of surgical complications may be higher for hemoglobin levels of 12 g/dl than for higher levels.29 These findings suggest that the diagnosis of anemia should be considered whenever hemoglobin levels drop below 13.5–14 g/dl. Epidemiology of anemia and aging Aging is associated with increased incidence and prevalence of anemia.15,30–32 This issue was studied in Olmstead County,15,30 in an Italian cross-sectional study,31 and in a longitudinal study in New Mexico.32 In Olmstead County, the real prevalence and incidence of anemia in the general population (Figure 37.1) can be easily assessed, because 98% of the population belongs to the same health management organization. Of interest, both incidence and

Figure 37.1 Prevalence (white bars) and incidence (black bars) of anemia in Olmstead County

Comprehensive Geriatric Oncology

784

prevalence increased steeply after age 65, and somehow the prevalence of anemia appeared lower among recent than long-term residents of the county.30 A cross-sectional study of more than 1400 Italian elderly showed that the average levels of hemoglobin were rather consistent between ages 65 and 85, and the average prevalence of anemia in the whole population was 8.5%.32 While it might have been desirable to have more information related to the prevalence of anemia among younger and older patients, this study is important for two reasons: it shows that the prevalence of anemia indeed increases after age 65, but at the same time anemia is not a normal consequence of age. Similar conclusions were reached by the longitudinal study of elderly persons in New Mexico, where hemoglobin was maintained constant by healthy elderly up to age 90.31 Several studies explored the causes of anemia in older individuals15,33 (Table 37.1). As expected, iron-deficiency anemia and anemia of chronic disease represent approximately 40% of the causes of anemia, but of special interest is the fact that in approximately 30% of cases the cause

Table 37.1 Causes of anemia33 Cause

Prevalence (%)

Chronic disease

35

Iron deficiency

15

Post-hemorrhagic

7

Renal failure; liver and endocrine disease

6.5

Myelodysplasia or acute leukemia

5.5

Chronic leukemia or lymphoma

5.5

Vitamin B12 or folate deficiency

5.5

Other hematological disease Unexplained causes

3 17

of anemia was unestablished. In part, this finding may reflect inadequate workup, and in part early myelodysplasia, but it is not far fetched to assume that in some cases it may represent relative EPO deficiency due to renal insufficiency, whose prevalence increases with age.34,35 In older individuals, renal insufficiency may be present also when the serum creatinine concentration is within normal limits, due to decreased muscular mass. This possibility is supported by the fact that in some older patients the production of EPO seems to be reduced with respect to younger patients.24,36–39 Of special interest is also the increasing prevalence of vitamin B12 deficiency with age. Although the estimates vary, B12 deficiency may be present in 5–15% of individuals over 65. This variation is due in part to the uncertainty on the best way to estimate B12 deficiency, whether by assaying the circulating levels of B12 or by using functional assays of B12 deficiency. The current standard laboratory levels of circulating B12 may lead to underestimation of B12 deficiency.40–41 Some tests revealing inadequate B12 stores include circulating levels of methylmalonic acid, histidine, and transcobalamine III: these tests

Anemia and aging: Relevance to the management of cancer

785

may be abnormal in the presence of B12 levels as high as 300 pg/fil. In most cases, B12 deficiency in the elderly is not due to pernicious anemia, but to decreased gastric acid production to a level that does not allow hydrolysis of food B12.42 Also, B12 deficiency may not be associated with anemia in older individuals, when folate supply is adequate, but may lead to dementia and peripheral neuropathy. Finally, it is important to mention rare forms of anemia that appear to be age-related. These include nutritional anemia,43 dysautonomic anemia,44 and synarthresis.45 Nutritional anemia is a normocytic, hypoproliferative anemia developing during proteincalorie malnutrition and reversible with nutritional replenishment.43 Dysautonomic anemia develops in concomitance with the Shy-Drager syndrome (primary autonomic insufficiency), and is responsive to EPO.44 Synarthresis develops in the course of monoclonal gammopathy, and is due to isolation of the erythroid precursors by a membrane formed by immunoglobulins.45 Age and the pathogenesis of anemia In addressing the question whether aging predisposes to anemia, we shall explore three distinct possibilities: • reduced erythropoietic reserve; • reduced production of EPO and other erythropoietic cytokines; • reduced sensitivity of aging hemopoietic precursors to EPO. Experimental and clinical data suggest that the reserve of hemopoietic progenitors decreases with age. In murine models: • The self-replicative ability of hematopoietic stem cells (colony-forming units-spleen, CFU-S) is progressively reduced in serial transplants.46 The hematopoietic progenitors may become exhausted with age, and consequently tolerance of hematopoietic stress becomes reduced with age. • Progressive reduction of telomere length and of telomerase activity in primitive hematopoietic stem cells of older animals also suggests a decline in the self-replicative potential of these elements with age.47 • Hematopoietic stress leads to a more rapid decline in the concentration of hematopoietic progenitors of the marrow in older than in younger animals.48–49 In humans: • The hematopoietic tissue shrinks with age; in the adult, it is limited to the flat bones, and the ratio between hematopoietic elements and fat continues to decline with age (see Chapter 36 of this volume50). • Mortality from infection is increased—possibly because of more limited neutrophil response (see Chapter 60 of this volume51). • The increment in the concentration of circulating early hematopoietic precursors following injection of granulocyte-macrophage colony-stimulating factor (GM-CSF)52 is more limited in persons over 70 than in those under 50. • The incidence and prevalence of anemia of unknown origin1,30–33,53 is increased.

Comprehensive Geriatric Oncology

786

• The risk of neutropenia and neutropenic infections and of thrombocytopenia following cytotoxic chemotherapy is increased.54–56 • The self-replicative ability of early pluripotent hematopoietic progenitors colonyforming units-granulocyte/macrophage (CFU-GM) declines progressively with age.57 • The concentration of circulating CD34+ cells declines progressively with age.58 An age-related decline in hematopoietic reserve is unlikely to be a cause of anemia by itself, since the hemoglobin concentration persists stably in healthy individuals until after the age of 85,31,32 but it may hasten the development of anemia in the presence of disease.31,59 The data relating to the production of EPO are inconclusive: Powers et al60 could not demonstrate any significant difference between the EPO response to anemia in younger and older adults. This study included a limited number of persons aged over 70, however, and included mainly patients with chronic anemia. This is important, because the initial EPO response to anemia may determine the increase in hemoglobin. More than to baseline concentrations of hemoglobin, erythropoietic precursors appear to be sensitive to rapid changes in concentration.23 Tasaki et al27 showed that the concentration of circulating EPO increased earlier in individuals over 70 than in those younger, during development of iron deficiency. While this study does not support an age-related decline in EPO production, it leads to important alternative suggestions: 1. Older individuals require a higher concentration of hemoglobin than younger individuals to maintain tissue oxygenation. Seemingly, obliteration of small vessels and tissue fibrosis are responsible for this effect. 2. Erythropoietic precursors are less sensitive to stimulation by EPO in older than in younger individuals. In a number of studies,24,28,36–39 the response of EPO to anemia was lower in older than in younger individuals. As expected, a high degree of variability in EPO production existed among patients of the same age. Although all patients had normal values of serum creatinine, creatinine clearance had not been measured or calculated. It is reasonable to assume that reduced EPO production was associated with reduced glomerular filtration rate. It is also reasonable to conclude that some older people present a condition of relative EPO insufficiency (i.e. they cannot mount an adequate EPO response to anemia) and that renal insufficiency is partly responsible for this. Age-associated decreases in EPO production have been reported in at least one type of anemia, namely anemia of primary autonomic failure.44 The results indicate that the anemia is associated with a blunted EPO response, resulting from an impaired stimulation of erythropoiesis by the sympathetic nervous system. Impaired responsiveness of hematopoietic progenitors to hematopoietic cytokines may explain all the cases of reduced tolerance of hematopoietic stress by older individuals48,48,52–56 (and see Chapters 36 and 6050,51). A number of experiments and clinical findings provide specific support to this possibility. In older polycythemic mice, the recovery of the original hematocrit after phlebotomy is more delayed than in younger animals, while the concentration of circulating EPO is the same.61 Morra et al62 and Hyrota et al63 found that the responsiveness of early erythropoietic precursors burstforming units-erythroid, BFU-E) to EPO was reduced, but indocin, which blocked suppressor T-cell activity, re-established sensitivity to EPO. Other authors found that

Anemia and aging: Relevance to the management of cancer

787

higher levels of circulating EPO were necessary in older individuals than in younger individuals, to obtain the same reticulocytic response.33,38 Of special interest, aging has been associated with an accumulation of inflammatory cytokines,64–66 some of which, including interleukin-6 (IL-6) and tumor necrosis factor (TNF) are known to reduce responsiveness to EPO. We must acknowledge that ample evidence to the contrary has also been provided. CD34+ cells from people aged 100 or older were found by Bagnara et al58 to have the same responsiveness to EPO, granulocyte colony-stimulating factor (GCSF), and GM-CSF as those of younger individuals. Other investigators found that the clinical response to pharmacological doses of G-CSF, GM-CSF,67 IL-11,68 megakaryocyte growth and development factor (MGDF), thrombopoietin (TPO),69 and EPO70 was the same in the young and the old. As in other areas of aging, we are faced with contradictory data, revealing the diversity of the older population and highlighting the inadequacy of chronological age in reflecting physiological aging. We may conclude by saying that: • There is no group of erythropoietic changes that one may consider specific of aging. • Although the reserve of hematopoietic stem cells and erythropoietic progenitors may become more limited with age, this fails to cause anemia by itself. At most, reduced hematopoietic reserve may compromise the tolerance of the elderly to hematopoietic stress, and favor the development of anemia in the course of different diseases. • The production of EPO is reduced in a minority of older individuals, likely owing to a reduced glomerular filtration rate. • Sensitivity to EPO may be reduced in a number of older individuals, owing to inflammatory cytokines and immune senescence. • The possibility of relative EPO insufficiency (i.e. production of EPO inadequate to support erythropoiesis in older individuals) is suggested by these findings, especially by the combination of reduced production of and reduced sensitivity to EPO. • Knowledge of erythropoiesis in the oldest old (85+) is very limited. The data from centenarians may not be reflective of the whole older population, because centenarians may owe their longevity to a favorable genetic combination that delays physiological aging.71 After exploring the mechanisms by which aging may favor the development of anemia, we want to explore the possibility that anemia may accelerate aging. This question is most appropriate at the time when we may be able to reverse anemia with rhEPO. It is tantalizing to hypothesize a vicious cycle linking anemia and aging (Figure 37.2). Chronic diseases cause anemia by various mechanism, including the accumulation of inflammatory cytokines in the circulation, anemia prevents the healing of chronic diseases, which leads to more cytokines and more anemia. In addition to reducing the sensitivity of hematopoietic precursors to EPO, inflammatory cytokines

Comprehensive Geriatric Oncology

788

Figure 37.2 The vicious cycle of anemia and aging. may cause sarcopenia,72 which in turns weakens immune defenses and perpetuates the disease; at the same time, protein deprivation by itself may be a cause of anemia. The hypothesis that the correction of anemia may interrupt the cycle and delay aging deserves to be tested in clinical trials, since it is clear that anemia has dire clinical consequences for the older person. Clinical consequences of anemia in the elderly Only recently has awareness of the clinical consequences of anemia fully developed. Irrespective of the causes, anemia has some severe consequences that may compromise survival and quality of life of older individuals.12–18 Anemia and survival At least five studies have shown that anemia is associated with a decreased survival of older individuals; this inverse relation may also exist for the young, but has never been explored.

Anemia and aging: Relevance to the management of cancer

789

Izaks et al14 reported that the 5-year mortality of Dutch men and women aged 85 and older was increased almost twofold in the presence of anemia, and anemia persisted as an independent risk factor even when the mortality was adjusted for function and chronic diseases. Of special interest, there was a direct correlation between the degree of anemia and the risk of mortality. Almost-identical results were reported by Kikuchi et al13 among elderly Japanese men and women. Gagnon et al16 reported that anemia was associated with increased risk of cardiovascular death in persons over 70. Of special interest, Ania et al15 reported that the risk of death was correlated with anemia even in persons aged 65 and older, and was independent of functional status and comorbidity. Thus, anemia is not a problem just for the oldest old and the frail elderly. Particularly provocative is the study by Chaves et al.12 In addition to confirming the data of Ania et al that anemia is associated with increased risk of death after age 65, this study may lead to a revision of the current definition of anemia. From a longitudinal study in 1002 community-dwelling women aged 65 and older (the Woman’s Health Study), these authors found that: • Mortality was higher for women with a hemoglobin level less than 12 g/dl than those with a hemoglobin level between 13 and 14 g/dl. • The risk of dying decreased 0.76 times for every increase of 1 g/dl in hemoglobin between 8 and 12 g/dl. • For hemoglobin levels less than 13.4 g/dl, anemia was an independent risk factor for death Anemia, fatigue, and functional dependence Fatigue involves a sensation of lack of energy that does not recover with rest, unlike normal tiredness, and that prevents the subject from having regular activity and conducting a normal life.17 The consequences and management of fatigue have been studied mainly in the cancer literature, because fatigue is the most common chronic symptom of cancer.8 Whereas fatigue is common in patients of all ages, it is particularly common after age 65. A recent study by Respini et al73 revealed fatigue in more than 90% of individuals aged 65 and over receiving chemotherapy. Fatigue has serious emotional and social consequences: approximately 50% of patients experiencing fatigue and 25% of their caregivers needed to change job or quit their job altogether because of fatigue.8 Of special concern, fatigue may cause functional dependence in older individuals,18 which in turn may lead to: • progressive functional decline, failure to thrive, and death; • delayed cancer treatment because of lengthy rehabilitation and suboptimal cancer control; • substantial increases in management costs due to the rehabilitation, the employment of a full-time caregiver, and the nutritional, emotional, functional, and medical complications of reduced mobility. The two main causes of fatigue are energy imbalance and emotional distress.74 The centrality of anemia in poor energy balance was highlighted in a number of studies that showed in cancer patients that:

Comprehensive Geriatric Oncology

790

• Correction of anemia with rhEPO is associated with improvement in fatigue.25,26,75–77 It should be underlined that one of these studies was randomized, placebo-controlled, and double-blinded.77 • The best incremental improvement of fatigue was obtained when the hemoglobin levels increased from 10 to 13 g/dl. • Improvement of fatigue was independent of the response of cancer to chemotherapy. In older individuals, other conditions beside anemia may contribute to an unfavorable energy balance, in particular the increased concentration of catabolic cytokines, which may cause anorexia and sarcopenia, in addition to anemia. Future studies in older individuals should try to establish whether the severity of fatigue correlates with the concentration of these substances in the circulation, whether correction of anemia is associated with a decline in the concentrations of cytokines, and whether adjuvant treatment with substances that may lower the cytokine levels (e.g. thalidomide) is beneficial. Anemia and cardiovascular complications Cardiovascular complications of anemia are of special concern in the elderly, since the incidence of coronary artery diseases and congestive heart failure increases with age.78 Dyspnea and angina are recognized symptoms of anemia. The majority of health institutions nowadays have guidelines for the use of blood transfusions aimed to prevent these manifestations.79 Metivier et al20 have illustrated how chronic anemia involves chronically increased cardiac output that may lead to left ventricular hypertrophy. Prior to the correction of anemia with rhEPO, this type of complication was almost universal in chronic renal failure.80 Every decrease in hemoglobin of 1 g/dl was associated with an increase in the risk of left ventricular hypertrophy by 6%. In older individuals, anemia is an adverse risk factor both for congestive heart failure and for coronary artery disease. Silverberg et al78 found a significant correlation in persons aged 70 and older between the incidence and severity of congestive heart failure and circulating hemoglobin levels. In the presence of severe anemia (hemoglobin <5 gm/dl) congestive failure developed even in the absence of pre-existing cardiovascular disease. Wu et al21 reported that mortality from coronary artery disease in a coronary care unit was increased for patients aged 65 and older if the hematocrit was below 33% and they did not receive blood transfusions. Anemia and cognition A correlation between anemia and the risk of Alzheimer’s disease was first identified by Beard et al,81 but the mechanism of this association has not been elucidated. A number of cognitive and emotional complications of anemia including headaches, loss of concentration, and depression, have been reported.82–84 In dialysis patients, anemia was found to be associated with confusion, inability to concentrate, decreased mental alertness, and impaired memory.22,85 A direct correlation between hemoglobin levels and cognition was established by Pickett et al.22 These authors found that increasing the hematocrit of chronic dialysis

Anemia and aging: Relevance to the management of cancer

791

patients above 33–36% with blood transfusions improved attention span, learning ability, and memory. Anemia and iatrogenic complications Anemia may influence the incidence of iatrogenic complications through several mechanisms, including: • a reduced volume of distribution of water-soluble drugs, which may be bound to red blood cells, and consequently an increased concentration of the drugs in the circulation; • reduced oxygenation of the tissues, which makes them more susceptible to iatrogenic complications—not surprisingly, the tissues with higher rates of oxygen consumption (e.g. the central nervous system and the bone marrow) are those most susceptible to iatrogenic complications in the presence of anemia.2–6,19 Anemia is of special concerns to cancer patients, in whom both the disease and the treatment may contribute to its pathogenesis.86 With progression of chemotherapy and radiation therapy, the risk of anemia also increases.87–89 At least five studies have shown that the risk of complications of cytotoxic chemotherapy (especially myelosuppression) increases in the presence of anemia.2–6 The relationship between anemia and therapeutic complications is particularly strong for medications that are heavily bound to red blood cells, including the anthracyclines, the epipodophyllotoxins, and the camptothecins. In younger individuals, the effects of anemia may be buffered in part by other tissues; this compensatory mechanism may be missing in older patients, as a result of sarcopenia.72,90 In at least one study, correction of anemia was associated with improved therapeutic response and disease-free survival.91 Patients with small cell lung cancer were randomized to receive rhEPO and placebo. Higher hemoglobin levels were associated with improved disease-free survival, possibly because radiation therapy to the chest and the brain was more effective for better tissue oxygenation. Another common iatrogenic complication of anemia is delirium. Marcantonio et al19 reported that postoperative delirium was three times as common for patients whose hemoglobin level was below 10 g/dl. Clearly, anemia seems to be associated with a general condition of poor health, which may compromise the outcome and the quality of life of older patients with cancer, and management of anemia should be a priority in these patients. Diagnostic workup and management of anemia The diagnostic workup of anemia in the older person is not different from the general diagnostic workup of anemia (Figure 37.3). The first step involves differentiation between hypoproliferative anemia and anemia due to increased blood loss. In the absence of acute bleeding, blood loss is due to hemolysis, which may be suggested by increased circulating levels of lactate dehydrogenase

Comprehensive Geriatric Oncology

792

Figure 37.3 Differential diagnosis of anemia. (LDH) and bilirubin. The main causes of hemolysis in older individuals include autoimmune hemolytic anemia, diagnosed by a positive direct Coombs test, and microangiopathic anemia, diagnosed with recognition of schistocytes in the peripheral blood smear. Microangiopathic anemia is seen in association with the following conditions:

Anemia and aging: Relevance to the management of cancer

793

• disseminated intravascular coagulation (DIC), the diagnosis of which is confirmed by prolongation of prothrombin time (PT) and partial thromboplastin time (PTT), an abnormally low fibrinogen level, increased levels of fibrin degradation products, thrombocytopenia, and increased circulating levels of D-dimer; • thrombotic thrombocytopenic purpura (TTP), whose diagnosis is established by the presence of thrombocytopenia, normal coagulation studies, renal insufficiency, mentation changes, and increased circulating levels of von Willebrand multimer; • trauma; • peripheral vascular disease (diabetes or hypertension). In older cancer patients, by far the most common anemias are the chronic ones. Table 37.2 explains tests of common use in the differential diagnosis of chronic anemias. Of note: • Vitamin B12 levels below 300 pg/ml should be considered abnormal, because below these levels, the concentrations of methylmalonic acid and histidine in the circulation are commonly elevated, indicating functional B12 deficiency.40,41 • B12 deficiency in older individuals is commonly due to poor digestion of food B12; these patients may respond to oral B12, although monthly injections may represent a more practical form of administration.42,43

Table 37.2 Diagnostic workup of anemia in the elderly: indication of specific tests Test

Indications

Significance

Reticulocyte counts All cases

To distinguish hypoproliferative anemia from anemia of increased blood loss

Lactate dehydrogenase (LDH)

All cases

Increased in presence of hemolysis, ineffective hematopoiesis, and cancer

Iron studles

All cases of microcytic and normocytic anemia

(1) Serum Fe

(1) Decreased in iron deficiency and anemia of chronic disease

(2) Iron-binding capacity

(2) Increased in iron deficiency; decreased in anemia of chronic disease

(3) Ferritin

(3) Decreased in iron deficiency; increased or normal in anemia of chronic disease; increased in acute inflammation and liver necrosis

Soluble transferrin receptors

To diagnose iron deficiency • when iron studies are • inconclusive

Increased in iron deficiency

Vitamin B12 and folate levels

All cases of macrocytic and normocytic anemia

B12 is decreased in pernicious anemia and all cases of B12 malabsorption

•

Decreased in anemia of chronic disease

Comprehensive Geriatric Oncology

•

Erythropoietin (EPO) levels

Bone marrow aspiration and biopsy

All cases of normocytic hypoproliferative anemia

794

Red blood cell folate is decreased in dietary deficiency and in the presence of drugs that interfere with absorption

Decreased in: •

Renal insufficiency;

•

Primary EPO deficiency

•

Relative EPO insufficiency

• All cases of pancytopenia Diagnostic for: • All cases in which myelophthysis is suspected

•

Aplastic anemia

•

Myelodysplasia and acute leukemia

• All cases in which a diagnosis cannot otherwise be established

•

Bone marrow invasion by cancer, infection, granulomas, and fibrosis

•

May be diagnostic of myelodysplasia

•

Prognostic value in myelodysplasia and acute myeloid leukemia

Cytogenetic studies Every time a diagnostic of bone marrow bone marrow aspiration is planned

• The concentration of soluble transferrin receptors increases in the presence of iron deficiency, and may be diagnostic of this condition when the ferritin levels may be non-specifically elevated by inflammation or liver injury.92 • The determination of serum EPO levels may be diagnostic of anemia of chronic renal insufficiency, primary EPO deficiency, and relative EPO deficiency, as seen in anemia of chronic disease. Relative EPO deficiency is diagnosed when the levels of circulating EPO are inadequate for the level of anemia. The management of anemia involves management of the primary cause, when this is found. In the case of anemia of renal insufficiency and anemia of chronic disease, a therapeutic trial of EPO is warranted. Weekly doses of EPO (40000 U per week) are as effective as thrice-weekly administration.25 The development of darbepoietin (to whose molecule has been added a number of sialic acid molecules) may allow even less frequent administration, which is particularly convenient for patients receiving chemotherapy every 3 weeks.93 The simultaneous administration of iron may improve the response to rhEPO.94 Iron can be administered orally or intravenously. Given the established benefits of correcting anemia in cancer patients, the National Cancer Centers Network (NCCN) guidelines for the management of cancer in the elderly recommend that the hemoglobin levels be maintained at or above 12 g/dl.95 Questions related to the management of anemia in the older aged person With it having been established that anemia is central to multiple pathologies in the older aged person, three clinical questions arise: • When are diagnostic investigations of anemia indicated?

Anemia and aging: Relevance to the management of cancer

795

• What are the benefits of reversing anemia in the older aged person? • What is the cost of investigating and managing anemia? Investigations of anemia: When and how? In the past, it has been recommended that anemia not be investigated in individuals aged 65 and older unless the hemoglobin levels are lower than 12 g/dl.31 This recommendation should be revised in view of new evidence indicating that even minimal levels of anemia may be detrimental to the older aged person.12 Unless a patient has a life-expectancy of 6 months or less, it appears reasonable to investigate any abnormal hemoglobin levels, irrespective of the patient’s age. What are the benefits of reversing anemia? The benefits of reversing anemia have been demonstrated in the following conditions: • In dialysis patients, correction of anemia leads to improved energy levels and reduces the risks of dementia and of congestive heart failure.22,80,85,96,97 • In patients with rheumatoid arthritis, correction of anemia has been associated with improved energy levels and quality of life.98 • In cancer patients, correction of anemia has led to improved quality of life, reduced risk of chemotherapy-related toxicity, and improved therapeutic response, at least in the case of small cell lung cancer.75–77,86,91 • In patients with acute coronary events, reversal of anemia with blood transfusions has prevented death from infarction.21 • In patients with severe congestive heart failure, reversal of anemia with rhEPO improves both cardiac and renal function.78 These results are encouraging and offer hope that correction of even mild anemia may prolong the survival and improve the function and general health of older individuals. The possibility that correction of anemia may delay aging is particularly attractive. These hypotheses should be explored in the context of clinical trials. Two concerns should be addressed: • Long-term side-effects of rhEPO: a recent report of aplastic anemia from anti-EPO antibodies in patients chronically treated with rhEPO99 has raised some concerns about the complete safety of this agent. Another concern is the possibility of stem cell competition and depletion of other blood elements. Overall, however, the safety profile of rhEPO appears to be excellent. • A more serious concern is that some of the physiologic changes of aging, including the increased concentration of circulating cytokines, have some unknown protective effects for the older individual. Short of improving the survival and the quality of life of these patients, reversal of anemia might accelerate their demise. This hypothesis is not far-fetched when one remembers that hyperalimentation of patients with metastatic cancer has resulted in increased tumor growth rate and reduced survival.

Comprehensive Geriatric Oncology

796

The cost of investigating and managing anemia It is self-evident that longer lives are associated with higher medical costs, and any new investigational and therapeutic intervention may further enhance this cost. The question of cost should be addressed in the following contexts: • It is ethically unacceptable to forgo interventions that may improve the life-expectancy of a population because of cost. • The medical cost is just one of the costs of managing older persons. If correction of anemia results in prevention of functional dependence—one of the most costly complications of aging—then the management of anemia may result in reduced overall costs.

References 1. Balducci L, Hardy CS. Anemia of aging. a model of cancer-related anemia. Cancer Control 1998; 5(Suppl):17–21. 2. Pierelli L, Perillo A, Greggi S et al. Erythropoietin addition to granulocyte-colony stimulating factor abrogates life-threatening neutropenia and increases peripheral blood progenitor-cell mobilization after epirubicin, paclitaxel and cisplatin in combination chemotherapy. J Clin Oncol 1999; 17:1288–96. 3. Ratain MJ, Schilsky RL, Choi KE et al. Adaptive control of etoposide administration. impact of interpatient pharmacodynamic variability. Clin Pharmacol Ther 1989; 45:226–33. 4. Silber JH, Fridman M, Di Paola RS et al. First-cycle blood counts and subsequent neutropenia, dose reduction or delay in early stage breast cancer therapy. J Clin Oncol 1998; 16:2392–400. 5. Extermann M, Chen A, Cantor AB et al. Predictors of toxicity from chemotherapy in older patients. Proc Am Soc Clin Oncol 2000; 19: 617a. 6. Schijvers D, Highley M, DuBruyn E et al. Role of red blood cell in pharmakinetics of chemotherapeutic agents. Anticancer Drugs 1999; 10:147–53. 7. Glaspy J. Anemia and fatigue in cancer patients. Cancer 2001; 92: 1719–24. 8. Rieger PT. Assessment and epidemiologic issues related to fatigue. Cancer 2001; S6:1733–6. 9. Vailidres RU, Escalante C, Manzullo E. Fatigue and debilitating symptoms. Nursing Clin North Am 2001; 36:685–94. 10. Balducci L, Hardy CL, Lyman GH. Hemopoietic growth factors in the older patient. Curr Opin Hematol 2001; 8:170–87. 11. Duthie EH. Physiology of aging: relevance to symptoms, perceptions, and treatment tolerance. In: Comprehensive Geriatric Oncology (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:207–22. 12. Chaves PH, Volpato S, Fried L. Challenging the World Health Organization criteria for anemia in the older woman. J Am Geriatr Soc 2001; 49:S3, A10. 13. Kikuchi M, Inagaki T, Shinagawa N. Five-year survival of older people with anemia. variation with hemoglobin concentration. J Am Geriatr Soc 2001; 49:1226–8. 14. Izaks GJ, Westendorp RGJ, Knook DL. The definition of anemia in older persons. JAMA 1999; 281:1714–7. 15. An_a BJ, Suman VJ, Fairbanks VF et al. Incidence of anemia in older people. an epidemiologic study in a well defined population. J Am Geriatr Soc 1997; 45:825–31. 16. Gagnon DR, Zhang TJ, Brand FN, Kannel WB. Hematocrit and the risk of cardiovascular disease—the Framingham Study. a 34-year follow-up. Am Heart J 1994; 27:674–82. 17. Cleeland CS. Introduction. Cancer 2001; 92(S6): 1657–61. 18. Liao S, Ferrell BA. Fatigue in an older population. J Am Geriatr Soc 2000; 48:426–30.

Anemia and aging: Relevance to the management of cancer

797

19. Marcantonio ER, Flacker JM, Michaels M et al. Delirium is independently associated with poor functional recovery after hip fracture. J Am Geriatr Soc 2000; 48:618–24. 20. Metivier F, Marchais SJ, Guerin AP et al. Pathophysiology of anemia. focus on the heart and blood vessels. Nephrol Dial Transplant 2000; 15:14–18. 21. WU WC, Rathore SS, Wang Y et al. Blood transfusions in elderly patients with acute myocardial Infarction, N Engl J Med 2001; 345: 1230–6. 22. Pickett JL, Theberge DC, Brown WS et al. Normalizing hematocrit in dialysis patients improves brain function. Am J Kidney Dis 1999; 33:1122–30. 23. Spivak JL. Serum immunoreactive erythropoietin in HIV infected patients, JAMA 1989; 261:3104. 24. Goodnough LT, Price TH, Parvin CA. The endogenous erythropoietin response and the erythropoietic response to blood loss anemia. the effects of age and gender. J Lab Clin Med 1995; 125:57–64. 25. Gabrilove JL, Einhorn LH, Livingston RB et al. Once-weekly dosing of epoetin alfa is similar to three-times weekly dosing in increasing hemoglobin and quality of life. Proc Am Soc Clin Oncol 1999; 18: 574a. 26. Cleeland CS, Demetri GD, Glaspy J et al. Identifying hemoglobin levels for optimal quality of life. Results of an incremental analysis. Proc Am Soc Clin Oncol 1999; 18:574a. 27. Tasaki T, Ohto H, Noguchi M et al. Iron and erythropoietin measurements in autologous blood donors with anemia: implications for management. Transfusion 1994; 34:337–43. 28. Carpenter MA, Kendall RG, O’Brien AE et al. Reduced erythropoietin response to anaemia in elderly patients with normocytic anaemia. Eur J Haematol 1992; 49:119–21. 29. Thurer RL. Evaluating transfusion triggers. JAMA 1998; 279:238–9. 30. Ania BJ, Suman VJ, Fairbanks VF, Melton LJ III. Prevalence of anemia in medical practice: community versus referral patients. Mayo Clin Proc 1994; 69:730–5. 31. Garry PJ, Goodwin JS, Hunt WC. Iron status and anemia in the elderly: new findings and a review of previous studies. J Am Geriatr Soc 1983; 31:389. 32. Inelmen EM, Alessio MD, Gatto MRA et al. Descriptive analysis of the prevalence of anemia in a randomly sele.cted sample of elderly people living at home: some results of an Italian multicenter study. Aging Clin Exp Res 1994; 6:81–9. 33. Joosten E, Van Hove L, Lesaffre E et al. Serum erythropoietin levels in elderly in-patients with anemia of chronic disorders and iron deficiency anemia. J Am Geriatr Soc 1993; 41:1301–4. 34. Norlund L, Grubb A, Fex G et al. The increase of plasma homocysteine concentrations with age is partly due to the deterioration of renal function as determined by plasma cystatin C. Clin Chem Lab Med 1998; 36:175–8. 35. Clyne N, Jogestrand T, Lins LE, Perhrsson SK. Progressive decline in renal function induces a gradual decrease in total hemoglobin and exercise capacity. Nephron 1994; 67:322–6. 36. Kario K, Matsuo T, Kodama K et al. Reduced erythropoietin secretion in senile anemia. Am J Hematol 1992; 41:252–7. 37. Matsuo T, Kario K, Kodoma K, Asada R. An inappropriate erythropoietic response to iron deficiency anemia in the elderly. Clin Lab Haematol 1995; 17:317–21. 38. Nafziger J, Pailla K, Luciani L et al. Decreased erythropoietin respon siveness to iron deficiency anemia in the elderly. Am J Hematol 1993; 43:172–6. 39. Nilsson-Ehle H, Jagenburg R, Landahl S et al. Haematological abnormalities and reference intervals in the elderly. A cross-sectional comparative study of three urban Swedish population samples aged 70, 75 and 81 years. Acta Med Scand 1988; 224:595–604 40. Pennypacker LC, Allen RH, Kelly JP et al. High prevalence of cobalamine deficiency in elderly outpatients. J Am Geriatr Soc 1992; 40: 1197–204 41. Carmel R. prevalence of undiagnosed pernicious anemia in the elderly. Arch Intern Med 1996; 156:1097–100. 42. Herbert V. The elderly need oral vitamin B12. Am J Clin Nutr 1994; 67:739–40. 43. Hoffbrand AV, Herbert V. Nutritional anemias. Semin Hematol 1999; 36(4 Suppl 7):13–23.

Comprehensive Geriatric Oncology

798

44. Biaggioni I, Robertson D, Krantz S et al. The anemia of primary autonomic failure and its reversal with recombinant erythropoietin. Ann Intern Med 1994; 121:181–6. 45. Cramer EM, Garcia I, Masse JM et al. Erythroblastic synarthresis. an auto-immune dyserythropoiesis. Blood 1999; 94:3683–93. 46. Albright JW, Makinodan T. Decline in the growth potential of spleen-colonizing bone marrow stem cells of long-lived aging mice. J Exp Med 1976; 144:1204–13. 47. Van Zant G. Stem cells and genetics in the study of development, aging, and longevity. Results Probl Cell Differ 2000; 29:203–35. 48. Lipschitz DA. Age-related decline in hemopoietic reserve capacity. Semin Oncol 1995; 22:3–6. 49. Baraldi-Junkins CA, Beck AC, Rothstein G. Hematopoiesis and cytokines. Relevance to cancer and aging. Hematol Oncol Clin North Am 2000; 14:45–61. 50. Moscinsky LC. Hematopoiesis and aging. In: Comprehensive Geriatric Oncology (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:427–41. 51. Green JN. Management of infectious complications in the aged cancer patient. In: Comprehensive Geriatric Oncology (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:803–12. 52. Chatta C.S, Price TH, Allen RC et al. Effects of ‘in vivo’ recombinant methionyl human granulocyte colony-stimulating factor on the immune response and peripheral blood colonyforming cells in healthy young and elderly adult volunteers. Blood 1994; 84:2923–9. 53. Kirkeby OJ, Fossum S, Risoe C. Anemia in elderly patients. Incidence and causes of low hemoglobin concentration in a city general practice. Scand J Prim Health Care 1991; 9:167–71. 54. Armitage JO, Potter JF. Aggressive chemotherapy for diffuse histiocytic lymphoma in the elderly. J Am Geriatr Soc 1984; 32:269–73. 55. Kim YJ, Rubenstein EB, Rolston KV et al. Colony stimulating factors (CSFS) may reduce complications and death in solid tumor patients (pts) with fever and neutropenia. Proc Am Soc Clin Oncol 2000; 19: 612a (Abst 2411). 56. Gomez H, Mas L, Casanova L et al. Elderly patients with aggressive non-Hodgkin’s lymphoma treated with CHOP chemotherapy plus granulocyte-macrophage colony-stimulating factor: identification of two age subgroups with differing hematologic toxicity. J Clin Oncol 1998; 16:2352–8. 57. Marley SB, Lewis JL, Davidson RJ et al. Evidence for a continuous decline in hemopoietic cell function from birth: application to evaluating bone marrow failure in children. Br J Haematol 1999; 106:162–6. 58. Bagnara GP, Bonsi L, Strippoli P et al. Hemopoiesis in healthy old people and centenarian, well maintained responsiveness of CD34+ cells to hemopoietic growth factors and remodeling of cytokine network. J Gerontol A Biol Sd Med Sci 2000; 55:B61–70. 59. Rothstein G. Hematopoiesis in the aged: a model of hematopoietic dysregulation? Blood 1993; 82:2601–4. 60. Powers JS, Krantz SB, Collins JC et al. Erythropoietin response to anemia as a function of age. J Am Geriatr Soc 1991; 39:30–2. 61. Boggs DR, Patrene KD. Hematopoiesis and aging III: Anemia and a blunted erythropoietic response to hemorrhage in aged mice. Am J Hematol 1985; 19:327–41. 62. Morra L, Moccia F, Mazzarello GP et al. Defective burst-promoting activity of T lymphocytes from anemic and non-anemic elderly people. Ann Hematol 1994; 68:67–71. 63. Hyrota Y, Okamura S, Kimura N et al. Hematopoiesis in the aged as studied by ‘in vitro’ colony assay. Eur J Haematol 1988; 40:83–90. 64. Hamermann D, Berman JW, Albers GW et al. Emerging evidence for inflammation in conditions frequently affecting older adults. Report of a symposium. J Am Geriatr Soc 1999; 47:995–9. 65. Cohen HJ, Pieper CF, Harris T et al. The association of plasma IL-6 levels with functional disability in community-dwelling elderly. J Gerontol A Biol Sci Med Sci 1997; 52:M201–8.

Anemia and aging: Relevance to the management of cancer

799

66. Cohen HJ, Piper CS, Harris T. Markers of inflammation and coagulation predict decline in function and mortality in community dwelling elderly. J Am Geriatr Soc 2001; S1:A3. 67. Chatta GS, Price TH, Stratton JR, Dale DC. Aging and marrow neutrophil reserves. J Am Geriatr Soc 1994; 42:77. 68. Smith JW 2nd. Tolerability and side effect profile of rhIL-II. Oncology (Huntingt) 2000; 1(9 Suppl 8):41–7. 69. Harker LA, Roskos LK, Marzec UM et al. Effects of megakaryocyte growth and development factor on platelet production, platelet life span, and platelet function in healthy human volunteers. Blood 2000; 95:2514–22. 70. Cascinu S, Del Ferro E, Fedeli A et al. Recombinant human erythropoietin treatment in elderly cancer patients with cisplatin-associated anemia. Oncology 1995; 52:422–6. 71. Yashin AI, Ukraintseva SV, Debenedictis G et al. Have the oldest old adults ever been frail in the past? A hypothesis that explains modern trends in survival. J Gerontol 2001; 56A:B432–42 72. Melton LJ, Khosla S, Crowson CS et al. Epidemiology of sarcopenia. J Am Geriatr Soc 2000; 48:625–30. 73. Respini D, Jacobsen PB, Thors C et al. Issues of fatigue in the elderly. Crit Rev Oncol Hematol 2003; 47:273–9. 74. Gutstein HB. The biologic basis of fatigue. Cancer 2001; 92(S6): 1678–83. 75. Glaspy J, Bukowski R, Steinberg C et al. Impact of therapy with epoietin alfa on clinical outcomes in patients with non-myeloid malignancies during cancer chemotherapy in community oncology practices. J Clin Oncol 1997; 15:1218–34. 76. Demetri GD, Kris M, Wade J et al. Quality of life benefits in chemotherapy patients treated with epoietin alfa is independent from disease response and tumor type. Result of a prospective community oncology study. The Procrit Study Group. J Clin Oncol 1998; 16: 3412–20. 77. Littlewood TJ, Bajetta E, Nortier JW et al. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemothrapy. results of a radomized, double-blind, placebo-controlled trial. J Clin Oncol 2001; 19:2865–74. 78. Silverberg DS, Wexler D, Blum M et al. The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations. J Am Coll Cardiol. 2000; 35:1737–44. 79. Goodnough LT, Bach RG. Anemia, transfusion and mortality. N Engl J Med 2001; 345:1272–4. 80. Levin A, Singer J, Thompson CR et al. Prevalent left ventricular hypertrophy in the predialysis population. identifying opportunities for intervention. Am J Kidney Dis 1996; 27:347–54. 81. Beard CM, Kokmen E, O’Brien P et al. Risk of Alzheimer’s disease among elderly patients with anemia: population-based investigations in Olmsted County, Minnesota. Ann Epidemiol 1997; 7:219–24. 82. Cella DC. The Functional Assessment of Cancer Therapy-Anemia (FACT-An) scale. A new tool for the assessment of outcomes in cancer anemia and fatigue. Semin Hematol 1997; 34:13– 9. 83. Katz IR, Beaston-Wimmer P, Parmelee P et al. Failure to thrive in the elderly. exploration of the concept and delineation of psychiatric components. J Geriatr Psychiatry Neurol 1993; 6:161–9. 84. Yellen SB, Cella DF, Webster K et al. Measuring fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J Pain Sympt Manag 1997; 13: 63–74. 85. Nissenson AR. Epoetin and cognitive function. Am J Kidney Dis 1992 20:21–4. 86. Beguin Y. Erythropoietin and the anemia of cancer. Acta Clin Belg 1996; 51:36–52. 87. Coiffier B. Retrospective analysis of hematological parameters and transfusion requirements in no-platinum chemotherapy-treated patients. Proc Am Soc Clin Oncol 1998; 16:90a (Abst 346). 88. Dalton JD, Bailey NP, Barrett-Lee PJ, O’Brien MER. Multicenter UK audit of anemia in patients receiving cytotoxic chemotherapy. Proc Am Soc Clin Oncol 1998; 17:418a (Abst 1611).

Comprehensive Geriatric Oncology

800

89. Harrison LB, Shasha D, White C, Ramdeen RB. Radiotherapy-associated anemia: the scope of the problem. Oncologist 2000; 5:1–7. 90. Astani A, Smith RC, Allen BJ. The predictive value of body proteins for chemotherapy induced toxicity. Cancer 2000; 88:796–903. 91. Pirker R, Vansteekinste J, Gateley J et al. A phase 3, double blind placebo-controlled, randomized study of novel erythropoiesis stimulating protein (NESP) in patients undergoing platinum treatment for lung cancer. Proc Am Soc Clin Oncol 2001; 20:394a (Abst 1572) 92. Wians FH, Urban JE, Keffer JH et al. Discriminating between iron deficiency anemia and anemia of chronic disease using traditional indices of iron status versus transferrin receptor concentration. Am J Clin Pathol 2001; 115:112–118. 93. Egrie J, Browne J. development and characterization of novel erythropoiesis stimulating protein (NESP). Br J Cancer 2001; 84(Suppl 1):3–10 94. Charytan C, Levan N, Al Saloum M et al. Efficacy and safety of iron sucrose for iron deficiency in patients with dialysis-associated anemia. North American clinical trial. Am J Kidney Dis 2001; 37: 300–7. 95. Balducci L, Yates G. General guidelines for the management of older patients with cancer. Oncology (Huntingt) 2000; 14:221–7. 96. Barany P, Freyschuss U, Pettersson E, Bergstrom J. Treatment of anaemia in haemodialysis patients with erythropoietin. Long-term effects on exercise capacity. Clin Sci 1993; 84:441–7. 97. Barany P, Pettersson E, Konarski-Svensson JK. Long-term effects of quality of life in haemodialysis patients of correction of anaemia with erythropoietin. Nephrol Dial Transplant 1993; 8:426–32. 98. Hochberg MC, Arnold CM, Hogans BB et al. Serum immunoreactive erythropietin in rheumatoid arthritis impaired response to anemia. Arthritis Rheum 1988; 31:1318–21. 99. Casadevall N, Nataf J, Viron B et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 2002; 14:469–475.

38 Radiotherapy in the elderly Pierre Scalliet, Thierry Pignon Introduction In North America and Europe, more than 12% of the population is over 65 years of age. All older persons are facing decisions at the end of life that will affect their families and society.1 The simple fact that this book and this chapter have been written proceeds from the belief that older individuals constitute a distinct group deserving special consideration regarding diagnosis, treatment, and the general management of cancer. Epidemiological data, however, do not define a group of older persons clearly separated from younger persons. Rather, age is a discrete variable without clear-cut boundaries, and the incidence of cancer increases monotonically with age. Radiation oncology is an important form of cancer treatment, which may prove particularly valuable in the older cancer patient. The main issue of radiation oncology in the elderly concerns the preservation of treatment effectiveness while minimizing the risk of therapeutic complications. This goal is dictated by several considerations. Older persons may present a reduced tolerance to cytotoxic drug treatment, due to a reduced reserve in hematopoietic and mucosal stem cells, and in the functional reserve of multiple organ systems, such as cardiovascular, pulmonary, and renal function. Older patients may develop tumors with decreased aggressiveness. In addition, the picture is frequently complicated by the presence of associated conditions, which are known to influence tolerance to radiotherapy. Aged patients are more exposed to comorbidities such as diabetes, hypertension, and heart or lung insufficiency, which may complicate the clinical course of their cancer and impair their ability to sustain a long, and sometimes aggressive, curative treatment. The effects of age and the effects of chronic disease often converge, reducing the tolerance of stress by older individuals. However, because aging is highly individualized, the respective effects of age and of chronic diseases other than cancer on treatment tolerance need to be assessed separately. It is not unusual to find persons of advanced age in excellent general condition. It would be inappropriate to deny the benefits of aggressive antineoplastic treatment to these patients. No guidelines have been established for adapting treatment strategies to a patient’s age (except, perhaps, in hematology), yet older patients are, as already mentioned, often treated in a different, less aggressive way than younger patients. The few available studies relevant to this question do not, however, support the indiscriminate reduction of radiation dose/intensity.

Comprehensive Geriatric Oncology

802

Lack of radiobiological data Data regarding age and radiobiology remain scanty and inconclusive.2 Most experimental work has explored the influence of age on radiobiology by comparing the effects of irradiation in immature and in young adult animals. These investigations were designed to study the benefits and the toxicity of irradiation in children, not to obtain information about older adults. Biological as well as logistical problems impede the study of radiation in older animals. As a matter of fact, working with old mice or rats close to the end of their lifespan is quite impractical in general for all radiation effects and, in particular, for late effects. The comorbidity of older animals may cloud the investigation of acute radiation toxicity; the short lifespan of these animals prevents the study of late radiation effects. Few in vitro data deal with the age of cell cultures. Human fibroblasts were found to have similar survival parameters independently from the donor’s age (range 11–78 years),3 although the proliferative potential of such cultures decreases with age,4 presumably owing to telomere shortening. In contrast, the rate of DNA damage removal has been found to decrease with increasing age in rat skin,5 but this observation has no obvious in vivo counterpart.6 These experiments, however, did not explore skin reactions in very old animals. A study of age-related radiation alterations of the rectum was performed in young and old female Wistar rats.7 Minimal radiation-induced histological differences were observed between the two groups of animals, particularly in the development of ulceration and vascular changes, indicating that there are no major differences in radiosensitivity with age. Interesting data have been obtained regarding the effect of host age on the microenvironmental heterogeneity of EMT6 tumors implanted into young and aging mice. The mice had been housed 15–18 months before starting the experiments, and hence could be considered very old. The most conclusive result of these experiments was the finding of a much higher radiobiological hypoxic fraction in older than in younger animals (41% versus 19%), although an identical number of tumor cells had been implanted in all mice. A higher radiobiological fraction shelters the tumor from the cytotoxicity of radiation, and has an obvious impact on curability. Mitomycin C, an agent with selective toxicity to hypoxic cells, produced greater antineoplastic effect in tumors in aging mice and enhanced the effect of radiation in older mice more effectively than in younger animals.8 These experimental data, however, are at odds with the clinical impression that tumor radiocurability does not change with the age of the patient. Effect of comorbidity on tissue tolerance Comorbid conditions, such as pelvic inflammatory diseases, hypertension, and diabetes, may complicate the outcome of treatment. However, if impaired vital functions are more frequent in older patients, they are not intrinsic features of the elderly. Because these conditions are more frequent in older people, being old tends to be confused with being

Radiotherapy in the elderly

803

chronically ill. It is therefore essential to make the proper distinction between the influence of age as such versus the effect of comorbidities on tolerance to treatment, which is not the purpose of this chapter. Technical conditions Safe delivery of radiotherapy requires immobilization of the patient, generally in a supine position, and a high degree of collaboration between patient and staff. This can be a problem in old patients with chronic arthritis, respiratory or cardiac insufficiency, etc. Generally speaking, if the simulation is feasible, then the treatment will not pose any problem, since each session lasts only a few minutes. Patient refusal on technical grounds is uncommon, and the development of soft, efficient devices for immobilization further reduces the limitation on radiotherapy in elderly patients. Socioeconomic data A major problem for elderly patients is to come to the hospital five times a week for treatment. Transportation often depends on family or partner support, on community support, or on the availability of public transportation. The distance from the treatment center appeared to have a major impact in a Dutch study reviewing the pattern of cancer care in the southeastern Netherlands.9 A distance of 35km or more between the residence of the patient and the radiotherapy facility did not affect the use of radiotherapy as a primary treatment, except for older patients with lung cancer—the percentage of older individuals receiving radiotherapy decreased from 48% to 28%. This observation might have only reflected regional conditions, but it is nonetheless important. It revealed the influence of parameters independent of the disease and the patient’s physical condition on the management of older persons. In fact, a decline in the use of radiotherapy with age may be related to a decrease in referral to radiation oncologists with age or to decisions subsequent to referral to radiation oncologists who do not recommend treatment. A study in Ontario addressed this issue.10 In a series of patients with head and neck cancer at a potentially curable stage, the referral and the treatment rates were relatively constant from age 45 to 75, but patients older than 75 had significantly lower referral and treatment rates. For cervical cancer, there was a significant trend of a decreased referral with age, but treatment was not altered. In rectal and breast cancer, not only was the referral decreased with age, but the treatment was also altered, although to a lesser extent. Similar observations were made for palliative treatments. This large magnitude of the decline in radiotherapy with age was not explained by functional status but largely by the decline in referral, pointing to the need for adequate information about the benefits of radiotherapy in older people. Frail patients require active treatment of comorbid conditions; homecare and rehabilitation are important, since coping with mild discomfort or disability can be a problem. Resting only at the weekend is often not sufficient, because weekends are often

Comprehensive Geriatric Oncology

804

dedicated to visits from or to family and other social activities, which are equally tiring. Hospitalization is probably of no real help, because depriving a patient of home surroundings may give rise to disorientation and depression. Accepting one or more leisure days during radiotherapy invariably prolongs treatment, which may be detrimental to its efficacy. Alterna-tively, larger daily fractions are sometimes advocated in order both to keep the treatment protraction within acceptable limits and to offer an additional rest day during the week. Such an approach entails a higher risk of late effects and should only be considered in the framework of a palliative treatment. The modern family is mobile and dispersed in many Western countries. As long as family members remain well and independent, this geographical separation is of limited consequence. The impact on families of prolonged illness and disability, on the contrary, can be profound and requires attention from health professionals. There is no other guideline to advocate than to appreciate, on a personal and familial basis, a solution that is adapted to each particular case. The consequences of all possible options need to be openly discussed before any treatment decision is made. It is wise to include a social worker in the radiotherapy department staff to help with all these aspects. Prostate cancer The controversy regarding the best treatment for localized prostate carcinoma has been raging for decades. Consensus meetings trying to settle the issue in the absence of appropriately controlled studies usually recommend radical radiotherapy for men aged over 70.11 A survey of the Metropolitan Detroit Cancer Surveillance System did indeed confirm that there is an increased awareness of radiotherapy as a means of treatment in the elderly (over 75). This may have caused a migration to this form of therapy.12 However, this migration was not found to be age-dependent in the aforementioned study from The Netherlands, since identical trends were identified in younger age groups.9 Yet, it is acknowledged that attitudes regarding radical treatment of prostate carcinoma differ widely between the USA and Europe. The artificial age limit of 70 in the consensus statement actually represents a surrogate for a life-expectancy of 10 years. This recommendation proceeds from the urologist’s belief that radical radiotherapy is inferior to radical prostatectomy and that it can provide adequate control of the tumor for only up to 10 years. In addition, early recurrence and death from prostate cancer represent a smaller loss in life-expectancy for individuals aged 70 and older than for younger men. A true comparison between surgery and radiotherapy, however, does not exist; attitudes regarding treatment are therefore rather a matter of belief than of science. Quality of life after treatment may be affected by gastrointestinal or urological symptoms. Gastrointestinal complications, including radiation enteritis and colitis, and even small-bowel obstruction, are more common with radiotherapy; urological complications, especially urinary incontinence, are more common with surgery. The risk of complications should be openly discussed with the individual patient, allowing him to express his own view on which aspect of quality of life he would be more prepared to trade for tumor control. As far as the patient’s preference is concerned, a US Veterans Administration study revealed that older patients are more willing to accept an impotence

Radiotherapy in the elderly

805

outcome than a urinary incontinence outcome. Yet, older patients were less willing to accept the impotence outcome than younger patients, even though the reported incidence of impotence increased with age.13 This study underlined the importance of obtaining information related to quality of life directly from the patients and not to make assumptions about a patient’s preferences. One cannot overemphasize the risk of younger practitioners assuming that older patients have an already-compromised quality of life and reduced interest in pleasurable activity. Adequate informed consent is as important in the elderly as it is in other age groups. This is all the more true since a report from Karolinska Institute suggesting that the incidence of impotence after radiotherapy might be far from negligible, i.e. much more than is usually reported, and with a measurable negative impact on the patient’s perception of his own quality of life.14 Regarding radical radiotherapy, the Pattern of Care Study and a series by the Fox Chase Cancer Center revealed that the outcome of this form of treatment was similar in men aged 70 and over and in younger men.15 These conclusions concern all aspects of cancer control and the whole gamut of treatment-related late morbidity. Therefore, radiation treatment should not be withheld from appropriately selected elderly patients with prostate cancer because of concerns about the patient’s tolerance of treatment. Also, three-dimensional conformal irradiation reduces the incidence of acute treatment complications and appears particularly advisable in advanced age.16 Five- and eight-year biological relapse-free survival rates have been analyzed in a series of 1041 patients treated at the Cleveland Clinic Foundation (mean age 69). A multivariate analysis was performed using the following parameters: age, race, T-stage, initial prostate-specific antigen (iPSA), Gleason grade, adjuvant hormonal treatment, radiation technique and radiation total dose. Only T-stage, iPSA and total dose were independent predictors of outcome; age was not.17 Head and neck cancer Comorbidity is very common in patients with squamous cell carcinomas of the head and neck, which are mostly due to cigarette smoking and consumption of alcoholic beverages. Locoregional spread of these neoplasms may rapidly compromise the two vital functions of swallowing and breathing, with a dramatic impact on quality of life. Despite the excess of comorbidity, cancer is the most common cause of death and suffering in this population. Consequently, radical treatment is used even in patients with compromised function of multiple organ systems, and simple palliative procedures are seldom used. However, elderly or frail patients are less likely to be offered surgery or combined radiotherapy and surgery (or chemotherapy); they are rather referred to radiotherapy departments for radical treatment. In contrast, the relative low rate of aged patients in published series could be an indication that they are treated only in relation to their age and not in relation to the real course of their illness.18 In a French retrospective series of 331 elderly patients, 104 had a medical contraindication to general anesthesia.19 The mean age was 75 (range 70–95). As far as survival was concerned, performance status proved to be a much better predictor of treatment outcome than age. Psychological problems (including confusion) interfered

Comprehensive Geriatric Oncology

806

with treatment in 8% of cases—more prominently in the subgroup aged 80 and more. Otherwise, age and general status did not appear to have influenced the mucosal tolerance to treatment. This finding is corroborated by another series of 277 patients in which body weight loss during radical radio- therapy was prospectively recorded and analyzed according to patient age. The mean age was 63.3 (range 29–91); the average body weight loss during irradiation was 4% (maximum 15%). If any trend was recognizable, it was a slight positive effect of age on treatment tolerance. Patient age had no influence on survival probability.20 At variance with the previous study in which 11 patients succumbed apparently from lack of recovery after radical irradiation, there were no treatment-related deaths in this series, which probably reflects the positive patient selection. A third retrospective study in 88 elderly patients treated in the period 1980–1985 at the Prince of Wales Hospital supported the safety and effectiveness of radiotherapy in this indication.21 A survey of the European Organization for Research and Treatment of Cancer (EORTC) database of all head and neck patients included in five prospective trials between February 1980 and March 1995 was carried out at the Central Office in Brussels.22 In this survey, 1589 subjects were identified. Data regarding local control, survival, and early and late tolerance were available for all or part of the series. The mean age was 57 (range 20–82), i.e. relatively young given the trial exclusion criteria often mentioning 70 as the age limit. There were still 20% of patients aged 65 or more and 13% aged 70 or more. Age was not a prognostic factor for locoregional control, body weight loss, acute objective mucosal reactions, or late effects. The only statistical difference was an age-related worse functional acute toxicity of radical radiotherapy (essentially pain as experienced by the patient). It was interesting to note this discrepancy between acute objective and functional side-effects; it suggested that younger and older patients experienced equivalent severity levels of mucositis differently. Body weight loss, as mentioned above, was, however, similar in both groups. A similar observation has been made in the analysis of the CHART trial; 918 patients were prospectively entered in this randomized study. Early effects were dependent on the radiotherapy schedule (CHART versus conventional), on the volume irradiated, and on the duration of the treatment, but not on patient age.23 Combined chemotherapy-radiotherapy and particularly concomitant schedules are now considered as an alternative to improve results in unresectable advanced head and neck cancer, yet at a higher cost regarding side-effects than radiation alone.24 In the elderly population, this approach is used less frequently,25 although it was not found to be more toxic in older than in younger patients.26 The excess of toxicity observed in other studies27 may be limited by more aggressive nutritional support, such as enteral alimentation by gastrostomy.28 Lung cancer Initial treatment patterns for elderly patients with non-small cell lung cancer (NSCLC) vary widely. Patients inoperable for medical reasons29 or simply because of age30 are often referred to radiotherapy. Elderly patients with advanced stage III tumors receive benefit from curative radiotherapy.31 Radical irradiation improves survival in those with a

Radiotherapy in the elderly

807

small initial tumor (<4cm), and provides valuable symptom palliation in the majority of other patients.30 In a recent retrospective study, age did not adversely influence the delivery, tolerance, or efficacy of thoracic irradiation in stage I NSCLC.32 Tumor control requires advanced planning and a total dose of at least 60–65 Gy, which can be delivered safely.33–35 It has been suggested that the initial field size does not critically influence the probability of local control and survival; in small tumors, irradiation of the primary was sufficient, without prophylactic mediastinal lymph node irradiation.30 Whether this is an equivalent treatment option to surgery remains unknown, since comparative data are not so far available. A longitudinal prospective study described functional tolerance in a sample of 45 elderly patients (mean age 69.8; range 61–86) receiving radiotherapy for breast or lung cancer. The outcome variables were weight and multidimensional functional status. The great majority had at least one comorbid condition. Radiotherapy was well tolerated. The functional status of these elderly patients was well preserved overall, despite some transient limitations in usual activities during treatment.36 In a study including 1208 patients from six prospective EORTC trials receiving thoracic irradiation for lung or esophagal cancer, there was no difference in distribution of acute toxicity over age. Only weight loss was significantly different with regard to age, with a trend toward increased weight loss in older age groups. No difference was observed in the occurrence of late toxicity.37 Limited-stage small cell lung cancer (SCLC) is best treated by combined chemotherapy and radiotherapy, but elderly patients are often treated with palliative intent, in order to avoid toxicity. It is not clear, however, how well elderly patients tolerate intensive chemoradiotherapy, and it has been suggested by Jeremic et al38 that a combined approach could be used in this population without major problem of toxicity. In a large Dutch series, the incidence of grade 3 and 4 acute and late toxicities was equivalent in younger and in older patients.39 Esophagitis was dependent on the total dose of radiation but not on age. Field size (i.e. treatment volume), total dose, protraction, and compliance with treatment were similar in the two groups of patients. There was no difference in the efficacy of treatment between young and old people. Similar results were found in an intergroup trial, except for hematological toxicities, which were greater among the elderly.40 Thus, it appears that age per se is not a limiting factor for curative thoracic radiotherapy, even when an association with chemotherapy is indicated. Breast cancer There are several reports indicating that both tumor staging and treatment are inadequate in older women, particularly regarding the use of radiotherapy after conservative surgery.41–44 Since treatment selection depends chiefly on tumor staging, incomplete staging procedures are prone to lead to inappropriate therapeutic strategies. In a population-based series of 2268 patients aged 55 and older, the clinical stage was unknown twice as frequently in the oldest age group (18%) as in younger patients (8%).42 Breast cancer patients of 75 and older were treated by adjuvant radiotherapy less often than younger patients. Instead, the oldest age group received surgery alone or surgery

Comprehensive Geriatric Oncology

808

followed by adjuvant hormonal therapy. This was not fully explained by stage progression with age, although stages III and IV were more frequent in older patients. Appropriateness of treatment was retrospectively investigated in a series of 492 patients from Middelheim Hospital (mean age 54.1; range 24–81). Multivariate analysis revealed that, after correction for stage, younger patients were more often offered conservative surgery than older patients. Moreover, node dissection was less frequent in older patients. Elderly patients treated with breast conservation procedures received a breast boost much less frequently than younger individuals. Finally, older patients were less likely to receive axillary irradiation, even in the absence of axillary lymph node dissection.45 Failure to use adjuvant radiotherapy appropriately may have a serious negative impact on treatment outcome, since local relapse usually occurs in the first 4 postoperative years. It is therefore likely to become a problem during the patient’s lifetime.44 Replacing adjuvant irradiation by adjuvant hormonotherapy in locally advanced stages should therefore be restricted to women with a very short life-expectancy. In a randomized trial in which women older than 75 received either surgery or tamoxifen alone, surgery was found to be the appropriate treatment for elderly patients with operable breast cancer.46 Tamoxifen as a unique treatment only delayed the need for surgery, which then had to be carried out more often under adverse conditions. This was confirmed in another series of 85 patients aged 75 and older with locoregional disease (stages I and II). Complete remission lasting for their lifetime was obtained in only 12 patients (median follow-up 28 months; range 3–97 months). All the others were exposed to cancer morbidity, since it was not well controlled by hormonal therapy. Another 12 died from cancer in the followup period.47 In a series from Rochester, a preferential allocation of aged women to conservative breast surgery without radiotherapy was observed—a policy that cannot be advocated, since the recurrence rate exceeded 25%, versus only 7% if postoperative radiotherapy was given.48 Veronesi has questioned whether adjuvant radiotherapy is required in all cases of conservative surgery in the analysis of a randomized study in Milan. Between 1987 and 1989, 567 women with small breast tumors (<2.5cm) were randomly assigned to quandrantectomy followed by radiotherapy versus quandrantectomy alone. The incidences of local recurrence were 0.3% versus 8.8%. However, there was a substantial effect of age: women older than 55 had a lower recurrence rate of 3.8% in the absence of adjuvant irradiation.49 This finding has prompted an EORTC trial aiming at assessing the value of adjuvant radiotherapy in postmenopausal women treated for a small stage I tumor. Owing to a very low accrual, this trial has been prematurely stopped; most surgeons were reluctant to enter patients in the surgery-only arm and it was a trial that was difficult to explain to patients (like most de-escalation trials). A large EORTC trial investigating the role of a boost dose after adjuvant whole-breast irradiation enrolled 5569 patients. The relapse rate was identical in the postmenopausal patients (age range 51–83.5); it was halved by an additional 15 Gy boost on the tumor bed, with an equivalent impact in patients aged 51–60 and patients over 60. There was no indication of a lower risk of local relapse with advanced age.50 As far as irradiation is concerned, the few available reports do not support any difference in the early or late tolerance to radiotherapy of elderly patients.43,44 An original comparison of local outcome after a free tissue transfer procedure for various tumor sites

Radiotherapy in the elderly

809

(including breast) in elderly patients previously treated or not by radiotherapy and/or chemotherapy concluded that free tissue transfer success rates were high in both patient categories. Previous radiotherapy did not decrease the possibility of reconstructive surgery.51 Van Limbergen et al52 did not find any influence of age on the cosmetic outcome of conservative breast cancer treatments in a multivariate analysis of a large group of patients. In contrast, a small negative impact of age on cosmesis was suggested by another series, although it did not reach statistical significance and was, at least to some extent, confounded by variations in the extent of surgery.53 Another paper, dealing with the risk of developing a brachial plexus injury after radiotherapy for breast cancer, found no correlation with age (449 patients, with age range 18–92).54 The only predictor for plexus injury was the use of large daily radiation doses. This contrasts with the conclusions of a French trial in a series of elderly women (average age 81) advocating the use of large single weekly doses (seven fractions of 6.5 Gy over 6 weeks) associated with tamoxifen.55 Hypofractionation always increases the risk of late radiation damage unless the total dose or the treated volume is reduced appropriately, which, in turn, decreases the effect on the tumor. A dose of 2 Gy per fraction emerged through experience as the best compromise between effectiveness and morbidity of radiotherapy. Departing from this protocol requires a very careful assessment of all factors involved, in particular the lifeexpectancy of the individual patient. Since many older women are anxious to preserve their breasts, they should certainly be offered the conservative treatment option combining surgery and adjuvant irradiation whenever the local stage allows for it.56,57 Tolerance of adjuvant radiotherapy should not be of a different concern than it is in any other age group. It is also important to keep in mind that a woman of 85 can expect to live on average 7 more years, and may therefore experience local recurrence of her cancer during her lifetime.58 Gynecological malignancies Women presenting with a cervical carcinoma inoperable for medical reasons are often referred to radiotherapy. Radical irradiation is not always possible, given the high frequency of comorbid conditions, which are often the same as those that contraindicated surgery. However, if the patient is fit enough for radical treatment, the chance of cure is equivalent with surgery or with radiotherapy.59 Carcinoma of the vulva is a rare tumor with a peak frequency in those aged over 70. Radical or postoperative radiotherapy play a role in the treatment of this cancer.60 In two series where the majority of patients were aged over 65, radiotherapy displayed a benefit in survival for all patients, with no difference in relation to age. In addition, chemoradiotherapy was better than radiation alone for locally advanced tumors.61 Radiotherapy at a dose of more than 45 Gy was efficient for improving the overall survival of limited tumors incompletely treated with surgery.62 Daly et al63 analyzed a series of 188 women irradiated for ovarian cancer with large pelvic fields and presenting later on with radiation ileitis. Age had no influence on the risk of complications, but obese women or women older than 75 were treated

Comprehensive Geriatric Oncology

810

systematically with 1.8 Gy instead of 2 Gy per fraction, with the same total dose. Similar observations have been reported by others.64 The feasibility of gynecological brachytherapy is sharply dependent on the individual anatomy of each patient. The size and depth of the vaginal cavity changes with age. Senkus-Koneflka et al65 investigated the influence of age on the size of applicators used and the dose distribution, with special attention being paid to doses to critical normal tissues. They concluded that, owing to a reduction in the size of the vagina, there was a consistent increase in rectal and bladder doses (due to the use of smaller ovoid). This study was unfortunately not complemented with an analysis of morbidity. Data regarding morbidity of brachytherapy were available from a prospective study of the Institute Gustave Roussy in which patients treated for cervical or endometrial carcinoma were randomized between two different brachytherapy schedules.66 When adjusted for tumor size and nodal involvement, age had an unfavorable influence on overall and recurrence-free survival. In contrast, age had no influence on the rate of overall and late complications (i.e. those developing from 6 months after treatment onwards). Pelvic malignancies The entire EORTC database has been searched to identify those patients who participated in trials including pelvic or abdominopelvic irradiation.67 Out of nine trials initiated by the Radiotherapy Cooperative Group or the Gastrointestinal Group between 1975 and 1991 (cancers of the rectum, prostate, bladder, uterus, and anal canal), 1619 patients were identified. The mean age was 61 (range 47–80). The originality of this database is that each of these patients has been followed according to strict trial criteria regarding the prospective scoring of side-effects and complications. Acute side-effects Nausea and vomiting occurred when the irradiated volume encompassed the upper abdomen, and were more frequent in younger patients. The same trend was identified regarding severe diarrhea (grade 2 and 3). In contrast, acute effects on skin and the urinary tract, deterioration of performance status, and body weight loss were evenly distributed among all age groups investigated. Late effects and complications In each age group, 80% of patients were free of late toxicity by 5 years. There were no differences in the occurrence of late diarrhea, fibrosis, or rectal complications between the different age groups. Older patients seemed to have more skin effects than younger individuals, but the small number of events prevented a more detailed analysis of this complication. Data about sexual function were available in patients enrolled in prostate cancer trials. Radio-therapy caused more late sexual dysfunction in aged patients than in younger ones, which was expected, since elderly patients were more frequently subject to sexual dysfunction than younger patients. Unfortunately, quality of life assessment was

Radiotherapy in the elderly

811

not incorporated in these trials; therefore, it has been difficult to draw definitive conclusions about the effects of radiotherapy on the quality of life of older individuals. Brain tumors Malignant tumors have a growing incidence in the elderly population, partly because of a more aggressive approach to the diagnosis of neurological affections and partly as a result of improvements in radiological techniques. In addition, epidemiological changes are also at the origin of the increased rate of primary tumors in the elderly. With longer survival of patients affected by cancer, there is also a higher proportion of patients with secondary brain tumors. Radiotherapy is a usual treatment for primary and metastatic brain tumors. Toxicity of radiotherapy is a major concern, since this treatment has little activity against these malignancies with a very poor prognosis. This is particularly true for aged people with malignant gliomas. However, the outcome of patients with primary or secondary brain tumors is so short that late complications often do not have time to occur. Thus, although older people are suspected to tolerate brain radiotherapy less well, the true incidence of its side-effects is unknown. More than in other cancer locations, the benefit of such treatment has to be balanced with toxicity. Indications for radiotherapy and its schedule have to take account of prognostic factors such as age (with a cutoff at 50 or 65 years, depending on publications), performance status, and extent of surgical debulking. Guidelines have been proposed on the basis of these factors.68 Full-dose radiotherapy (60 Gy) in limited fields is offered to patients with gliomas when they are in good general condition and when the tumor has been completely removed surgically. Short-course radiotherapy (30 Gy in 10 fractions) is preferred for patients with extensive tumors inaccessible to surgery, since late neurotoxicity will not have time to occur. Elderly patients in poor condition with no surgical debulking may gain more benefit from supportive care than from radiotherapy. For older patients with secondary tumors, it is recommended to avoid whole-brain radiotherapy, which leads to a higher incidence of cognitive impairment. When surgery is indicated, it will not be followed by radiotherapy, since the life-expectancy of a significant proportion of these patients is long enough to experience neurotoxicity. Alternatively, they can be treated by radiosurgery to avoid aggressive intervention. When multiple intracranial lesions are present, the only possible treatment is whole-brain irradiation. The indication will be taken on an individual basis, considering performance status, primary tumor evolution, and neurological symptoms. Apart from cognitive items, the tolerance of the brain of curative radiotherapy seems to be independent of age. In a series of 1008 patients treated for nasopharyngeal cancer (age range 18–84), the risk of temporal lobe necrosis was only dependent on the total dose (and fractionation).69

Comprehensive Geriatric Oncology

812

The oldest old Nearly a third of the very elderly (85 or older) have some degree of dementia.70 They require active treatment of comorbid conditions. Homecare and revalidation are even more important in this age group, since coping with even a minor disability can be a problem. Patient transportation can be a serious problem too. It relies on family or partner support, on community support, or on availability of public transportation. As already mentioned, a long distance between the home and the hospital has apparently prevented some very old lung cancer patients from receiving appropriate radiotherapy. It is not uncommon in our practice that surgeons favor radical mastectomy in cases of small breast tumors in order to spare the patient 5 or 6 weeks of adjuvant radiotherapy. There is of course nothing wrong with this, provided that the patient has been honestly offered all the possible alternatives. However, this is not a universal event: in a population-based study of 2268 patients with breast cancer, no correlation was found between the use of adjuvant radiotherapy and the distance of the patient’s home.41 A central problem with respect to treatment strategy in the oldest old is the dilemma of palliative versus radical treatment. A precise definition of what is a palliative treatment in this context is a challenging intellectual exercise. It may tentatively be put in the following way: in some circumstances, a palliative treatment schedule (with lesser burden) will give sufficient tumor regression to cover the expected survival time, a more radical treatment being otherwise still theoretically possible. This means that palliation may only be offered to some patients whose life-expectancy is obviously short or very short. Looking at our own practice, there are less than a handful of such patients each year. They all share the same handicap, namely the association of advanced age and a severe degree of dementia, so that the minimum of active collaboration necessary for the treatment to be delivered in good conditions is not guaranteed. There is also a common feeling with such patients that their quality of life is already impaired to such an extent that attempts to prolong life seem meaningless. This attitude, however, is mainly related to the philosophical convictions of the doctor, of the medical staff, and hopefully of the patient himself/herself, as assessed during conversations with him/her (or with their family if contact with the patient has been definitively lost). This is a very delicate matter, indeed. Conclusions Most frequently, tumor-related factors (stage, histology, etc) override considerations of age in the choice of treatment, if a curative option exists. As extensively discussed elsewhere in this book, there is no indication in the majority of cancers that age is an appropriate factor for stratification. Patients with a good performance status are likely to respond to treatment in general, and to radiotherapy in particular, independently of their chronological age. It can even be suggested that many of the retrospective series in which age had a detrimental effect on prognosis were biased in several possible ways: inappropriate staging, unconventional curative treatment, replacement of a curative

Radiotherapy in the elderly

813

treatment by a palliative approach, a wait-and-see policy instead of appropriate treatment, etc. Hodgkin lymphoma, for example, is considered as having a less positive prognosis in patients aged 60 and over, yet two reports showed that patients whose conditions were adequate enough to allow them to receive standard therapy had similar outcomes to younger patients. The less favorable outcome in some of the older patients was very likely to result from alterations in the standard treatment schedule.71,72 Many patients who are not eligible for major surgery or for major chemotherapy can still tolerate the alternative of radical radiotherapy quite well, and there is no suggestion that age will have a major influence on tolerance. Indeed, a substantial proportion of patients undergoing radiotherapy are aged over 70, and patients over 80 are regularly seen. Advanced follow-up during their treatment will help them to get through treatment without major acute side-effects. The use of appropriate care, such as antiemetic, antispasmodic, or anticholinergic drugs, and more recently sucralfate, for instance, has allowed reductions in bowel discomfort to be achieved.73 The fact that older patients more often die from intercurrent disease than from their tumor does not mean that they are not exposed to cancer-related morbidity before ultimately dying from another cause. Less aggressive strategies based on the higher incidence of intercurrent disease74 must therefore be established very carefully, after a thorough appreciation of the potential cancer morbidity that will result from a less intensive therapy. Other strategies, based on the belief that cosmesis is a less prominent concern in older patients,75 are also not supported by data; there is no evidence that body self-image is less important with advancing age. ‘Reduced’ treatment is never a solution, unless the life-expectancy of the patient is obviously so short that tumor recurrence is unlikely to occur or at least to produce substantial morbidity before the patient has died from another cause. References 1. Gordon M, Singer PA. Decisions and care at the end of life. Lancet 1995; 346:163–6. 2. Scalliet P. Radiotherapy in the elderly. Eur J Cancer 1991; 27:3–5. 3. Little JB, Nove J, Strong LC, Nichols WW. Survival of human diploid skin fibroblasts from normal individuals after X-irradiation. Int J Radiat Biol Phys 1988; 54:899–910. 4. Martin GH, Sprague CA, Epstein CJ. Replicative life span of cultivated human cells. Effects of donor’s age, tissue and genotype. Lab Invest 1970; 23:86–92. 5. Sargent EV, Burns FJ, Repair of radiation-induced DNA damage in rat epidermis as a function of age. Radiat Res 1985; 102:176–81. 6. Denekamp J. Residual radiation damage in mouse skin 5 to 8 months after irradiation. Radiology 1975; 115:191–5. 7. Olofsen-van Acht MJJ, van Hooije MC, van den Aardweg G JMJ et al. Effect of age on radiation-induced early changes of rat rectum. A histological time sequence. Radiother Oncol 2001; 59:71–9. 8. Rockwell S, Hughes CS, Kennedy KA. Effect of host age on micro environmental heterogeneity and efficacy of combined modality therapy in solid tumors. Int J Radiat Oncol Biol Phys 1991; 20:259–63.

Comprehensive Geriatric Oncology

814

9. De Jong B, Crommelin M, van der Heijden LH, Coebergh JWW. Patterns of radiotherapy for cancer patients in south-eastern Netherlands, 1975–1989. Radiother Oncol 1994; 31:213–21. 10. Tyldesley S, Zhang-Salomons J, Groome PA et al. Association between age and the utilization of radiotherapy in Ontario. Int J Radiat Oncol Biol Phys 2000; 47:469–80. 11. Denis LJ, Murphy GP, Schroder FH. Report of the Consensus Workshop on Screening and Global Strategy for Prostate Cancer. Cancer 1995; 75:1187–207. 12. Severson RK, Montie JE, Porter AT, Demers RY. Recent trends in incidence and treatment of prostate cancer among elderly men. J Natl Cancer Inst 1995; 87:532–4. 13. Mazur DJ, Merz JF. Older patient’s willingness to trade off urologic adverse outcomes for a better chance at five-year survival in the clinical setting of prostate cancer. J Am Geriatr Soc 1995; 43:979–84. 14. Helgason AR, Frederikson M, Adolfsson J, Steineck G. Decreased sexual capacity after external radiation therapy for prostate cancer impairs quality of life. Int J Radiat Oncol Biol Phys 1995; 32:33–9. 15. Hanks GE, Hanlon A, Owen JB, Schultheiss TE. Patterns of radiation treatment of elderly patients with prostate cancer. Cancer 1994; 74:2174–7. 16. Hanks GE, Schultheiss TE, Hunt MA, Epstein B. Factors influencing incidence of acute grade 2 morbidity in conformal and standard radiation treatment of prostate cancer. Int J Radiat Oncol Biol Phys 1995; 31:25–9. 17. Kupelian PA, Mohan DS, Lyon J et al. Higher than standard radiation dose (≥72 Gy) with or without androgen deprivation in the treatment of localised prostate cancer. Int J Radiat Oncol Biol Phys 2000; 46:567–74. 18. Metges JP, Eschwege F, de Crevoisier R et al. Radiotherapy in the elderly: a challenge. Crit Rev Oncol Hematol 2000; 34:195–203. 19. Lusinchi A, Bourhis J, Wibault P et al. Radiation therapy for head and neck cancer in the elderly. Int J Radiat Oncol Biol Phys 1990; 18: 819–23. 20. Scalliet P, Van den Weyngaert D, Van der Schueren E. Radiotherapy. In: Cancer in the Elderly. Treatment and Research (Fentiman IS, Monfardini S, eds). Oxford: Oxford Medical Publications, 1994: 28–37. 21. Chin R, Fisher RJ, Smee RI, Barton MB. Oropharyngeal cancer in the elderly. Int J Radiat Oncol Biol Phys 1995; 32:1007–16. 22. Pignon T, Horiot JC, Van den Bogaert W et al. No age limit for radical radiotherapy in head and neck tumors. Eur J Cancer 1996; 12: 2075–81. 23. Bentzen SM, Saunders MI, Dische S, Bond SJ. Radiotherapy-related early morbidity in head and neck cancer: quantitative clinical radiobiology as deduced from the CHART trial. Radiother Oncol 2001; 60: 123–35. 24. Calais G, Alfonsi M, Bardet E et al. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced stage oropharynx carcinoma. J Natl Cancer Inst 1999; 91: 2081–6. 25. Kennedy BJ. Ageing and cancer. J Clin Oncol 1989; 6:1903–11. 26. Cascinu S, Del Ferro E, Catalano G. Toxicity and therapeuthic response to chemotherapy in patients aged 70 years or older with advanced cancer. Am J Clin Oncol 1996; 19:371–4. 27. Bourhis J, Pignon JP, Designe M et al. Meta-alysis of chemotherapy in head and neck cancer (MACH-NC): (1) loco-regional treatment versus same treatment plus chemotherapy. Proc Am Soc Clin Oncol 1998; 17:Abst 1486. 28. Tyldesley S, Sheenan F, Munk P et al. The use of radiologically placed gastrostomy sondes in head and neck cancer patients receiving radiotherapy. Int J Radiat Oncol Biol Phys 1996; 36:1205–9. 29. Dosoretz DE, Galmarini D, Rubenstein JH et al. Local control in medically inoperable lung cancer: an analysis of its importance in outcome and factors determining the probability of tumor eradication. Int J Radiother Oncol 1993; 13:83–9.

Radiotherapy in the elderly

815

30. Nordijk EM, van der Poest Clement E, Hermans J et al. Radiotherapy as an alternative to surgery in elderly patients with resectable lung cancer. Int J Radiat Oncol Biol Phys 1988; 27:507–16. 31. Tombolini V, Bonanni A, Donato V et al. Radiotherapy alone in elderly patients with medically inoperable stage IIIA and IIIB non-small cell lung cancer. Anticancer Res 2000; 20; 4829–33. 32. Gauden SJ, Tripcony L. The curative treatment by radiation therapy alone of stage I non-small cell lung cancer in a geriatric population. Lung Cancer 2001; 32; 71–9. 33. Hayakawa K, Mitsuhashi N, Katano S et al. High-dose radiation therapy for elderly patients with inoperable or unresectable non-small cell lung cancer. Lung Cancer 2001; 32; 81–8. 34. Lonardi F, Coeli M, Pavanato G et al. Radiotherapy for non small cell lung cancer in patients aged 75 and over: safety, effectiveness and possible impact on survival. Lung Cancer 2000; 28; 43–50. 35. Patterson CJ, Hocking M, Bond M, Teale C. Retrospective study of radiotherapy for lung cancer in patients aged 75 years and over. Age Ageing 1998; 27; 515–18. 36. Lindsey AM, Larson PJ, Dodd MJ et al. Comorbidity, nutritional intake, social support, weight and functional status over time in older cancer patients receiving radiotherapy. Cancer Nurs 1995; 17: 113–24. 37. Pignon T, Gregor A, Schaake Koning C et al. Age has no impact on acute and late toxicity of curative thoracic radiotherapy. Radiother Oncol 1998; 46:239–48. 38. Jeremic B, Shibamoto Y, Acimovic L, Ilisalevic S. Carboplatin, etoposide and accelerated radiotherapy for elderly patients with limited small cell lung carcinoma: a phase II study. Cancer 1998 82; 836–41. 39. Quon H, Shepherd FA, Payne DG et al The influence of age on the delivery, tolerance and efficacy of thoracic irradiation in the combined modality treatment of limited stage small cell lung cancer. Int J Radiat Oncol Biol Phys 1999; 43:39–45. 40. Yuen AR, Zou G, Turrisi AT et al. Similar outcome of elderly patients in intergroup trial 0096: cisplatin, etoposide and thoracic radiotherapy administered once or twice daily in limited stage small cell lung carcinoma. Cancer 2000; 89; 1953–60. 41. Bergman L, Dekker G, van Leeuwen FE et al. The effect of age on treatment choice and survival in elderly breast cancer patients. Cancer 1991; 67:2227–34. 42. Bergman L, Kluck HM, Van Leeuwen FE et al. The influence of age on treatment choice and survival of elderly breast cancer patients in south-eastern Netherlands: a population-based study. Eur J Cancer 1992; 28A:1475–80. 43. Martin LM, Le Pechoux C, Calitchi E et al. Management of breast cancer in the elderly. Eur J Cancer 1994; 30A:590–6. 44. Morrow M. Breast disease in elderly women. Surg Clin North Am 1994; 74:145–61. 45. De Winter K, Van den Weyngaert D, Becquart D, Scalliet P. Breast cancer: influence of age on treatment choice of surgeon and radiation oncologist. Eur J Cancer 1993; 29A(Suppl 6):S73. 46. Robertson JFR, Todd JH, Ellis IO et al. Comparison of mastectomy with tamoxifen for treating elderly patients with operable breast cancer. BMJ 1988; 297:510–14. 47. Bergman L, van Dongen JA, van Ooijen B, van Leeuwen FE. Should tamoxifen be a primary treatment choice for elderly breast cancer patients with locoregional disease? Breast Cancer Res Treat 1995; 34: 77–83. 48. Kantorowitz DA, Poulter CA, Rubin P et al. Treatment of breast cancer with segmental mastectomy alone or segmental mastectomy plus radiation. Radiother Oncol 1989; 15:141–50. 49. Veronesi U, Luini A, Del Vecchio M et al. Radiotherapy after breast-preserving surgery in women with localized cancer of the breast. N Engl J Med 1993; 328:1587–91. 50. Bartelink H, Horiot JC, Poortmans P et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 2001; 345:1378– 87.

Comprehensive Geriatric Oncology

816

51. Reece GP, Schusterman MA, Miller MJ et al. Morbidity associated with free-tissue transfer after radiotherapy and chemotherapy in elderly cancer patients. J Reconstr Microsurg 1994; 10:375–82. 52. Van Limbergen E, Rijnders A, van der Schueren E et al. Cosmetic evaluation of breast conserving treatment for mammary cancer. 2. A quantitative analysis of the influence of radiation dose, fractionation schedules and surgical treatment techniques on cosmetic results. Radiother Oncol 1989; 16:253–68. 53. Steeves RA, Phromratanapongse P, Wolberg WH, Tormey DC. Cosmesis and local control after irradiation in women treated conservatively for breast cancer. Arch Surg 1989; 124:1369– 73. 54. Powell S, Cooke J, Parsons C. Radiation-induced brachial plexus injury: follow-up of two different fractionation schedules. Radiother Oncol 1990; 18:213–20. 55. Maher M, Campana F, Dreyfus H et al. Breast cancer in elderly women: a retrospective analysis of combined treatment with tamoxifen and once weekly irradiation. Int J Radiat Oncol Biol Phys 1995; 31:783–9. 56. Toonkel TM, Fix I, Jacobson LH, Bamberg N. Management of elderly patients with primary breast cancer. Int J Radiat Oncol Biol Phys 1988; 14:677–81. 57. Amsterdam E, Birkenfield S, Gilad A, Krispin M. Surgery for carcinoma of the breast in women over 70 years of age. J Surg Oncol 1987; 35:180–3. 58. Bouvier-Colle MH, Vallin J, Hatton F. Mortalite et causes de décès en France. Paris: Editions Inserm-DOIN, 1991. 59. Landoni F, Maneo A, Colombo A et al. Randomised study of radical surgery versus radiotherapy for stage Ib-IIa cervical cancer. Lancet 1997; 350:535–40. 60. Perez CA, Grigsby PW, Clifford Chao KS et al. Irradiation in carcinoma of the vulva: factors affecting outcome. Int J Radiat Oncol Biol Phys 1998; 42:335–44. 61. Han SC, Kim DH, Higgins SA et al. Chemoradiation as primary or adjuvant treatmentfor locally advanced carcinoma of the vulva. Int J Radiat Oncol Biol Phys 2000; 47:1235–44. 62. Bush M, Wageber B, Schaffer M, Diihmke E. Long-term impact of postoperative radiotherapy in carcinoma of the vulva FIGO I/II. Int J Radiat Oncol Biol Phys 2000; 48:213–18. 63. Daly NJ, Izar F, Bachaud J-M, Delannes M. The incidence of severe chronic ileitis after abdominal and/or pelvic external irradiation with high energy photon beams. Radiother Oncol 1989; 14:287–95. 64. DeWinter K, Van den Weyngaert D, Becquart D, Scalliet P. Panabdominal radiotherapy in ovarian carcinoma: a retrospective analysis of survival and complications. In: Proceedings of the 9th Annual Meeting ESTRO, Montecatini. 1990:157. 65. Senkus-Konefka E, Kobierska A, Jassem J et al. The impact of patient and disease related factors on the quality of pelvic dose distribution in cervical cancer patients. Radiother Oncol 1995; 35:S4. 66. Lambin P, Gerbaulet A, Kramar A et al. Phase III trial comparing two low dose rates in brachytherapy of cervix carcinoma: report at two years. Int J Radiat Oncol Biol Phys 1993; 25:405–12. 67. Pignon T, Horiot JC, Bolla M et al. Age is not a limiting factor for radical radiotherapy in pelvic malignancies. Radiother Oncol 1997; 42:107–20. 68. Grau JJ, Verger E, Brandes AA et al. Radiotherapy of the brain in elderly patients. Eur J Cancer 2000; 36:443–52. 69. Lee AW, Foo W, Chappell R et al. Effect of time, dose, and fractionation on temporal lobe necrosis following radiotherapy for nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 1998; 40:35–42. 70. Skoog I, Nilsson L, Palmertz B et al. A population-based study of dementia in 85-year-olds. N Engl J Med 1993; 328:153–8. 71. Zietman AL, Linggood RM, Brookes AR et al. Radiation therapy in the management of early stage Hodgkin’s disease presenting in later life. Cancer 1991; 68:1869–70.

Radiotherapy in the elderly

817

72. Diaz-Pavon JR, Cabanillas F, Majlis A et al. Outcome of Hodgkin’s disease in elderly patients. Hematol Oncol 1995; 13:19–27. 73. Henriksson R, Frantzen L, Littbrand B. Prevention and therapy of radiation-induced bowel discomfort. Scand J Gastroenterol 1992; 27(Suppl 191):7–11. 74. Papillon J. Present status of radiation therapy in the conservative management of rectal cancer. Radiother Oncol 1990; 17:275–84. 75. Abbatucci JS, Boulier N, Laforge T, Lozier JC. Radiation therapy of skin carcinomas: results of a hypofractionated irradiation schedule in 675 cases followed for more than 2 years. Radiother Oncol 1989; 14:113–20.

39 Cancer chemotherapy in the older patient Dario Cova, Lodovico Balducci Introduction This chapter explores the effects of aging on the pharmacology of antineoplastic agents. Aging involves progressive changes in organ and cellular function and in tumor growth (see Chapters 7, 12, and 18 of this volume1–3). These changes may alter the pharmacokinetics and the pharmacodynamics of drugs.4,5 Also, a progressive decline in the physiologic reserve of many organ systems may make older individuals more susceptible to the therapeutic complications of cytotoxic medications.4–10 Aging is highly individualized, and chronological age is a poor predictor of the extent of physiologic changes in each individual. The practitioner managing older patients should be aware of the diversity of the older population and should tailor antineoplastic treatment to these individual variations. Pharmacokinetics Figure 39.1 summarizes the most important pharmacokinetic parameters. All of these may undergo age-related variations. We shall discuss each parameter separately, and we shall highlight the implications of age-related variations.

Figure 39.1 Summary of the most important pharmacokinetic parameters.

Cancer chemotherapy in the older patient

819

Absorption Drug absorption may be affected by a number of digestive changes. These include decreased gastrointestinal motility, decreased splanchnic blood flow, decreased secretion of digestive enzymes, and mucosal atrophy10–14 (see Chapter 16 of this volume14). The net result of these changes is a reduction in the drug absorption rate (i.e. in the amount of drug absorbed per unit time), rather than reduced overall absorption of drugs.10 Of special concern is the bioavailability of drugs in the oldest old, i.e. in persons over 80. The diffuse atrophy of the digestive mucosa described in persons of advanced age may significantly impair the oral absorption of drugs (see Chapter 1614). Absorption abnormalities are of special interest, because of the development of different cytotoxic agents in oral form.15 In addition, many of the newer agents that target a specidic aspect of tumor metabolism, including inhibitors of tyrosine kinase and farnesyl transferase, are available in oral form.16–18 Oral formulations of drugs are of practical use in the management of older individuals, given their convenience of administration and flexibility of dosing.15 In addition, the following areas deserve special attention: • treatment involving administration of oral leucovorin (folinic acid), such as high-dose methotrexate with leucovorin rescue, or treatment regimens exploiting the synergy of 5-fluorouracil (5-FU) and leucovorin—the absorption of oral folates, and seemingly the absorption of oral leucovorin, are decreased in older patients;10 • management of lymphoid malignancies with oral alkylating agents and steroids—in persons over 70, it may be advisable to spread the total dose of the medications over 4–7 days, to allow more complete absorption of the drugs (see Chapter 48 of this volume19); • management of nausea and vomiting with oral agents (compazine, ondansetron, granisetron, and metoclopramide);20 • management of pain with oral opioids.21 The evidence relating to drug absorption in the aged is limited. Studies involving the management of older individuals with oral capecitabine15,22 and etoposide15,23 suggest that age does not alter the bioavailability of these agents—at least until the age of 80. Further studies, especially in the oldest old, are necessary to clarify the issue. Distribution The volume of distribution (Vd) of water-soluble drugs is a function of body water, of the concentration of circulating plasma proteins,24 and of hemoglobin concentration.9 With age, there is a progressive decline in total body water and a progressive accumulation of total body fat, which results in a decreased Vd for water-soluble agents and an increased Vd for fat-soluble compounds. Also, a progressive decline in the concentration of plasma proteins may further reduce the Vd of water-soluble drugs, especially of those that are heavily protein-bound, such as the vinca alkaloids, the taxanes, the anthracyclines, and the epipodophyllotoxins. Although the AUC (area under the curve) of drugs is unaffected by changes in Vd, the shape of the AUC may change. While water-soluble drugs may exhibit higher plasma levels associated with shorter half-lives, lipid-soluble agents may experience lower plasma concentrations and more prolonged half-lives.

Comprehensive Geriatric Oncology

820

The changes in AUC shape may influence both the effectiveness and the toxicity of drugs. For example, a more rapid decline in plasma levels of phase-specific agents (e.g. methotrexate and cytarabine) may be associated with lessened therapeutic efficacy; higher plasma peak levels of cardiotoxic anthracyclines may be associated with enhanced cardiac toxicity. Special attention should be paid to changes in the Vd of the oldest old. After age 80– 85, new changes in body composition may occur, with atrophy of many organs and depletion of total body fat (see Chapter 1614). The role of hemoglobin has emerged from a number of studies suggesting that anemia is an independent risk factor for chemotherapy-induced myelodepression.25–29 This finding is not surprising, since a number of drugs, including the anthracyclines, the epipodophyllotoxins and the alkaloids29 are largely bound to red blood cells. In the presence of anemia, the concentration of free drug in the circulation, and hence the risk of drug-related toxicity, increase. Metabolism The liver is the main site of drug metabolism. The effects of hepatic metabolism of antineoplastic drugs are described in Table 39.1. Hepatic metabolism involves two types of metabolic reactions. Type I reactions are dependent on the cytochrome P450 mixedfunction oxidase

Figure 39.2 Metabolism of cyclophosphamide. system (MFOS), and may lead to active as well as inactive compounds.24,30 One of the best known of these reactions, which are oxidation/reduction (redox) reactions, is the activation of the oxazaphosphorine alkylators cyclophosphamide and ifosfamide to the active compounds phosphoramide mustard and 4hydroxycyclophosphamide/aldophosphamide (Figure 39.2).

Cancer chemotherapy in the older patient

821

Type II reactions are conjugation reactions, which may involve glucuronidation and lead to inactive compounds, excretable through the biliary system.24 This scheme of drug metabolism is probably too simple. It has been found that some of the glucuronides, such as morphine 6-glucuronide, are as active or more active than the parent compounds.32 Table 39.1 illustrates very well the complex task of predicting drug effectiveness and toxicity based on hepatic function. Oxazaphosphorines are both activated and deactivated by cytochrome P450 microsomal reactions, and it is impossible to predict which process will be more prominent in the case of liver dysfunction.32 5-FU and cytarabine are predominately activated intracellularly, and are partly catabolized by the liver: dose adjustments for these drugs are recommended only in the presence of severe liver insufficiency.33–34 In some instances (e.g. anthracyclines and vinca alkaloids), both the parent compound and some hepatic metabolites are active, and it may be problematic to establish the respective contributions to the antineoplastic effect of the drug.35,36 The 13-ol derivatives of the anthracyclines provide a good example of this difficulty. Doxorubicinol and epirubicinol are formed in negligible amounts, and have lower activity than the parent compounds, whereas daunorubicinol and especially idarubicinol are responsible for a substantial antineoplastic effect. These 13-ol derivatives are mostly excreted in the urine. In the case of idarubicin, no dose adjustment of the drug is recommended in the presence of hyperbilibinemia, because the majority of the active drug is eliminated through the kidney.

Table 39.1 Effects of hepatic metabolism on commonly used agents Drug

Metabolic products

Product Dose activity adjustments

Methotrexate

7-Hydroxymethotrexate

No

No

5-Fluorouracil (5FU)

CO2, NH3, α-fluoro-β-alanine

No

No

Cytarabine (cytosine arabinoside)

Uracil arabinoside

No

No

4Hydroxycyclophosphamide/aldophosphamide

Yesa

No

Phosphoramide mustard

Yesa

—

4-Ketocyclophosphamide

No

—

Carboxyphosphamide

No

—

TEPA

Yes

?

Nitrogen

No

?

Hydroxyl radical

Yes

?

Antimetabolites

Alkylating agents Cyclophosphamide, ifosfamide

Thiotepa

b

Carmustine (BCNU)

b

Comprehensive Geriatric Oncology

822

Chloroethyl radical

Yes

?

Anthracyclines and anthracenediones

Deoxyaglycones, glucuronides

No

—

Doxorubicin, daunorubicin, epirubicin

Doxorubicinol, daunorubicinol, epirubicinol

Yes

Yesc

Idarubicin

Idarubicinol

Yes

No

Mitoxantrone

Not characterized

No

Yesc

4-Deacetyl derivatives

Yes

Yesc

N-oxide derivatives

No

—

Others

No

—

Hydroxy derivatives

No

Yesc

No

No

Hydroxy derivatives

No

—

Epiaglycones

Yes

—

Vinca alkaloids Vincnstine, vinblastine, vindesine, vinorelbine Taxanes Paclitaxel, docetaxel Epipodophyllotoxins Etoposide, teniposide Glucuronides

a

Only phosphoramide mustard acts as an alkylator. The majority of the phosphoramide mustard is formed within the tumor cell. The cytotoxic action of 4-hydroxycyclophosphamide and aldophosphamide involves mainly transport within the cells of the precursors of phosphoramide (Figure 39.2). b Thiotepa is triethylenethiophosphoramide; TEPA is triethylenephosphoramide. c Current recommendations are one-half dose for bilirubin ≥1.5mg and one-quarter dose for bilirubin ≥3.0mg. It should be noted, however, that these recommendations are not based on extensive data: the need for dose adjustment should be left to the judgment of the practitioner in individual clinical situations.

Hepatic metabolism plays a central role in the activation of capecitabine, a prodrug of 5FU that is active when administered orally.37 Both animal and human studies indicate that phase I reactions may become less active with age. It is not clear, however, to what extent this decrease in activity is a function of susceptibility to environmental factors, such as tobacco smoking, diet, and other drugs. What is clear is that frailty is associated with decreased activity of phase I reactions.13,38 Also, these reactions are influenced by a number of drugs, including cimetidine, which is inhibitory, and phenobarbital, which enhances the activity of the reactions.38 Polypharmacy, a common problem in older individuals, may also affect phase I reactions (see Chapter 41 of this volume39). Phase II reactions appear to be unaffected by age.

Cancer chemotherapy in the older patient

823

Excretion Urinary and biliary excretions are the main routes of drug disposal (Table 39.2). A few drugs, such as 5-FU and cytarabine, are catabolized intracellularly to inactive products.33,34 Some of these metabolic products, including carbon dioxide, are excreted though respiration. For other drugs, such as cisplatin, the final fates of the drug and its products are not fully known.40

Table 39.2 Excretion of antineoplastic agents, with dose adjustments (percentage of regular dose) for renally excreted agents according to creatinine clearance (CrCl) CrCl (ml/min) ≤60

≤45

≤30a

Bleomycin

70%

60%

NR

Carboplatin

Calvert’s formula

Carmustine

80%

75%

NR

Cisplatin

75%

50%

NR

Cladribine

Not established

Cytarabine (high-dose)

60%

50%

NR

Dacarbazine

80%

75%

70%

Fludarabine

80%

75%

65%

Hydroxyurea

85%

80%

75%

Idarubicin

Not established

Ifosfamide

80%

75%

70%

Melphalan

85%

75%

70%

Methotrexate

65%

50%

NR

Renal excretion

Hepatic excretion Doxorubicin Daunorubicin Epirubicin Vinca alkaloids Taxanes Mixed excretion

Comprehensive Geriatric Oncology

824

Epipodophyllotoxins Mitomycin C a

NR, drug is not recommended in these circumstances.

A progressive decline in glomerular filtration rate (GFR) is one of the most consistent findings of normal aging41 (see Chapter 183). Controversy lingers over whether this decline is avoidable. Some investigators believe that a reduction in daily protein intake may delay or prevent the age-related reduction in GFR.41 What is clear is that comorbid conditions, including poorly controlled hypertension and diabetes, may accelerate the development of renal insufficiency, and so may the chronic intake of certain drugs, such as acetaminophen (paracetamol) and non-steroidal anti-inflammatory drugs (NSAIDs).42 The recent introduction of cyclooxygenase-2 (COX-2) inhibitors as analgesic/antiinflammatory agents may reduce the risk of drug-induced nephropathy.43 Unlike COX-1, which is a structural enzyme, necessary for the function of many normal tissues, COX-2 is inducible and present in substantial amounts only in pathologic conditions. The importance of GFR impairment in the management of older persons with cancer has been highlighted by a seminal study by Gelman and Taylor.44 These authors treated metastatic breast cancer in 167 women with a combination of cyclophosphamide, methotrexate, and 5-FU. The doses of cyclophosphamide and methotrexate were adjusted to the patients’ GFR, in women aged 65 and older. The therapeutic response was similar in younger and older women, but the myelotoxicity was less severe in the older women. Kintzel and Dorr45 calculated the dose adjustment with declining renal function for drugs whose parent compounds, active metabolites, or toxic metabolites are excreted through the kidneys (Table 39.2). They based this calculation on the fraction of drug or drug derivative undergoing renal excretion, according to the following formula: adjusted dose=(normal dose)×[f(Kf−1)+1] where f is the fraction of the parent compound and/or active or toxic metabolite excreted through the kidneys and Kf is the patient’s creatinine clearance (CrCl, in ml/min) divided by 120. This reference formula might be very helpful to the busy practitioner. It should be pointed out, however, that many of these adjustments were not tested in the clinical context. We recommend—ideally in all patients, but especially in those aged 50 and older— that CrCl be calculated and the dosage of renally excreted medications be adjusted accordingly.44 We also recommend that CrCl (in ml/min) be calculated using the formulae of Cockcroft and Gault:45 for males,

for females,

Cancer chemotherapy in the older patient

825

Using the plasma clearance of technetium-99m DPTA as the gold standard measurement of GFR, Waller et al46 demonstrated that the calculation of CrCl using these formulae had smaller variation coefficients than direct measures of CrCl from 2-, 4-, and even 24-hour urine collections, or calculations using different formulae. Of interest, the variation coefficients were larger for GFR >50ml/min. Thus, these formulae are especially reliable in patients with reduced GFR. It is not clear how well they may apply to patients over 75, however, owing to marked variations in body composition. The Levine formula, introduced recently, may be more accurate for older individuals, but is less user-friendly, because of the complex calculation involved.47 We recommend that the doses of methotrexate given by intravenous push be adjusted according to the formula proposed by Gelman and Taylor,44 which has proved adequate in the management of older individuals: dose of methotrexate=D×CrCl/70 where D is the dose of methotrexate for persons with normal renal function. When methotrexate is given at high doses by continuous infusion, the infusion rate may be calculated as follows:48 Infusion rate=plasma[MTX]×Cl(MTX) where plasma[MTX] is the desired plasma level of methotrexate and Cl(MTX) is the clearance of methotrexate calculated for an initial push dose of 50mg/m2. The Calvert formula allows the practitioner to calculate the dose of carboplatin for the desired AUC based on age and serum creatinine.49 For other drugs, we recommend the dose adjustment proposed by Kintzel and Dorr45 (Table 39.2). Several drugs, such as etoposide, have a mixed hepatic and renal excretion.50 In these circumstances, a reduction of GFR of up to 25ml/min does not seem to prevent adequate drug excretion, as long as biliary obstruction is not present. In general, biliary excretion seems to be unaffected by age. Robert and Hoerni51 and Egorin et al52 have studied the half-lives of doxorubicin and daunorubicin, respectively, in persons of different ages and were unable to demonstrate the presence of age-related changes. Likewise, Lichtman et al53 found a high variability in the half-life of paclitaxel in older individuals. Paclitaxel and other taxanes are metabolized in the liver and their metabolites are excreted through the bile; less than 10% of the parent compound is found unchanged in the urine.54 Of special interest is a study by Burkowski et al,55 who investigated the pharmacokinetics of nine drugs in patients younger than 65 and aged 65 and over. The drugs were dichloromethotrexate, hexamethylene bisacetamide, N-methylformamide, trimetrexate, paclitaxel, piroxantron, topotecan, bequinar, and menogaril. Eighty-one patients were aged over 65, 35 over 70, and 5 over 75; the oldest patient was 77. Fiftyone percent of patients over 65 and 53% of those under 65 received a dose of chemotherapy equal to or higher than the maximal tolerated dose (MTD); 25.9% of the older patients and 31.7% of the younger experienced dose-limiting toxicity (DLT) equal to or higher than grade 3. Of special interest was the experience with dichloromethotrexate: while the renal clearance of the drug decreased with age, in accord with a decline in CrCl, the total clearance of the drug did not decrease, suggesting compensatory increased hepatic clearance. This study is very important for several

Comprehensive Geriatric Oncology

826

reasons: (i) it was the first study to include older individuals in phase I trials; (ii) it demonstrated that the pharmacokinetics of many drugs does not change with the age of the patient; (iii) it suggested the possibility of compensatory changes in drug clearance for agents with mixed excretion. The main limitation of the study was the scarce representation of patients aged 75 and older. In the same line, Yamamoto et al56 studied the pharmacokinetics of cisplatin in lung cancer patients of different ages, and found that the drug concentration was increased for a more prolonged period of time in older individuals, indicating a decreased rate of drug elimination. Similar conclusions were reached by Lichtman et al57 in a more recent study. The pharmacokinetics of the most common antineoplastic agents are summarized in Table 39.3. Pharmacodynamics Age-related changes in pharmacodynamics are highly speculative. This is an open and important area of research aimed at explaining age-related differences in the responsiveness of certain tumors to chemotherapy. These tumors include acute myeloid leukemia (AML), epithelial carcinoma of the ovaries, and possibly non-Hodgkin lymphomas (NHL).5 We shall explore three reasonable hypotheses to account for these differences: • Age is associated with a higher prevalence of neoplastic cells with multidrug resistance (MDR). • Age is associated with abnormalities in tumor enzymes that are the targets of specific agents. • Age is associated with changes in tumor kinetics, which prevent the cytotoxic effect of cell cycle-active drugs. Other important potential mechanisms of drug resistance include alterations in the mechanism of intracellular transport, and intracellular activation and deactivation of drugs. Age and multidrug resistance (MDR) MDR may result from several mechanisms.58,59 One of the best understood forms of drug resistance is the expression of the MDR1 gene, which encodes P-glycoprotein, a 170 kDa membrane protein that extrudes from the cell natural antineoplastic agents, including antibiotics, vinca alkaloids, epipodophyllotoxins, and taxanes. The function of this pump is related to slow calcium channels and may be reversed by calcium channel blockers and by cyclosporine (cyclosporin A, CSA) and its derivatives. MDR1 is also expressed in normal tissues, such as hematopoietic stem cells and the endothelial cells lining

Cancer chemotherapy in the older patient

827

Table 39.3 Pharmacokinetic parameters of major antineoplastic agents Drug

Active parent compound

Active Elimination of metabolites active compounds

Dose adjustment

Methotrexate

Yes

—

Renal

Yes

5-Fluorouracil (5-FU)

—

Yes

Cellular and No hepatic metabolism

Cytarabine (cytosine arabinoside)

—

Yes

Cellular and Noa hepatic metabolism

Fludarabine

—

Yes

Renal

Yes

Cladribine (2chlorodeoxyadenosine)

—

Yes

Renal

?

Antimetabolites

Alkylating agents Bischloroet thylamines mines ines Oxazaphosphorines (cyclophosphamide, ifosfamide)

—

Yes

Hepatic metabolism; renal

Yesb

Chlorambucil

Yes

—

Hepatic metabolism; renal

?

Melphalan

Yes

—

Hepatic metabolism; renal

Yesc

Yes

Yes

Hepatic metabolism; renal

?

Carmustine (BCNU), Yes lomustine (CCNU), semustine (methyl-CCNU), streptozocin

Yes

Hepatic metabolism

?

Aziridines Thiotepa Nitrosoureas

Platinum analogs Cisplatin

Yes

No

Inactivated intracellularly and in the circulation; renal (minor)

Nod

Carboplatin

Yes

No

Renal

Yes

Antibiotics

Comprehensive Geriatric Oncology

828

Anthracyclines and anthracenediones Daunorubicin, doxorubicin

Yes

Yes

Biliarye

Yes

Idarubicin

Yes

Yes

Renal

?

Mitoxantrone

Yes

No

Biliaiy

Yes

Yesf

No

Hepatic metabolism; renal

No

Etoposide

Yes

No

Mixed hepatic and renal for reduced CrCl

Yes

Teniposide

Yes

No

Mixed hepatic and renal

No

Yes

No

Biliary

Yes

Yes

No

Hepatic metabolism

?

Yes

No

Renal

?

Others Mitomycin C Plant derivatives Epipodophyllotoxins

Vinca alkaloids Vincristine, vinblastine, vinorelbine Taxanes Paclitaxel, docetaxel Others Hydroxyurea a

High doses contraindicated for CrCl<50 ml/min; may also be contraindicated in patients over 60. Especially for ifosfamide. c Halve dose for BUN>30mg/ml d Dose adjustment should be made to prevent further renal damage. e Over 50% of these drugs is tissue-bound and is not accounted for in urine or stools. f Spontaneously activated in hypoxic conditions and in acidic environments. b

the blood vessels of the central nervous system and of the testicles.58,59 The relative resistance of these tissues to cancer chemotherapy may be explained in part by MDR. Willman et al60 found that MDR1 is expressed by the neoplastic cells of 67% of patients with AML aged 60 and over, and in 17% of those younger. The association of AML and MDR1 in the elderly reflects the association of AML and myelodysplasia (MDS) in the elderly.61 MDS is a disease of a pluripotent hematopoietic progenitor cell. This observation provided the first definitive proof that the biology of certain neoplasms may change with age. Circumstantial evidence suggests that MDR1 may play a role in the shorter duration of remission of patients aged 60 and older with large cell lymphomas treated with

Cancer chemotherapy in the older patient

829

doxorubicin-containing combination chemotherapy62 and of patients with ovarian cancer.63 The mechanism by which tumors of older individuals may develop MDR is not clear. The acquisition of MDR is a spontaneous mutation whose incidence is a function of the number of mitoses undergone by the tumor cell.58,59 Older organisms may not support tumor growth as well as younger organisms;64 thus, the incidence of tumor cell death may be higher in older individuals and a higher number of mitoses may be required for a sizable tumor. MDR is modulated by cyclosporine and its derivatives,65,66 but clinical trials of these compounds in older individuals with AML have enhanced the toxicity of treatment without clear clinical benefits. These results reflect the reduced hematopoietic reserve in older patients with AML due to involvement of hematopoietic stem cells in the disease process, rather than any lack of efficacy of the compounds. A second form of MDR is related to abnormalities of the enzymes targeted by cytotoxic agents. The best described abnormalities concern the enzyme topoisomerase II, targeted by the anthracyclines and the epipodophyllotoxins.67 Synthesis of aberrant proteins is one of the molecular abnormalities of aging.68 A third form of MDR involves increased concentration of glutathione reductase, which allows a more complete scavenging of free radicals generated by drugs and radiation and consequent prevention of cellular damage from these compounds.69 There is no evidence that the concentration of glutathione reductase increases with age in neoplastic or in normal cells. There is evidence of a higher degree of hypoxia, however, in tumors occurring in older animals, and hypoxia may prevent the formation of free radicals.70 A fourth form of MDR concerns alterations in the mechanism of cellular death. Clearly, many drugs, including the epipodophyllotoxins and the purine analogs, cause cell death by apoptosis, which requires intact p53 and BCL2 genes.71 When these genes are altered, as is the case in many tumors, the drugs may lose their effectiveness. The BCL2 oncogene is altered in many of the marginal

Table 39.4 Enzymes inhibited by specific chemotherapy agents Drug

Enzyme(s)

Methotrexate

Dihydrofolate reductase (DHFR)

5-Fluorouracil (5-FU)

Thymidylate synthase (TS)

Cytarabine (cytosine arabinoside)

DNA polymerase α

Fludarabine

DNA polymerase α Ribonucleotide reductase DNA primase DNA ligase 1

Cladribine (2-chlorodeoxyadenosine)

Ribonucleotide reductase

Hydroxyurea

Ribonucleotide reductase

Comprehensive Geriatric Oncology

Anthracyclines

830

Topoisomerase II

zone lymphomas (maltomas), whose incidence increases in older individuals.71 Abnormalities of the BCL2 oncogene were also found more frequently in non-small cell lung cancer (NSCLC) in older individuals.72 Thus some circumstantial evidence suggests that the prevalence of this type of MDR may increase with the age of the patient. A fifth (and so far only theoretical) form of MDR includes enhanced repair of DNA damage caused by cytotoxic agents. In general, the ability to repair DNA appears to be decreased in aging tissues, and this form of MDR is unlikely to be of interest in older patients. Age and synthesis of enzyme targets of antimetabolites The mechanism of action of antimetabolites involves the inhibition of one or more enzymes necessary for DNA synthesis (Table 39.4). As in the case of topoisomerase II, the synthesis of these enzymes may be abnormal in tumors occurring in older individuals.66 The abnormal enzyme may escape the block effected by the drugs. In certain circumstances, drug resistance is a consequence of an amplification of the gene encoding the target enzyme.73 This mechanism of drug resistance was demonstrated in vivo for methotrexate. Amplification of the gene encoding the target enzyme dihydrofolate reductase followed prolonged exposure to the drug, and the excess enzyme overcame the metabolic block.73 Age and tumor kinetics The biology of some tumors may be altered in the older tumor host. These biologic alterations may include slower tumor growth due to a reduction of the tumor growth fraction. This possibility was demonstrated in experimen-tal animals (see Chapter 122). In humans, Valentinis et al74 demonstrated that the labeling index of breast cancer was significantly higher in women under 70 than in older women. Daidone et al have also found a decreased proliferation rate of lung cancer in older individuals (see Chapter 14 of this volume75). A reduced growth fraction may be associated with drug resistance, since the majority of antineoplastic agents are active against replicating cells. It should be noted that as a result of these changes, tumors may become both more indolent and less sensitive to cytotoxic agents. Pharmacodynamic changes may also influence the development of drug toxicity: Rudd et al76 have recently reported that DNA adducts with cisplatin are completely clear in 48 hours from circulating monocytes of individuals aged 20–25 but may persist indefinitely in the monocytes of individuals aged over 70. These effects suggest an inadequate ability of DNA repair in the normal tissue of older individuals, which may lead to cumulative and irreversible toxicity. Organ-specific toxicity

Cancer chemotherapy in the older patient

831

The most common complications of antineoplastic treatment are listed in Table 39.5. Some of these complications, such as myelotoxicity, nausea and vomiting, and mucositis, are almost universal; the others are drug-specific. Myelotoxicity Myelotoxicity is the most common complication of cancer chemotherapy.77 A brief review of hematopoiesis is necessary to understand the mechanisms of myelotoxicity and the treatment strategies that may minimize this complication8 (see Chapter 36 of this volume78). A common view of hematopoiesis (Figure 39.3), holds that from a pluripotent hematopoietic stem cell (PHSC), hematopoietic progenitors committed to the erythroid, myeloid, megakaryocytic, and lymphoid series are derived

Table 39.5 Common chemotherapy-related toxicities Universal • Myelodepression • Mucositis • Nausea and vomiting Drug-specific • Cardiotoxicity • Pulmonary toxicity • Central and peripheral neurotoxicity • Nephrotoxicity

Figure 39.3 Hematopoiesis. The dark area represents the proliferative rate; the clear area, the ability for selfreplication. PHSC, pluripotent hematopoietic stem cell.

Comprehensive Geriatric Oncology

832

(see Chapter 3678). From these progenitors, the recognizable precursors of circulating blood elements originate. The PHSC is unique in two aspects: its extensive self-renewal potential and its ability to become committed to different hematopoietic lines. The committed progenitors instead have limited potential of self-renewal and can differentiate only into a single hematopoietic line. The PHSC and committed progenitors can be recognized from clonal growth in vitro and from specific cell markers, such as CD34.79 The processes of proliferation, commitment, and differentiation require an intact hematopoietic stroma80,81 and are modulated by a host of hematopoietic growth factors (Table 39.6).82 The functions of the hematopoietic stroma include the homing of the PHSC and the production of some of these growth factors. Any alterations in the number or function of PHSC, in the structure and function of the stroma, and in the production of growth factors may compromise hematopoiesis. The PHSC are largely sheltered from cytotoxic injury. Their low proliferation rate limits the proportion of cells vulnerable to cell cycle-active drugs. In addition, PHSC express the MDR1 gene, which, as already mentioned, encodes P-glycoprotein, a powerful membrane pump that extrudes natural cytotoxic agents from the cell.59 Low proliferation also shelters to some extent the committed progenitors from antineoplastic agents, while highly proliferating, differentiated precursors are particularly vulnerable to these drugs. Chemotherapy-induced losses of late marrow precursors are repaired by increased differentiation of committed progenitors and enhanced commitment of PHSC. With age, the full and timely replacement of destroyed hematopoietic elements may be hindered by three causes: exhaustion of the PHSC reserve, dysfunctional marrow stroma, and decreased production of endogenous growth factors. There is circumstantial evidence, both in experimental systems and in humans, that the hematopoietic reserve may decline with age, owing to a combination of factors. These include a decline in the number of PHSC, decreased production of growth factors, reduced sensitivity to growth factors, inhibition of hematopoietic maturation

Table 39.6 Hematopoietic growth factors • Granulocyte colony-stimulating factor (G-CSF): – Stimulates proliferation and maturation of granulocyte progenitors – Synergistic with other factors in causing cycling of pluripotent hematopoietic stem cells (PHSC) • Granulocyte-macrophage colony-stimulating factor (GM-CSF): – Supports proliferation of PHSC (after exit from G0 phase of the cell cycle) – Stimulates proliferation and maturation of granulocyte-macrophage progenitors – Stimulates thrombopoiesis • Erythropoietin (EPO): – Stimulates proliferation and maturation of early and late erythropoietic progenitors: burstforming units-erythroid (BFU-E) and colony-forming units-erythroid, respectively. CFU-E are more sensitive than BFU-E • Macrophage colony-stimulating factor (M-CSF):

Cancer chemotherapy in the older patient

833

– Stimulates proliferation and differentiation of macrophage progenitors • Leukemia inhibitory factor (LIF) • Stem cell factor (SCF); also known as Steel factor (SF) and c-Kit ligand: – Survival factor for PHSC in G0 phase of the cell cycle – Stimulates thrombopoiesis • Thrombopoietin (TPO); also known as megakaryocyte growth and development factor (MGDF): – Stimulates thrombopoiesis • Interleukins (IL): IL-3: – Stimulates PHSC and early progenitors to enter the cell cycle – Stimulates proliferation of PHSC and early progenitors – Survival factor for PHSC IL-5: – Stimulates proliferation and maturation of macrophage-monocyte progenitors – Stimulates proliferation and differentiation of eosinophil progenitors IL-4, IL-6, IL-11, IL-12: – Act synergistically with other hematopoietic factors in different hematopoietic steps

and differentiation, and degenerating stroma. In a series of elegant experiments, Lipschitz83 exposed older and younger mice to crowding, which represents a hematopoietic stress in this system. Older mice experienced a rapid decline in the concentration of PHSC that was not seen in younger mice. More recently, the exhaustion of the PHSC was also suggested by the experiments of Van Zant,84 who reported a progressive shortening of telomeres in murine PHSC. In aging humans, the incidence of aplastic anemia increases,85 the percentage of functional marrow tissue is progressively reduced,85 and the ability to cope with some forms of hematopoietic stress, such as infection and bleeding, is progressively impaired. Chatta et al86 studied the response to granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in volunteers aged 20–30 and 70–80. They found that comparable degrees of neutrophilia followed G-CSF administration in younger and older individuals. The concentration of PHSC in the peripheral blood following GM-CSF, however, was twofold higher in younger subjects. Marley et al87 reported a progressive decline in the self-replicative ability of pluripotent hematopoietic precursors (colony-forming units-granulocyte/macrophage, GM-CFU) in aging humans. Information related to the production of hematopoietic cytokines in the aged is inconclusive.82 A French study reported that the production of GM-CSF by human monocytes grown in vitro declines.82 Bagnara et al88 reported decreased production of GM-CSF in vitro after phytohemoagglutinin (PHA) stimulation from mononuclear cells

Comprehensive Geriatric Oncology

834

obtained from healthy subjects aged 100 and older. Interestingly, no difference was found between mononuclear cells obtained from patients aged 66–73 and those aged 30–45. In some cases of otherwise-unexplained anemia, reduced circulating levels of erythropoietin were found in older patients;89–93 it is not clear, however, whether mild degrees of renal insufficiency might have also been present in those patients, since aging is generally associated with a progressive decline in the GFR (see Chapter 183). The possibility of inhibition of hematopoiesis is suggested by two lines of evidence. In senescence-accelerated mice (SAM—transgenic mice undergoing early senescence), Kumagai et al94 reported an increased production of colony-inhibiting activity (CIA) in the bone marrow in response to lipopolysaccharide (LPS), whereas in young mice, LPS induced increased production of colony-stimulating activity. In humans, aging is associated with a number of biochemical changes that, woven together, may lead to a catabolic conditions known as somatopause.95–97 These changes include increased concentration in the circulation of inflammatory cytokines such as interleukin6 (IL-6) and tumor necrosis factor (TNF) and decreased secretion of growth hormone and consequently of insulin-like growth factor I (IGF-I). This combination may have an inhibitory effect on hematopoiesis. Information concerning the aging hematopoietic stroma is limited,97 but indicates a progressive loss in the ability to provide homing for PHSC, which may lead to a depletion of the PHSC reserve. The response to hematopoietic growth factors of PHSC and early progenitor cells may be delayed and blunted in older animals.97,98 It is important to recognize, however, that the response to pharmacologic doses of G-CSF and erythropoietin is well preserved in older individuals,99–105

Table 39.7 Age and myelotoxicity of cancer chemotherapy: results of five retrospective trials Authors

No. of patients

No. of Source/comments patients aged over 70

Begg and Carbone106

5459

Gelman and Taylor44

231

31 (13%) Dana Farber Cancer Center. Patients over 65 had been treated prospectively with dose adjustment for cyclophosphamide and methotrexate and two-thirds 5FU dose. Results were compared with 161 fully evaluable younger patients. Patients over 80 experienced shortened survival

Christman et al107

170

70 (41%) Piedmont Oncology Group database. There was a high degree of patient selection

GiovannazziBannon et al108

672

780 (14%) ECOG database

≥65:271 Illinois Cancer Center phase II trials (40%) ≥70:? (25%)

Cancer chemotherapy in the older patient

Ibrahim et al109

1011

Ibrahim et al110

390

835

≥65:244 MD Anderson Hospital patients with metastatic breast (24%) cancer aged 50 and older ≥70:? (<20%) ≥65:65 MD Anderson Hospital patients with breast cancer (17%) receiving anthracycline-containing adjuvant ≥70:? chemotherapy (<10%)

and these compounds may represent the strongest bulwark against myelotoxicity in the aged. From this brief review of hematopoiesis and age, we may draw three conclusions: 1. Aging is associated with a progressive reduction in hematopoietic reserve. 2. By itself, the decline in hematopoietic reserve does not produce abnormalities of the circulating blood; these may occur as a consequence of hematopoietic stress. 3. Hematopoietic growth factors are effective in promoting granulopoiesis and erythropoiesis in older individuals. Is age associated with increased risk of chemotherapy-induced myelotoxicity? At least five retrospective studies gave a negative answer to this question (Table 39.7)44,106–110 The resuits Of these studies should be treated with caution, however, for the following reasons: • These data were derived from studies performed by major cooperative groups or major cancer centers, where patients had to fulfill exacting eligibility criteria. That this was a selected population of older individuals is proven by the fact that only 10% of the patients were aged 70 and older. If the studies had reflected the current prevalence of cancer, patients aged 70 and older would have accounted for 40% of the study population. • Virtually no individual was aged 80 and over. • In the study by Begg and Carbone,106 the risk of myelotoxicity was eventually increased after age 70 for certain drugs, such as the nitrosoureas. A more realistic picture of the risks of myelodepression emerges from a number of studies related to the treatment of large cell lymphoma (Table 39.8).103–105,111–116 With the exception of the study by Armitage and Potter,116 all the other studies were prospective. The incidence of grade 3 and 4 neutropenia was consistently higher than 50% in all studies; the risk of neutropenic infections was as high as 47%105 and the risk of treatmentrelated deaths as high as 20% in persons aged 70 and older.112 The association of myelotoxicity and age was supported by a small prospective study of the adjuvant treatment of breast cancer with cyclophosphamide and doxorubicin by Dees et al.117 These investigators found that the neutrophil nadir varied inversely with age and that women over 65, unlike younger women, experienced cumulative myelodepression with successive courses of treatment. A retrospective study by Kim et al118 also found an association between age and myelodepression. Myelodepression is also more common in older than in younger patients treated with combination chemotherapy for AML (see Chapter 45 of this volume119). In the case of

Comprehensive Geriatric Oncology

836

AML, however, the disease itself may be responsible for the decline in PHSC reserve, through myelophthisis and involvement of PHSC in the disease itself.61 In conclusion, it is clear that the risk of neutropenia and neutropenic infections increases with age, and the risk of neutropenic deaths is particularly high after age 70, with moderately toxic chemotherapy of dose intensity comparable to that of the CHOP regimen (cyclophosphamide,

Table 39.8 Incidence of life-threatening neutropenia; neutropenic infections and death in older individuals with large cell NHL treated with CHOP-like regimens Authors

No. of Regimen patients

Zinzani et al104

161 VNCOP-B

≥60

44

32

1.3 —

Sonneveld et al111

148 CHOP CNOP

≥60 ≥60

NR NR

NR NR

14 — 13 —

Gomez et al115

26 CHOP

≥60 ≥70

24 73

8 42

0 GM20 CSF GMCSF

Tirelli et al112

119 VMP CHOP

≥70 ≥70

50 48

21 21

7 — 5 —

Bastion et al113

444 CVP CTVP

≥70 ≥70

9 29

7 13

12 — 15 —

O’Reilly et al114

63 POCE

≥65

50

20

8 —

Bertini et al103

90 VEBCP

≥60

44

9

2 —

411 CHOP/CNOP ≥70

91

47

8 —

NR

NR

30 —

Bjorkholm et al105 Armitage and Potter116

20 CHOP

Age Neutropenia Neutropenic Treatment- Growth (%) fever (%) related factor deaths (%) use

≥70

NR, not reported.

doxorubicin, vincristine, and prednisone). In the meantime, filgrastim (recombinant human G-CSF) appears to be effective in reducing by 50–75% the risk of neutropenia and neutropenic infections in these patients.102–105 The risk of thrombocytopenia appears also to increase with age, although it has not been associated with treatment-related death.

Cancer chemotherapy in the older patient

837

The incidence of anemia has attracted renewed interest, since anemia has been directly associated with fatigue. In addition to deterioration in quality of life, fatigue may cause disability and functional dependence, which is more common in the elderly and calls for homecare.120 The highest incremental improvement of fatigue is obtained when the hemoglobin levels increase from 11 to 13 g/dl.120,121 A number of studies,121–124 including a randomized controlled study, have proven conclusively that erythropoietin at doses of 40000–60000 units weekly improves both anemia and fatigue in patients receiving combination chemotherapy. Erythropoietin is particularly effective when administered in combination with iron and in patients with endogenous erythopoietin levels of 100pg/ml or less. Anemia has also been associated with enhanced risk of chemotherapy-induced myelotoxicity,25–29 as a result of a restriction of the Vd of water-soluble agents. This risk maybe particularly serious in older individuals who already experience a decline in total body water and total body proteins (see Chapter 183). Other unwanted consequences of anemia in the aged include an increased risk of iatrogenic complications, such as postoperative delirium,125 a higher incidence of falls, cognitive dysfunction, and congestive heart failure.126 Since the incidence of anemia increases with age, as the hematopoietic reserve declines, older individuals are at increased risk of chemotherapyinduced anemia. After reviewing the existing data, the National Cancer Center Network (NCCN) in the USA has issued the following recommendations:127 • Individuals aged 65 and older receiving moderately toxic chemotherapy should also receive prophylactic hematopoietic growth factors • The hemoglobin of older individuals receiving cancer chemotherapy should be maintained at 12 g/dl or higher. The American Society of Clinical Oncology (ASCO) has also concurred with these recommendations.9 Alternative strategies include reduction of chemotherapy doses, the use of prophylactic oral antibiotics and antifungal agents for the prevention of neutropenic infections, and blood transfusions for the management of anemia. None of these strategies appear as satisfactory as the NCCN recommendations for the following reasons: • Reduced doses of chemotherapy have been associated with inferior outcome, at least in the case of large cell lymphoma114,128,129 and AML.130 • Prophylactic oral antibiotics have not been associated with a reduction in the most lethal types of infections, namely those due to Pseudomonas and Staphylococcus aureus.131 • Blood transfusions may offset the acute complications of anemia, such as myocardial ischemia and congestive heart failure, but they cannot support the steady hemoglobin levels necessary to overcome fatigue and the other chronic effects of anemia.126 Seemingly, the NCCN recommendations should not increase the cost of managing older individuals, and may even be cost-effective. Lyman et al132 have laid down the criteria for a cost-effective use of hematopoietic growth factors. These include a risk of neutropenic infection of 45% or higher. This risk was observed in the majority of studies involving patients over 70.105,112,114 Furthermore, in an update of the original study, Lyman et al133 found that the cost-effectiveness of filgrastim varied with the duration and the cost of

Comprehensive Geriatric Oncology

838

hospitalization, which in older individuals is more prolonged than for younger patients. Cremieux et al134 reported that the cost of erythopoietin is comparable to the cost of blood transfusions, if three or more blood transfusions are needed each month. The introductions of a pegylated form of filgrastim that may be administered once weekly135 and of darbepoietin, which may be administered every 2–3 weeks,136 will further reduce both the cost and the inconvenience of the treatment with hematopoietic growth factors. Mucositis Mucositis, caused by the destruction of rapidly proliferating gastrointestinal cells, may be particularly severe with methotrexate, 5-FU, bleomycin, cytarabine, and 5-FU/leucovorin combinations. The manifestations of mucositis include inflammation of the upper digestive mucosas, with dysphagia, odynophagia, reduced oral intake of fluids, food, and medications, and severe diarrhea. Clinical evidence that older persons are at risk for severe mucositis is compelling. Gelman and Taylor44 could not prevent mucositis by adjusting the dose of methotrexate to the GFR in older patients, and suggested that the repair of mucosal damage becomes compromised with aging. The Gastrointestinal Tumor Study Group (GITSG) reported ten deaths from diarrhea in patients over 65 treated with 5-FU and leucovorin, and concluded that both mucositis and dehydration are particularly severe in older persons.137 Brower et al138 also reported that only 40% of patients over 70 with colon cancer were able to complete a full year of adjuvant treatment with 5-FU and levamisole, with mucositis being the major dose-limiting toxicity. Two retrospective reviews of the experiences of two major cooperative groups, the North Central Cancer Treatment Group (NCCTG)7 and the GITSG,139 showed that age was an independent prognostic factor for the development of diarrhea and mucositis. A number of recent advances may ameliorate the risk and severity of mucositis related to fluoropyrimidines. First, the new orally administered agent capecitabine has markedly decreased the risk of mucositis in patients of all ages 8,140,141 Capecitabine is a prodrug of 5-FU and is resistant to dihydropyrimidine dehydrogenase, which allows its absorption through the intestinal mucosa. Capecitabine is converted into 5-FU in a series of enzymatic reactions, involving carboxylesterase (in the liver), cytidine deaminase (mainly in the liver and tumor tissue), and thymidine phosphorylase (in the tumor tissue).37 Thus, the exposure of the tumor to the drug is enhanced and that of normal tissues minimized. Second, in phase II trials, a keratinocyte growth factor seems effective in preventing the risk of chemotherapy-induced mucositis.142 In the presence of diarrhea or impaired fluid intake, the older patient should be hospitalized and given aggressive fluid resuscitation. Prophylactic sucralfate slurs may ameliorate symptoms of mucositis and allow better fluid intake. Nausea and vomiting Several forms of chemotherapy-related nausea and vomiting have been described.143 Of these, the most common form follows almost immediately after administration of drugs and is due to stimulation of the chemoreceptor trigger zone of the medulla. Anticipatory

Cancer chemotherapy in the older patient

839

nausea and vomiting is a learned reaction triggered by thoughts or sensory stimulations related to chemotherapy. Both types of nausea and vomiting seem to be less severe in older persons. A third form of nausea and vomiting, whose pathogenesis is less well understood, is delayed nausea and vomiting.144 This includes any form of nausea and vomiting persisting 48 hours or longer after chemotherapy. Delayed nausea and vomiting are more common and more severe in the elderly, and may respond to management with dexamethasone and metoclopramide. The serotonin receptor (5-HT3) antagonists ondansetron, granisetron, and dolasetron have been very effective in the prevention of immediate nausea and vomiting.145 Two strategies have ameliorated the risk of delayed nausea and vomiting. One includes prophylactic treatment of patients receiving chemotherapy at high emetogenic potential with 5-HT3 antagonists for 3 days after the administration of chemotherapy.146 The second includes the management of delayed nausea and vomiting with a combination of 5-HT3 and neurokinin antagonists.147 Cardiotoxicity Cardiotoxicity is a complication of anthracyclines, mitoxantrone, mitomycin C, and high doses of cyclophosphamide.36 Anthracycline cardiotoxicity, the pathology of which has been best described, may be caused by an excess of free radicals in the sarcoplasm.148 Age is a risk factor for cadiotoxicity, since the myocardial reserve may be reduced in older patients. In addition, old myocardial sarcomeres may have lost the ability to scavenge free radicals. It is likely, but not conclusively established, that coronary artery disease, hypertension, and valvular heart disease predispose the patient to cardiac complications of chemotherapy. Several precautionary measures may prevent heart failure in patients at risk.148 These include reduction of the total dose of anthracyclines, administration of anthracyclines by continuous infusion,149 the concomitant administration of digoxin and anthracyclines, the concomitant administration of anthracyclines and dexrazoxane (bispiperazinedione), a substance that prevents the formation of free radicals,150 or amifostine, a cytoprotective agent,151 and the use of liposomal doxorubicin.152 Of these measures, infusional doxorubicin and the concomitant administration of doxorubicin and dexrazoxane have been best studied. It is important to underline the limitation of these studies. First, they were confined to doxorubicin, and it is not clear whether the conclusions can be extended to other anthracyclines. Second, only two diseases have been extensively studied: breast cancer and sarcomas. Third, the percentage of older individuals included in these studies was small (mean ages 55 and 57; oldest ages 75 and 77) and inadequate to draw firm conclusions about the effectiveness of these approaches in the elderly. Fourth, the main advantage of these approaches became evident for patients who received a total dose of doxorubicin of more than 600mg/m2, which is seldom reached in older individuals. Fifth, the subjects of these studies were almost exclusively women. Sixth, continuous infusion of doxorubicin was associated with an increased risk of mucositis, and the use of dexrazoxane was associated with an increased risk of myelotoxicity: these complications are of particular concern in older individuals. Finally, these strategies may substantially increase the cost of treatment. Serial monitoring of the cardiac ejection fraction by

Comprehensive Geriatric Oncology

840

radionuclide angiography has been recommended in any patient receiving anthracyclines and particularly in older patients. The benefits of serial MUGA scans have recently been questioned. The main limitations of this approach are that MUGA scans do not detect diastolic dysfunctions, which may be present in as many as 30% of individuals over 65, they are unreliable in patients with atrial fibrillation, and the performance of MUGA scans is costly and time-consuming. Originally, MUGA scans were used to screen patients who needed myocardial biopsy, not to dictate discontinuance of doxorubicin. Separated from myocardial biopsy, radionuclide angiography may direct discontinuance of the drug in patients who may still benefit from it.149 Also, permanent myocardial damage is very rare (<1%) prior to a total dose of doxorubicin of 300mg/m2.149 Our current approach, in older patients without symptoms of congestive heart failure, is to obtain a baseline MUGA scan after a doxorubicin dose of 300mg/m2 and to repeat the test thereafter for each additional dose of 100mg/m2. Another alternative is the use of mitoxantrone153 or epirubicin in lieu of doxorubicin.154 Neither strategy has conclusively demonstrated benefits. It is not clearly established that mitoxantrone is as effective as doxorubicin in the management of lymphoma.103–105,111,113,155 Although epirubicin may be less cardiotoxic than doxorubicin, the equivalence of the effectiveness of the same doses of these agents is not clear.154 Pulmonary toxicity Pulmonary toxicity is a common complication of chemotherapy, particularly when bleomycin, mitomycin C, busulfan, or nitrosoureas are part of the treatment. Although decrements in vital capacity and in forced expiratory volume suggest an increased vulnerability of older patients to pulmonary injury, an excess of pulmonary toxicity with aging has not been reported.156 Nephrotoxicity Many chemotherapeutic agents, in particular cisplatin, mitomycin C, nitrosoureas, ifosfamide, and fludarabine, are toxic to the proximal renal tubule. Although one may expect enhanced nephrotoxicity in older patients, clinical studies with cisplatin have so far failed to demonstrate this correlation.40,157 Seemingly, the age-related reduction in the maximal reabsorptive capacity of the tubule may limit tubular exposure to nephrotoxic drugs. The cytoprotectant amifostine may protect the cancer patient from cisplatin nephrotoxicity.151 Cisplatin is contraindicated in patients of any age with renal dysfunction (CrCl<50ml/min). Carboplatin, a congener of cisplatin with similar antineoplastic activity but no relevant nephrotoxicity, may be substituted for cisplatin in many of these cases.158 An important caveat concerns proper adjustment of the dose of carboplatin to the CrCl, since myelotoxicity may be overwhelming in renal insufficiency.49 Peripheral neurotoxicity Peripheral neuropathy is a common complication of vinca alkaloids (vincristine and vinblastine), epipodophyllotoxins (etoposide and teniposide), synthetic alkaloids (e.g.

Cancer chemotherapy in the older patient

841

vindesine and vinorelbine), taxanes (especially paclitaxel), and cisplatin.159 Neurotoxicity is also the dose-limiting toxicity for oxaliplatin, a new congener of cisplatin that is active in tumors of the gastrointestinal tract.160 Manifestations of neurotoxicity appear in a stepwise fashion, and include paresthesias, abolishment of deep tendon reflexes, and weakness. Autonomic neuropathy, manifested as postural hypotension, ileus, or bradycardia, may also occur. The main indication for discontinuing these drugs is progressive weakness, which is easily detectable by serial measurements of the strength of the upper extremities. Vincristine neurotoxicity is reversible, but this may take several months. Prevention of vincristine neurotoxicity with 1.5g of oral glutamic acid daily is advisable for older patients who are at increased risk for this complication.161 A common manifestations of paclitaxel neurotoxicity, which is devastating for older individuals, is compromise of fine movements, such as ability to button one’s shirt. Dose reductions and increased interval between consecutive administrations may ameliorate this disturbing symptom. An idiosyncratic form of neurotoxicity produced by cisplatin does not appear to be dose-related and may be irreversible. Patients receiving cisplatin should undergo serial assessments of muscular strength and of touch and temperature sensitivity. Any abnormality of these parameters appearing at total doses of cisplatin lower than 300mg/m2 mandates discontinuance of the drug.162 The combination of two neurotoxic agents should be avoided whenever possible in older individuals. In combination with paclitaxel or etoposide, carboplatin is preferable to cisplatin. A special form of neurotoxicity is dysfunction of the acoustic nerve from cisplatin. Hearing loss is caused by destruction of the outer hair cells of the organ of Corti.163 Cisplatin-related hearing impairment is seldom of clinical consequence, since it affects mainly frequencies outside the spoken language hearing range. In patients with preexisting hearing dysfunction, serial audiographic exams during cisplatin treatment and avoidance of other ototoxic drugs—furosamide, ethacrynic acid, and aminoglycosides— are advisable. Hearing impairment may be devastating in older individuals, since it may isolate them from the environment and may cause manifestations of pseudodementia.164 Central neurotoxicity The central nervous system (CNS) may be affected at different levels by antineoplastic agents. Older patients may be especially vulnerable to CNS toxicity due to age-related loss of neurons (see Chapter 183). Cerebellar toxicity from high-dose cytarabine is more frequent in older persons,165 but this effect may be secondary to reduction in GFR, which impairs the excretion of uracil arabinoside, responsible for cerebellar dysfunction.166 Neurotoxicity from 5-FU, nitrosoureas, dacarbazine, and fludarabine may also be increased. The neurotoxicity of fludarabine is of special concern, since this drug is becoming the frontline treatment of chronic lymphocytic leukemia (CLL), a disease whose incidence increases with age.167,168 Interest in the cognitive complications of chemotherapy has been renewed by a number of reports indicating that women receiving adjuvant chemotherapy for breast cancer experienced cognitive decline.169,170 Seemingly, subtle changes in cognition may herald the development of more serious dysfunctions and suggest discontinuance of the drug. Given the special vulnerability of the CNS of

Comprehensive Geriatric Oncology

842

older patients, intracarotideal chemotherapy or concomitant administration of CNS radiotherapy and systemic chemotherapy may be ill advised. Special considerations related to new cytotoxic agents A number of new cytotoxic agents have been developed over the last decade or so, and present distinctive characteristics of special interest to older patients. These include a favorable toxicity profile and improved dose flexibility due to oral or weekly intravenous administration. Oral agents A number of oral agents have entered the market or are undergoing clinical trials.15 Of the oral fluoropyrimidines, capecitabine proved as effective as intravenous 5-FU in the management of cancer of the large bowel,140,141 as effective as paclitaxel in metastatic cancer of the breast resistant to anthracyclines,171 and more effective and safer than CMF (cyclophosphamide, methotrexate, and 5-FU) as front-line treatment of metastatic breast cancer.172 It is reasonable to expect that capecitabine may substitute for 5-FU in all of its present indications. Thanks to the reduced risk of mucositis and negligible risk of myelotoxicity, the drug appears preferable to 5-FU in older individuals. The main doselimiting complication is the hand-foot syndrome, preventable in a number of cases with oral pyridoxine.37 Another oral fluorinated pyrimidine formulation, UFT, is available to practitioners, albeit not in the USA.173 UFT is a combination of uracil and tegafur (ftorafur). By reversibly inhibiting dihydropyrim- idine dehydrogenase, uracil allows the oral absorption and more prolonged antineoplastic activity of tegafur, which is a prodrug of 5-FU. UFT is active in cancer of the large bowel173–175 and of the breast.176,177 The incidence of mucositis is lower than with intravenous 5-FU, but is still doselimiting.173,174 For this reason, the toxicity profile of UFT appears to be not as favorable as that of capecitabine for older individuals. Oral etoposide is active in the management of small cell lung cancer (SCLC), large cell lymphoma, and celomic ovarian cancer.178–181 Despite initial promise,179 this drug caused more severe toxicity and produced inferior survival than standard intravenous chemotherapy in older patients with SCLC.180 Its use is now largely limited to patients with recurrent ovarian cancer.181 An oral formulation of dacarbazine, temozolomide,182 is now available for the management of malignant melanoma183 and brain tumors.184 Its main use in older individuals may be palliation of primary and secondary brain tumors recurring after chemotherapy. Oral forms of other agents, including vinorelbine,185 platinum,186 taxanes,187 and topoisomerase I inhibitors188 are undergoing clinical trials. Of these, satraplatin appears particularly promising for older individuals with lung cancer,186 owing to a very favorable toxicity profile.

Cancer chemotherapy in the older patient

843

Agents suitable for weekly administration with low toxicity profile A number of cytotoxic drugs, including gemcitabine,189 vinorelbine,190 taxanes in low weekly doses,191,192 and liposomal doxorubicin,193 may be administered on a weekly schedule with excellent tolerability. Their broad spectrum of action and their toxicity profile, and the convenience of weekly administration (which allows dose flexibility), make these compounds very useful in the palliation of cancer in older individuals, especially so-called ‘frail’ patients. The construct of frailty involves negligible functional reserve with risk of succumbing to minimal stress.194–196 The prevalence of frailty increases with age,194 and it is estimated that approximately 400000 frail persons live with cancer. These are older women with breast cancer or older men with prostate cancer metastatic to the bones, who need effective palliation of their disease, and who may experience severe complications from opioids.197 For such patients, alternative forms of palliation, including low-toxicity chemotherapy, are highly desirable. Hormonal agents Hormonal agents available for the management of cancer are listed in Table 39.9 The selective estrogen receptor modulators (SERMs) play a major role in the management of breast cancer.198 The mixed agonists/antagonists have similar activities both against metastatic breast cancer199 and in the adjuvant setting.200 The complications are the same, and include rarely endometrial cancer,201 deep-vein thrombosis (DVT),202 and cerebrovascular accident,202 in addition to the more common vasomotor and vaginal complications.200 Of interest in the present context, the risk of vascular complications increases with age. In a large Finnish study comparing tamoxifen and toremifene in the adjuvant management of breast cancer, the suggestion emerged that toremifene may be associated with a lower risk of cerebrovascular accidents and endometrial cancer.200 Tamoxifen reduces by approximately 50% the incidence of new breast cancer in women at high risk202 and in women with a previous history of breast cancer,203 and the progression to invasive breast cancer of ductal carcinoma in situ (DCIS).204 There are no data related to chemoprevention of breast cancer with toremifene, but it is reasonab’ to assume that it may be as effective as tamoxifen. Both drugs delay osteoporosis.198 Another SERM, raloxifene, has recently been approved for the prevention of osteoporosis in postmenopausal women.198 Unlike tamoxifen and toremifene, raloxifene has no proven activity against breast cancer, and does not seem to cause endometrial cancer; the other complications are similar to those of tamoxifen. Of special interest, raloxifene seems to prevent the occurrence of new breast cancer.205,206 An ongoing clinical trial is comparing tamoxifen and raloxifene in chemoprevention of breast cancer. The most recent addition to the SERMs is a pure estrogen antagonist, fulvestrant (ICI 182,780, Faslodex).207 The main advantages of this srbstance are its activity even in patients who have failed tamoxifen and toremifene, and the absence of estrogenic like complications, including cerebrovascular accidents and DVT. The incidence of vascrnotor and urogenital complications is similar to that of other SERMs. Monthly intramuscular administration as a depot preparatiori may ensure compliance in a

Comprehensive Geriatric Oncology

844

population likely to forget to take daily tablets. A possible concern related to long-term treatment with fulvestrant is osteoporosis. Aromatase inhibitors have assumed a central role in the management of breast cancer.208 Both letrozole and anastrozole proved superior to tamoxifen in metastatic breast cancer.209–211 The incidence of complications was lower than with tamoxifen. Exemestane is active in approximately 24% of patients who fail non-steroidal aromatase inhibitors.212 Other advantages of this compound, of special interest to older patients, include a lower incidence of hot flushes and activity in visceral disease, which generally does not respond to hormonal treatment.213 Progestins,214 estrogens in high doses,215 and androgens216 are now seldom used. It is important to remember, however, that as front-line treatment, both estrogen and progestin have activity comparable to tamoxifen in metastatic breast cancer, and that approximately 15% of patients progressing on tamoxifen still respond to estrogen or to progestins. Progestins are also palliative of pain in prostate cancer,217 and, in high doses may be used to stimulate the appetite and reverse cancer-related cachexia.218 Luteinizing hormone-releasing hormone (LHRH) analogs are standard treatment for metastatic prostate cancer217 and have demonstrated activity in a rare form of ovarian cancer, granulosa cell tumor.219 These compounds seem to be extremely well tolerated by persons of any age, the main complication of treatment being the development of hot flushes. The depot forms of LHRH analogs are

Table 39.9 Hormonal agents available for the management of cancer Agents

Indications

Complications

Selective estrogen receptor modulators (SERMs) Mixed • Tamoxifen

Breast cancer treatment and prevention

• Toremifene

Breast cancer treatment and possibly prevention

• Raloxifene

Possibly breast cancer prevention

Endometrial cancer, DVT, cerebrovascular accidents, hot flushes, vaginal discharge

Pure • Fulvestrant

Breast cancer treatment

Hot flushes, vagina discharge, osteoporosis?

Aromatase inhibitors Non-steroidal • Anastrozole • Letrozole Steroidals

Breast cancer treatment

Hot flushes, vaginal discharge, DVT, osteoporosis?

Cancer chemotherapy in the older patient

845

• Exemestane Progestins

Breast cancer

Fluid retention, weight gain, DVT

Prostate cancer Endometrial cancer Luteinizing hormone-releasing hormone (LHRH) modulators Analogs • Leuprolide

Prostate cancer

• Buserelin

Granulosa cell tumor of the ovary

Hot flushes, ostoporosis, loss of libido

Antagonists • Abarelix Estrogen

Breast cancer Prostate cancer

DVT, fluid retention, congestive heart failure

Androgens

Breast cancer

Virilism, increased libido

Ketoconazole

Prostate cancer

Hypoadrenalism, liver toxicity, interaction with statins

Antiandrogens Prostate cancer Steroidal

Gynecomastia, fluid retention, diarrhea, liver enzyme abnormalities

• Cyproterone Non-steroidal • Flutamide • Bicalutamide • Anandron DVT, deep-vein thrombosis

particularly convenient for older and confused patients, for whom compliance may be a problem. Of some concern is the possibility that over several years these compounds may cause osteoporosis. Bone density should be measured in men with early-stage prostate cancer treated with these compounds, and treatment with bisphosphonates or calcitonin should be instituted when the patients appear at risk. Unlike LHRH analogs, Abarelix is a pure antagonist of LHRH.220 The main advantage of this compound is the absence of tumor flare-up, which may follow treatment with analogs during the first 2 weeks. Ketoconazole in high doses (1200mg/day) inhibits steroidogenesis. At present, its main use is in the management of hormone-refractory prostate cancer.217 Owing to suppression of the adrenal gland, ketoconazole should be administered with replacement doses of hydrocortisone. Other precautions should include repeated assessments of liver enzymes and awareness of interaction with drugs metabolized by the cytochrome P450 system. These drugs include the statins, which are of common use in older individuals.221

Comprehensive Geriatric Oncology

846

Antiandrogens include several compounds of different structures that inhibit the interaction of dihydrotestosterone with cytoplasmic or nuclear receptors. Chemically, one can distinguish two main groups of antiandrogens: steroidal antiandrogens, the prototype of which is cyproterone, and non-steroidal antiandrogens, whose prototypes are flutamide and nilutamide.222 Cyproterone may cause DVT, congestive heart failure, and impotence in men. Flutamide is associated with fewer complications, of which gynecomastia is the most common. Although well tolerated by patients of any age, recent reports of hepatic toxicity cast some doubts on the safety of flutamide. Despite initial claims that combined androgen blockade with castration and antiandrogen was superior to castration alone in metastatic prostate cancer,217 this possibility was denied by two meta-analysis223,224 and by a randomized controlled study.225 Currently, the main use of antiandrogens is in prevention of tumor flare-up during the first 2 weeks of treatment with LHRH analogs, and management of patients whose tumor progresses after castration. Estramustine, a combination of nornitrogen mustard and estradiol, is an effective front-line treatment for metastatic prostate cancer.217 This compound is associated with the complications of both chemotherapy and estrogen therapy, but has the advantage of preserving sexual function in the majority of patients. These characteristics make estramustine the treatment of choice for sexually active patients in good general condition, while contraindicating the drug in frail and debilitated patients. Biologic response modifiers Treatment with biologic response modifiers is targeted to amplify an organism’s own immune defenses. This form of treatment is particularly attractive in the older aged person, in whom a progressive decline in cellular immunity and especially in the function of helper T cells may be observed (see Chapter 13 of this volume226). Biologic modulation of neoplasia has been facilitated by recombinant DNA technology, which has made effectors of immune response available in large amounts for clinical use. Of these, interferons and interleukin-2 (IL-2) have been tested in several clinical trials.227,228 Interferons Of the three major classes of interferons (IFN-α, IFN-β, and IFN-γ), only IFN-α is widely used in the treatment of malignancies. At low doses (3–7 million units (MU) daily subcutaneously), IFN-α has been very effective in some hematologic malignancies, such as hairy cell leukemia (HCL),228 chronic granulocytic leukemia (CGL),229–231 myeloproliferative disorders with thrombocytosis,228 and cutaneous T-cell lymphoma,228 as well as neuroendocrine tumors.232 In CGL, IFN-α has shown a unique ability to eliminate the Philadelphia chromosome-bearing hematopoietic clone in some patients. Unfortunately, the majority of these patients still harbor the BCR–ABL abnormality in their bone marrow, when tested with polymerase chain reaction (PCR). At low doses, IFN-α may cause fever and malaise during the initial course of treatment, along with neutropenia, thrombocytopenia, and

Cancer chemotherapy in the older patient

847

renal and hepatic dysfunctions, and sometimes cardiac dysfunction. These complications have not so far been more common or more severe in older patients. At higher does (9–50 MU daily or thrice weekly), IFN-α is active in a number of other malignancies, such as multiple myeloma, AIDS-related Kaposi sarcoma, malignant melanoma, renal cell carcinoma, colorectal cancer, and carcinoid tumors.228 Of special interest, IFN-oc at high doses has proven effective in curing stage III malignant melanoma.233 Of special concern to older individuals is a form of cataleptic psychosis that complicates high doses of IFN-α and whose incidence increases with age.234 Interleukin-2 Alone, or in combination with lymphokine-activated killer (LAK) cells, IL-2 has demonstrated activity in renal cell carcinoma and malignant melanoma.228 Although some older patients have been treated with these compounds, the numbers are not adequate to establish whether tolerance to IL-2 is a function of age. The substantial toxicity of IL-2, which includes acute respiratory distress syndrome (ARDS) from generalized capillary leak, contraindicates this compound in debilitated patients. Of special interest, IL-2 at low doses was found to be effective in eradicating minimal residual disease in leukemia patients. These doses appeared to be well tolerated in older individuals, and should be considered for the maintenance treatment of AML in older persons and possibly for the management of refractory anemia with excess blasts (RAEB). Tumor-specific antineoplastic therapy Perhaps the most important advance in antineoplastic treatment in recent years has been the development of therapy targeted on specific components or on specific

Table 39.10 Examples of tumor-specific antineoplastic agents Class of compounds

Mechanism of action

Indications

• Rituximab

Anti-CD20; ADCC and augmented CDC against B cells

B-cell malignancies

• Alemtuzumab (CAMPATH-1H)

Anti-CD52; ADCC and augmented CDC against B and T cells

Chronic lymphocytic leukemia

• Trastuzumab (Herceptin)

Competitive inhibition of the HER2/neu (c-ERB-2) growth factor receptors

Breast cancer and possibly other malignancies expressing HER2/neu

Monoclonal antibodies Untagged

Tagged

Comprehensive Geriatric Oncology

848

• Bexar; 90Y-rituximab

Radioactive destruction of tumor cells

B-cell malignancies

• Mylotarg

Destruction of tumor cells by ricin toxin conjugated to anti-CD33 antibody

Acute myeloid leukemia

• Oncotek

Destruction of tumor cells by diphtheria toxin conjugated to antiIL-2R antibody

Cutaneous T-cell lymphoma

Angiogenesis inhibitors Inhibition of specific metabolic pathways • Imatinib (STI571, Gleevec/Glivec)

Inhibition of BCR-ABL tyrosine kinase

• Iressa (ZD1839)

Inhibition of c-Ras-dependent tyrosine kinase

• C225 • Farnesyl transferase inhibitors

Chronic myelogenous leukemia; gastrointestinal stromal tumors

Non-small cell lung cancer Inhibition of signal transduction

Colorectal cancer

ADCC, antibody-dependent cellular cytotoxicity; CDC, complement-dependent cytotoxicity.

metabolic processes of neoplastic tissue. As it promises to minimize toxicity to normal tissues and to enhance antineoplastic activity, this form of therapy is of special interest for older individuals. In a certain sense, capecitabine is a form of tumor-specific treatment, since it exploits specific metabolic processes of the cancer to increase the concentration of 5-FU in the neoplastic cells and minimize the exposure of normal tissues.37 Table 39.10 provides example of tumor-specific agents and their mechanisms of action. Monoclonal antibodies Monoclonal antibodies are used in two forms: naked and in combination with a radioisotope or a toxin.235 When naked, they may stimulate immune destruction of the neoplasm, as is the case with rituximab,236 or block a growth factor receptor, as is the case with trastuzumab (Herceptin).237 Both agents are extremely well tolerated by older individuals, although trastuzumab may rarely cause congestive heart failure.238 As a single agent, rituximab induces a response rate of about 40% in patients with follicular lymphoma, and the response rate is more prolonged in patients with BCL2 gene rearrangements.239,240 In combination with chemotherapy, rituximab improves the response rate of follicular lymphoma241 and the response rate and survival of older individuals with large cell lymphoma.242 Rituximab has activity in other B-cell malignancies, including chronic lymphocytic leukemia (CLL)243 and Waldenström’s macroglobulinemia.244 Alemtuzumab (CAMPATH-1H) is another antibody that has shown activity in refractory CLL, but it causes significant myelotoxicity.245

Cancer chemotherapy in the older patient

849

As a single agent, trastuzumab may induce a response rate as high as 50% in patients whose HER2/neu overexpression is confirmed by fluorescence in situ hybridization (FISH).246 In combination with different forms of chemotherapy, trastuzumab enhances the response to chemotherapy of patients with metastatic breast cancer,246–249 and in some cases has prolonged patients’ survival.246,247 In combination with radioisotope, two anti-B-cell antibodies have produced a complete response rate of around 80% in patients with low-grade lymphomas,250,251 but the treatment has been associated with substantial myelosuppression, which may limit the use of these agents in older individuals. Likewise, different forms of monoclonal antibodies bound to toxins have produced substantial toxicity. Mylotarg is a combination of an antibody directed against the common myeloid antigen CD33 and ricin toxin.252 This agent is active in approximately 40% of cases of AML resistant or refractory to standard chemotherapy,252 but the treatment has been associated with 2–3 weeks of pancytopenia. Oncotek, a combination of a monoclonal antibody to the IL-2 receptor with diphtheria toxin, is active in cutaneous T-cell lymphoma, especially in the nodular form, but it causes severe capillary-leak syndrome.253 Antiangiogenic agents A number of antiangiogenic agents are undergoing clinical trials.254 Of these, thalidomide has shown activity in multiple myeloma.255 These agents have been associated with different types of toxicity, including diarrhea, constipation, and changes in sensorium. Tyrosine kinase inhibitors and farnesyltransferase inhibitors Perhaps the most noticeable advance in the formulation of new agents has been the development of imatinib (STI571; Gleevec/Glivec), a specific inhibitor of the BCR-ABL and c-Kit tyrosine kinases, with substantial activity in chronic myelogenous leukemia16,256 and gastrointestinal stromal tumors.257 Other drugs with proven activity include the inhibitors of c-Ras tyrosine kinase,17,258 and the farnesyl transferase inhibitors.18 Age-related factors that may influence cancer management At the beginning of this chapter, we stated that age is associated with multidimensional changes, all of which may adversely influence cancer treatment. The focus of this review has been on physical changes. However, this discussion would not be illustrative of the complexity of aging without exploring the effects of mental, emotional, and socioeconomic conditions on antineoplastic therapy. Inadequate treatment compliance may have different causes, such as limited access to clinic and hospital care, confusing medication schedules, and lessened motivation to withstand the ordeal of aggressive treatment. Comprehensive data on the effects of age on cancer treatment are difficult to retrieve. The main sources of information—clinical trials and tumor registries—have limitations, as described in Chapter 3 of this volume.259 Clinical trials tend to include

Comprehensive Geriatric Oncology

850

only a small minority of older patients, who are not representative of the general population, whereas tumor registries fail to provide comprehensive patient evaluation from multiple observers because of their retrospective data collection. The principles of geriatric assessment are described in Chapters 19 and 26 of this volume.260,261 In the present chapter, it is important to outline how a Comprehensive Geriatric Assessment (CGA) may influence treatment-related decisions in older cancer patients:127,262 • A CGA can unearth medical and social problems that may interfere with the management of cancer; these include previously undiagnosed or neglected conditions, inadequacy of caregivers, restricted access to care, dementia, and depression • A CGA may provide an estimate of the patient’s life-expectancy and of the probability that they may suffer or die of cancer during their lifetime. This estimate is particularly important in the case of adjuvant treatment.263 • A CGA may provide an estimate of tolerance of chemotherapy by an individual patient, based on functional status, comorbidity, understanding of the disease, and social support.28,264 Based on the CGA we have proposed a staging of aging that may help direct the treatment of individual patients265 (Table 39.11). Conclusions Despite the increased risk of complications, cancer chemotherapy may be beneficial to older cancer patients, as long as the treatment is individualized according to a careful balance of risks and benefits. A Comprehensive Geriatric Assessment is the key to individualized treatment. Based on a review of data that we presented, the NCCN has proposed the following guidelines for the management of the older cancer patient with antineoplastic chemotherapy: • Some form of geriatric assessment is indicated for all patients aged 70 and older. • Prophylactic use of filgrastim is indicated for patients aged 75 and older treated with moderately toxic chemotherapy (using CHOP as the reference of dose intensity). • Hemoglobin levels should be maintained at 12 g/dl or higher. • Dose adjustment should be applied for drugs where the parent compound or its active metabolites are excreted through the kidneys. As our understanding of aging deepens, these guidelines will be calibrated to fit better and better the needs of individual patients.

Table 39.11 Stages of aging as reference for treatment with cancer chemotherapy Stages Clinical aspects

Treatment

I

Full doses with usual precautions (filgrastim for moderately toxic chemotherapy, maintenance of h l bi l l d dj t t t GFR)

• Independent ADL and IADL • No function-limiting comorbidity

Cancer chemotherapy in the older patient

II

III (frailty)

851

• No dementia or depression

hemoglobin levels, dose adjustment to GFR)

• Dependent in IADL, but not ADL

Special precautions to include:

• Chronic conditions that hamper function (e.g. severe arthritis, diabetic neuropathy)

•

Initial dose reduction

•

Proper homecare arrangements

•

Timely transportation

• Dependence in one or more ADL • Multiple poorly controlled comorbid conditions

Palliation is the main goal of treatment; this may include chemotherapy at low doses

• Severe dementia or depression • Geriatric syndromes (multiple falls, failure to thrive, neglect and abuse, severe incontinence) ADL, activities of daily living; IADL, instrumental activities of daily living; GFR, glomerular filtration rate.

References 1. Ershler WB. Biology of aging and cancer. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:67–74. 2. Ershler WB. Tumor-host interactions, aging, and tumor growth. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:147–57. 3. Duthie E. Physiology of aging: relevance to symptoms, perceptions, and treatment tolerance. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:207–22. 4. Holmes FF. Clinical course of cancer in the elderly. Cancer Control 1994; 1:108–14. 5. Balducci L, Cox CE, Greenberg H et al. Management of cancer in the older aged person. Cancer Control 1994; 1:132–9. 6. Balducci L, Hardy CL, Lyman GH. Aging and risk of chemotherapy-induced neutropenia. To be published. 7. Jacobson SD, Cha S, Sargent DJ et al. Tolerability, dose intensity and benefit of 5FU based chemotherapy for advanced colorectal cancer (CRC) in the elderly. A North Central Cancer Treatment Group Study. Proc Am Soc Clin Oncol 2001; 20:384a (Abst 1534). 8. Balducci L, Hardy CL, Lyman GH et al. Hemopoietic growth factors in the older cancer patient. Curr Opin Hematology 2001:8:170–87. 9. Balducci L, Lyman GH. Patients aged ≥70 are at high risk for neutropenic infection and should receive hemopoietic growth factors when treated with moderately toxic chemotherapy. J Clin Oncol 2001; 19:1583–5. 10. Iber FL, Murphy PA, Connor ES. Age-related changes in the gastrointestinal system. Drugs Aging 1994; 5:34–48. 11. Crome P, Flanagan RJ. Pharmacokinetic studies in elderly people. Clin Pharmacokinet 1994; 26:243–7. 12. Ritschel WA. Identification of populations at risk in drug testing and therapy: application to elderly patients. Eur J Drug Metab Pharmcokin 1993; 18:101–11.

Comprehensive Geriatric Oncology

852

13. Johnson SL, Mayerson M, Conrad KA. Gastrointestinal absorption as a function of age: xylose absorption in healthy adults. Clin Pharmacol Ther 1985; 38:331–5. 14. Stanta G. Morbid anatomy of aging. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:187–93. 15. Balducci L, Carreca I. Oral chemotherapy for the older cancer patient. Drugs Aging (to be published). 16. Drucker BJ, Talpaz M, Resta DJ et al. Efficacy and safety of a specific inhibitor of the BCRABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344:1031–7 17. Swaisland H, Laight A, Stafford L et al. Pharmacokinetics and tolerability of the orally active selective epidermal growth factor receptor tyrosine kinase inhibitor in healthy volunteers. Clin Pharmacokinet 2001; 40:297–306. 18. Nammi S, Logadala DS, Ras farnesyltransferase inhibition: a novel and safe approach to cancer chemotherapy, Acta Pharmacol Sin 2000; 21:396–404. 19. Bloom S, Peterson B. Non-Hodgkin lymphomas. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:619–41. 20. Lindley C, Blower P. Oral serotonin type 3 receptor antagonists for prevention of chemotherapy induces hemesis. Am J Health Syst Pharm 2000; 15:1685–97. 21. D’olimpio J. Contemporary drug therapy in palliative care: new directions. Cancer Invest 2001; 19:413–23. 22. Bajetta E, Carnaghi C, Somma L et al. A pilot safety study of capecitabine, a new oral fluoropyrimidine in patients with advanced neoplastic disease. Tumori 1996; 82:450–2. 23. Ando M, Minami H, Uger DR et al. Pharmacological analysis of etoposide in elderly patients with lung cancer. Clin Cancer Res 1999; 5:1690–5. 24. Vestal RE. Aging and pharmacology. Cancer 1997; 80:1302–10. 25. Pierelli L, Perillo A, Greggi S et al. Erythropoietin addition to granulocyte-colony stimulating factor abrogates life-threatening neutropenia and increases peripheral blood progenitor-cell mobilization after epirubicin, paclitaxel and cisplatin in combination chemotherapy. J Clin Oncol 1999; 17:1288–96. 26. Ratain MJ, Schilsky RL, Choi KE et al. Adaptive control of etoposide administration: impact of interpatient pharmacodynamic variability. Clin Pharmacol Ther 1989; 45:226–33. 27. Silber JH, Fridman M, Di Paola RS et al. First-cycle blood counts and subsequent neutropenia, dose reduction or delay in early stage breast cancer therapy. J Clin Oncol 1998; 16:2392–400. 28. Extermann M, Chen A, Cantor AB et al. Predictors of toxicity from chemotherapy in older patients. Proc Am Soc Clin Oncol 2000; 19: 617a. 29. Schijvers D, Highley M, DuBruyn E et al. Role of red blood cell in pharmakinetics of chemotherapeutic agents. Anticancer Drugs 1999; 10:147–53. 30. Moore MJ, Ehrlichman C. Therapeutic drug monitoring in oncology. Problems and potentials in antineoplastic therapy. Clin Pharmacokin 1987; 13:205–27. 31. Kaijser GP, Bejinen JH. Oxazaphosphorines: cyclophosphamide and ifosfamide. In: A Clinician’s Guide to Chemotherapy Pharmacokinetics and Pharmacodynamics (Grochow LB, Ames MM, eds). Baltimore: Williams and Wilkins, 1998. 32. Sheehan DC, Forman WB. Symptomatic management of the older person with cancer. Clin Geriatr Med 1997:13:203–20. 33. Grem JL. 5-Fluoropyrimidines. In: Cancer Chemotherapy and Biotherapy (Chabner BA, Longo DL, eds). Philadelphia: Lippincott-Raven, 1996:149–211. 34. Chabner BA. Cytidine analogues. In: Cancer Chemotherapy and Biotherapy (Chabner BA, Longo DL, eds). Philadelphia: Lippincott-Raven, 1996:213–33. 35. Rowinsky EK, Donehwer RC. Antimicrotubular agents. In: Cancer Chemotherapy and Biotherapy (Chabner BA, Longo DL, eds). Philadelphia: Lippincott-Raven, 1996:263–96.

Cancer chemotherapy in the older patient

853

36. Robert J. Anthracyclines. In: A Clinician’s Guide to Chemotherapy Pharmacokinetics and Pharmacodynamics (Grochow LB, Ames MM, eds). Baltimore: Williams and Wilkins, 1998:93–173. 37. Budman GR, Meropol NJ, Reigner B. Preliminary studies of a novel oral fluoropyrimidine carbamate: capecitabine. J Clin Oncol 1998; 16: 1795–180. 38. O’Mahony MS, Woodhouse KW. Age, environmental factors, and drug metabolism. Pharmac Ther 1994; 61:279–87. 39. Corcoran ME. Polypharmacy in the senior adult patient. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:502–9. 40. Reed E, Dabholkar M, Chabner BA. Platinum analogues. In: Cancer Chemotherapy and Biotherapy (Chabner BA, Longo DL, eds). Philadelphia: Lippincott-Raven, 1996:357–78. 41. Anderson S, Brenner BM. Effects of aging on the renal glomerulus. Am J Med 1986; 80:435– 42. 42. Henrich WL. Analgesic nephropathy. Am J Med Sci 1988; 295:561–8. 43. Whelton A. Renal and related cardiovascular effects of conventional and COX-2 specific NSAID and non-NSAID analgesics. Am J Ther 2000; 7:63–74 44. Gelman RS, Taylor SG. Cyclophosphamide, methotrexate and 5 fluorouracil chemotherapy in women more than 65 year old with advanced breast cancer. The elimination of age trends in toxicity by using doses based on creatinine clearance. J Clin Oncol 1984; 2:1406–14. 45. Kintzel PE, Dorr RT. Anticancer drug renal toxicity and elimination: dosing guidelines for altered renal function. Cancer Treat Rev 1995; 21:33–64. 46. Waller DG, Fleming JS, Ramsay B et al. The accuracy of creatinine clearance with and without urine collection as a measure of glomerular filtration rate. Postgrad Med J 1991; 67:42–6. 47. Levey AS, Bosch JP, Lewis JB et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999; 130:461–70 48. Chu E, Allegra C. Antifolates. In: Cancer Chemotherapy and Biotherapy (Chabner BA, Longo DL, eds). Philadelphia: Lippincott-Raven, 1996:109–48. 49. Calvert AH, Newell DR, Gumbrell LA et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989; 7:1748–56. 50. Pommier Y, Fesen MR, Goldwasser F. Topoisomerase II inhibitors: the epipodophyllotoxins, m-AMSA, and the ellipticine derivatives. In: Cancer Chemotherapy and Biotherapy (Chabner BA, Longo DL, eds). Philadelphia: Lippincott-Raven, 1996:435–61. 51. Robert J, Hoerni B. Age dependence of the early phase pharmacokinetics of doxorubicin. Cancer Res 1983; 43:4467–9. 52. Egorin MJ, Zuhowsky EG, Thompson B et al. Age related alterations in daunorubicin pharmacokinetics. Proc Am Soc Clin Oncol 1987; 6:38. 53. Lichtmann SM, Egorin M, Rosner GM et al. Clinical pharmacology of paclitaxel in relation to patient age. Proc Am Soc Clin Oncol 2001; 20:67a (Abst 265). 54. Sonnichsen DS, Relling MV. Paclitaxel and docetaxel. In: A Clinicians Guide to Chemotherapy Pharmacokinetics and Pharmacodynamics (Grochow LB, Ames MM, eds). Baltimore: Williams and Wilkins, 1998:375–94. 55. Burkowski JM, Duerr M, Donehower RC et al. Relation between age and clearance rate of nine investigational anticancer drugs from phase I pharmacokinetic data. Cancer Chem Pharmacol 1994; 33: 493–6. 56. Yamamoto N, Tamura T, Maerla M et al. The influence of aging on cisplatin pharmacokinetics in lung cancer patients with normal organ function. Cancer Chemother Pharmacol 1995; 36:102–6. 57. Lichtman SM, Buckholtz M, Marino J et al. Use of cisplatin for elderly patients. Age Ageing 1992; 21:202–4.

Comprehensive Geriatric Oncology

854

58. Moscow JA, Schneider E, Cowan KH. Multidrug resistance. In: Cancer Chemotherapy and Biological Response Modifiers, Annual 16 (Pinedo HM, Longo DL, Chabner BA, eds). Amsterdam: Elsevier Science, 1996:111–31. 59. Murren JR, DeVita VT. Another look at multidrug resistance. PPO Update 1995; 9(11):1–12. 60. Willman CL. The prognostic significance of the expression and function of multidrug resistance transporter proteins in acute myeloid leukemia: studies of the South West Oncology Group research program. Semin Hematol 1997; 34:25–37 61. Lancet JE, Willman CL, Bennett JM. Acute myelogenous leukemia and aging: clinical interactions. Hematol Oncol Clin North Am 2000; 16:251–68: 62. Shipp MA. Prognostic factors in aggressive non-Hodgkin’s lymphoma: Who has ‘high risk’ disease? Blood 1994; 1165–73. 63. Thigpen T, Brady MF, Omura GA et al. Age as a prognostic factor in ovarian carcinoma: the Gynecologic Oncology Group experience. Cancer 1993; 71:606–14. 64. Chauncey TR. Drug resistance mechanisms in acute leukemia. Curr Opin Oncol 2001; 13:21–6. 65. Advani R, Saba HI, Tallman MS et al. Treatment of refractory and relapsed acute myelogenous leukemia with combination chemotherapy plus the multidrug resistance modulator PSC833 (Valspodar). Blood 1999; 93:787–95. 66. Ershler WB. A gerontologist’s perspective on cancer biology and treatment. Cancer Control 1994; 1:103–07. 67. Balducci L, Wallace C, Khansur T et al. Nutrition, cancer and aging: an annotated review. J Am Geriatr Soc 1986; 34:127–36. 68. O’Dwyer PJ, Hamilton TC, Yao K-S et al. Modulation of glutathione and related enzymes in reversal of resistance to anticancer drugs. Hematol Oncol Clin North Am 1995; 9:383–96. 69. Rockwell O, Hughes CS, Kennedy KA. Effect of host age on microenvironmental heterogeneity and efficacy of combined modality therapy in solid tumors. Int J Radiat Oncol Biol Phys 1991; 20: 259–63. 70. Reed JC. BCL-2: prevention of apoptosis as a mechanism of drug resistance. Hematol Oncol Clin North Am 1995; 9:450–73. 71. Ballester O, Moscinski L, Spiers A, Balducci L. Non-Hodgkin’s lymphoma in the older person: a review. J Am Geriatr Soc 1993; 41: 1245–54. 72. Pezzella F, Turley H, Kuzu I et al. bcl-2 protein in non-small cell lung carcinoma. N Engl J Med 1993; 329:690–4. 73. Ackland SP, Schilsky RL. High dose methotrexate: a critical reappraisal. J Clin Oncol 1987; 5:2017–31. 74. Valentinis B, Silvestrini R, Daidone MG et al. 3H-thymidine labeling index, hormone receptors and ploidy in breast cancer from elderly patients. Breast Cancer Res Treat 1991; 20:19–24. 75. Daidone MG, Silvestrini R, Costa A et al. Biologic characteristics of primary breast cancer. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:171–9. 76. Rudd GN, Hartley JA, Souhani RL. Persistence of cisplatin induced DNA interstrand crosslinking in peripheral blood mononuclear cells from elderly and younger individuals. Cancer Chemother Pharmacol 1995; 35:323–6. 77. Cohen HJ. Principles of treatment applied to medical oncology: an overview. Semin Oncol 1995; 22(Suppl 1):1–3. 78. Moscinsky LC. Hematopoiesis and aging. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:427– 41. 79. Krause DS, Fackler MJ, Civin CI et al. CD34: structure, biology, and clinical utility. Blood 1996; 87:1–13. 80. Ogawa M. Hematopoiesis. J Allergy Clin Immunol 1994; 94:645–50. 81. Gordon MY. Physiology and function of the haemopoietic microenvironment. Br J Haematol 1994; 86:241–3.

Cancer chemotherapy in the older patient

855

82. Baraldi-Junkins CA, Beck AC, Rothstein G. Hematopoiesis and cytokines. Relevance to cancer and aging. Hematol Oncol Clin North Am 2000; 14:45–61. 83. Lipschitz DA. Age-related decline in hemopoietic reserve capacity. Semin Oncol 1995; 22(Suppl 1):3–6. 84. Van Zant G. Stem cells and genetics in the study of development, aging and longevity. In: Results and Problems in Cell Differentiation, Vol 29. Berlin: Springer-Verlag, 2000:203–35. 85. Rothstein G. Hematopoiesis in the aged: a model of hematopoietic dysregulation? Blood 1993; 82:2601–4. 86. Chatta GS, Price TH, Allen RC et al. Effects of ‘in vivo’ recombinant methionyl human granulocyte colony-stimulating factor on the neutrophil response and peripheral blood colonyforming cells in healthy young and elderly adult volunteers. Blood 1994; 84:2923–9. 87. Marley SB, Lewis JL, Davidson RJ et al. Evidence for a continuous decline in hemopoietic cell function from birth: application to evaluating bone marrow failure in children. Br J Haematol 1999; 106: 162–6. 88. Bagnara GP, Bonsi L, Strippoli P et al. Hemopoiesis in healthy old people and centenarians; well maintained responsiveness of CD34+ cells to hemopoietic growth factors and remodeling of cytokine network. J Gerontol A Biol Sci Med Sci 2000; 55:B61–70. 89. Balducci L, Hardy CS. Anemia of aging: a model of cancer-related anemia. Cancer Control 1998; 5(Suppl):17–21. 90. Matsuo T, Kario K, Kodoma K et al. An inappropriate erythropoietic response to iron deficiency anemia in the elderly. Clin Lab Hematol 1995; 17:317–21. 91. Kario K, Matsuo T, Kodama K et al. Reduced erythropoietin secretion in senile anemia. Am J Hematol 1992; 41:252–7. 92. Goodnough LT, Price TH, Parvin CA. The endogenous erythropoietin response and the erythropoietic response to blood loss anemia: the effects of age and gender. J Lab Clin Med 1995; 126:57–64. 93. Nilsson-Ehle H, Jagenburg R, Landahl S et al. Haematological abnormalities and reference intervals in the elderly. A cross-sectional comparative study of three urban Swedish population samples aged 70, 75 and 81 years. Acta Med Scand 1988; 224:595–604. 94. Kumagai T, Morimoto K, Saitoh H et al. Age-related changes in myelopoietic response to lipopolysaccaride in senescence-accelerated mice. Mech Ageing Dev 2000; 112:153–7. 95. Martin F. Frailty and the the somatopause. Growth Hormone IGF Res 1999; 9:3–10. 96. Hamermann D, Berman JW, Albers GW et al. Emerging evidence for inflammation in conditions frequently affecting older adults: report of a symposium. J Am Geriatr Soci 1999; 47:995–9 97. Lipschitz DA, Udupa KB. Age and the hemopoietic system. J Am Geriatr Soc 1986; 34:448– 54. 98. Boggs DR, Patrene KD. Hematopoiesis and aging III: anemia and a blunted erythropoietic response to hemorrage in aged mice. Am J Hematol 1985; 19:327–41. 99. Chatta DS, Dale DC. Aging and haemopoiesis. Implications for treatment with haemopoietic growth factors. Drugs Aging 1996; 9: 37–47. 100. Cascinu S, Del Ferro E, Fedeli A et al. Recombinant human erythropoietin treatment in elderly cancer patients with cisplatin-associated anemia. Oncology 1995; 52:422–6. 101. Price TH, Chatta GS, Dale DC. Effect of recombinant granulocyte colony-stimulating factor on neutrophil kinetics in normal young and elderly humans. Blood 1996; 88:335–40. 102. Zagonel V, Babare R, Merola MC et al. Cost-benefit of granulocyte colony-stimulating factor administration in older patients with Non-Hodgkin’s lymphoma treated with combination chemotherapy. Ann Oncol 1994; 5(Suppl 2):127–32. 103. Bertini M, Freilone R, Vitolo U et al. The treatment of elderly patients with aggressive nonHodgkin’s lymphomas: feasibility and efficacy of an intensive multidrug regimen. Leuk Lymphoma 1996; 22:483–93.

Comprehensive Geriatric Oncology

856

104. Zinzani PG, Storti S, Zaccaria A et al. Elderly aggressive histology non-Hodgkin’s lymphoma: first line VNCOP-B regimen: experience on 350 patients. Blood 1999; 94:33–8. 105. Bjorkholm M, Osby E, Hagberg H et al. Randomized trial of R-methu granulocyte colony stimulating factors as adjunct to CHOP or CNOP treatment of elderly patients with aggressive non-Hodgkin’s lymphoma. Blood 1999; 94(Suppl):599a (Abst 2665). 106. Begg CB, Carbone P. Clinical trials and drug toxicity in the elderly. The experience of the Eastern Cooperative Oncology Group. Cancer 1983; 52:1986–92. 107. Christman K, Muss HB, Case D et al. Chemotherapy of metastatic breast cancer in the elderly. JAMA 1992; 268:57–62. 108. Giovannozzi-Bannon S, Rademaker A, Lai G et al. Treatment tolerance of elderly cancer patients entered onto phase II clinical trials. An Illinois Cancer Center study. J Clin Oncol 1994; 12:2447–52. 109. Ibrahim N, Frye DK, Buzdar AU et al. Doxorubicin based combination chemotherapy in elderly patients with metastatic breast cancer. Tolerance and outcome. Arch Intern Med 1996; 156:882–8. 110. Ibrahim NK, Buzdar AU, Asmar L et al. Doxorubicin based adjuvant chemotherapy in elderly breast cancer patients: the MD Anderson experience with long term follow-up. Ann Oncol 2000; 11:1–5. 111. Sonneveld P, de Ridder M, van der Lelie H et al. Comparison of doxorubicin and mitoxantrone in the treatment of elderly patients with advanced diffuse non-Hodgkin’s lymphoma using CHOP versus CNOP chemotherapy. J Clin Oncol 1995; 13:2530–9. 112. Gomez H, Mas L, Casanova L et al. Elderly patients with aggressive non-Hodgkin’s lymphoma treated with CHOP chemotherapy plus granulocyte-macrophage colony-stimulating factor: identification of two age subgroups with differing hematologic toxicity. J Clin Oncol 1998; 16:2352–8. 113. Tirelli U, Errante D, Van Glabbeke M et al. CHOP is the standard regimen in patients ≥70 years of age with intermediate and high grade non-Hodgkin’s lymphoma: results of a randomized study of the European Organization for the Research and Treatment of Cancer Lymphoma Cooperative Study. J Clin Oncol 1998; 16: 27–34. 114. Bastion Y, Blay J-Y, Divine M et al. Elderly patients with aggressive non-Hodgkin’s lymphoma: disease presentation, response to treatment and survival. A Groupe d’Etude des Lymphomes de l’Adulte Study on 453 patients older than 69 years. J Clin Oncol 1997; 15:2945–53. 115. O’Reilly SE, Connors JM, Howdle S et al. In search of an optimal regimen for elderly patients with advanced-stage diffuse large-cell lymphoma: results of a phase II study of P/DOCE chemotherapy. J Clin Oncol 1993; 11:2250–7. 116. Armitage JO, Potter JF. Aggressive chemotherapy for diffuse histiocytic lymphoma in the elderly. J Am Geriatr Soc 1984; 32:269–73. 117. Dees EC, O’Reilly S, Goodman SN et al. A prospective pharmaco-logic evaluation of agerelated toxicity chemotherapy in women with breast cancer. Cancer Invest 2000; 18:521–9. 118. Kim YJ, Rubenstein EB, Rolston KV et al. Colony-stimulating factors (CSFs) may reduce complications and death in solid tumor patients with fever and neutropenia. Proc Am Soc Clin Oncol 2000; 19:612a (Abst 2411). 119. Biichner T. Treatment of acute myeloid leukemia in older patients. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:553–60. 120. Cleeland CS, Demetri GD, Glaspy J et al. Identifying hemoglobin levels for optimal quality of life. Results of an incremental analysis. Proc Am Soc Clin Oncol 1999; 16:Abst 2215. 121. Gabrilove JL, Cleeland CS Livingston RB et al. Clinical evaluation of once weekly dosing of epoietin alfa in chemotherapy patients: improvements in hemoglobin and quality of life are similar to three times weekly dosing. J Clin Oncol 2001; 19:2875–83.

Cancer chemotherapy in the older patient

857

122. Glaspy J, Bukowski R, Steinberg C et al. Impact of therapy with epoietin alfa on clinical outcomes in patients with non-myeloid malignancies during cancer chemotherapy in community oncology practices. J Clin Oncol 1997; 5:1218–34. 123. Demetri GD, Kris M, Wade J et al. Quality of life benefits in chemotherapy patients treated with epoietin alfa is independent from disease response and tumor type. Result of a prospective community oncology study. The Procrit Study Group. J Clin Oncol 1998; 16:3412–20. 124. Littlewood TJ, Bajetta E, Nortier JWR et al. Effects of epoietin alpha on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double blind, placebo controlled study. J Clin Oncol 2001; 19:2865. 125. Marcantonio ER, Flacker JM, Michaels M et al. Delirium is independently associated with poor functional recovery after hip fracture. J Am Geriatr Soc 2000; 48:618–24. 126. Balducci L. Anemia and aging. Epidemiological and clinical aspects. J Am Geriatr Soc (to be published). 127. Balducci L, Yates G. General guidelines for the management of older patients with cancer. In: Oncology, NCCN Proceedings, November 2000:221–7. 128. Dixon DO, Neilan B, Jones SE et al. Effect of age on therapeutic outcome in advanced diffuse hisiocytic lymphoma: the Southwest Oncology Group experience. J Clin Oncol 1986; 4:295– 305. 129. Meyer RM, Browman GP, Samosh ML et al. Randomized phase II comparison of standard CHOP with weekly CHOP in elderly patients with non-Hodgkin’s lymphoma. J Clin Oncol 1995; 13: 2386–93. 130. Meyer RJ, Davis RB, Schiffer CH et al. Intensive postremission chemotherapy in adult with acute myeloid leukemia. N Engl J Med 1994; 31:896–903. 131. Kerr KG. The prophylaxis of bacterial infections in neutropenic patients. J Antimicrob Chemother 1999; 44:587–91. 132. Lyman GH, Lyman CG, Sanderson R et al. Decision analysis of hematopoietic growth factor use in patients receiving cancer chemotherapy. J Natl Cancer Inst 1993; 85:488–93. 133. Lyman GH, Kuderer N, Green J, Balducci L. The economics of febrile neutropenia: implications for the use of colony-stimulating factors. Eur J Cancer 1998; 34:1857–64. 134. Cremieux PY, Barrett B, Anderson K. Cost of outpatient blood transfusions in cancer patients. J Clin Oncol 2000; 18:2755–61. 135. Green M, Koelb H, Baselga J et al. A randomized double-blind phase 3 study evaluating fixed-dose one-per cycle pegylated filgrastim (SD/01) versus daily filgrastim to support chemotherapy for breast cancer. Proc Am Soc Clin Oncol 2001; 20:23a (Abst 90). 136. Pirker R, Vansteenkiste J, Gateley J et al. A phase 3 double-blind, placebo-controlled randomized study of novel erythropoiesis stimulating protein (NESP) in patients undergoing platinum treatment for lung cancer. Proc Am Soc Clin Oncol 2001; 20:394a (Abst 1572). 137. Petrelli N, Douglass HO, Herrera L et al. The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. J Clin Oncol 1989; 7:1419–26. 138. Brower M, Asbury R, Kramer Z et al. Adjuvant chemotherapy of colorectal cancer in the elderly. Population based experience. Proc Amer Soc Clin Oncol 1993; 12:195. 139. Stein BN, Petrelli NJ, Douglass HO et al. Age and sex are independent predictors of 5fluorouracil toxicity. Cancer 1995; 75:11–17. 140. Twelves C, Harper P, Van Cutsem E et al. A phase three trial in previously untreated advanced/metastatic colorectal cancer. Proc Am Soc Clin Oncol 1999; 18:263a. 141. Cox JV, Pazdur R, Thibault A et al. A phase III trial of Xeloda (capecitabine) in previously untreated advanced/metastatic colorectal cancer. Proc Am Soc Clin Oncol 1999; 18:265a. 142. Spielberger RT, Stiff P, Emmanouilides C et al. Efficacy of recombinant human keratinocyte growth factor (rHuKGF) in reducing mucositis in patients with hematologic malignancies undergoing autologous peripheral blood progenito cell transplantation after radiation-based conditioning. Results of a phase 2 trial. Proc Am Soc Clin Oncol 2001; 20:7a (Abst 25).

Comprehensive Geriatric Oncology

858

143. Diehl V, Marty M. Efficacy and safety of antiemetics. Cancer Treat Rev 1994; 20:379–92. 144. Kris MG, Gralla RJ, Tyson LB et al. Controlling delayed vomiting: double blind, randomized trial comparing placebo, dexamethasone alone, and metoclopramide plus dexamethasone in patients receiving cisplatin. J Clin Oncol 1989:7:108–14. 145. De Wit R, Schmitz PIM, Verweij J et al. Analysis of cumulative probabilities shows that the efficacy of 5HT3 antagonist prophylaxis is not maintained. J Clin Oncol 1996; 14:644–51. 146. Aapro MS, Sessa C, Thurlimann B et al. SAKK 90/95: a randomized double blind trial to compare the clinical efficacy of granisetron to metochlopramide, both combide to dexamethasone in the prophylaxis of chemotherapy-induced delayed emesis. Proc Am Soc Clin Oncol 2000; 19:600a (Abst 2360). 147. Horgan KJ, Eldridge KN, Carides A et al. Differential time course of cisplatin induced acute emesis with a 5-HT3 antagonist or an NKl antagonist: rationale for combination therapy. Proc Am Soc Clin Oncol 2001; 20:383a (Abst 1528). 148. Basser RL, Green MD. Strategies for prevention of anthracycline cardiotxicity. Cancer Treat Rev 1993; 19:57–77. 149. Legha SS, Benjamin RS, Mackay B et al. Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med 1982; 96:133–9. 150. Speyer JL, Green MD, Zeleniuch-Jacquotte A et al. ICRF-187 permits longer treatment wiht doxorubicin in women with breast cancer. J Clin Oncol 1992; 10:117–27. 151. Capizzi RL. Protection of normal tissues from the cytotoxic effects of chemotherapy by amifostine (Ethyol): clinical experiences. Semin Oncol 1994; 21(Suppl 11):8–15. 152. Uziely B, Gabizon A, Jeffers S et al. Liposomal doxorubicin (Doxil): antitumor activity and unique toxicities during two complementary phase I studies. Proc Am Soc Clin Oncol 1995; 14:483. 153. Wiseman LR, Spencer CM. Mitoxantrone: a review of its pharmacology and clinical efficacy in the management of hormone-resistant advanced prostate cancer. Drugs Aging 1997; 10:473– 85. 154. Italian Multicenter Breast Study with Epirubicin. Phase III randomized study of fluorouracil, epirubicin, and cyclophosphamide v fluorouracil, doxorubicin and cyclophosphamide in advanced breast cancer. J Clin Oncol 1988; 6:976–82. 155. Mainwaring PN, Cunningham D, Gregory W et al. Mitoxantrone is superior to doxorubicin in a multiagent weekly regimen for patients older than 60 with high-grade lymphoma: results of a BNLI randomized trial of PAdriaCEBO versus PMitCEBP. Blood 2001; 97:2991–7. 156. Shapiro CL, Yeap BY, Godleski J et al. Drug-related pulmonary toxicity in non-Hodgkin’s lymphoma. Cancer 1991; 68:699–705. 157. Thyss A, Saudes L, Otto J et al. Renal tolerance of cisplatin in patients more than 80 years old. J Clin Oncol 1994; 12:2121–5. 158. Muggia FM. Overview of carboplatin: replacing, complementing and expanding the therapeutic horizon of cisplatin. Semin Oncol 1989; 16(Suppl 5):7–18. 159. MacDonald DR. Neurotoxicity of chemotherapeutic agents. In: The Chemotherapy Source Book (Perry MC, ed). Baltimore: Williams and Wilkins, 1992:666–79. 160. Grolleau F, Gamelin L, Boisdron-Celle M et al. A possible explanation for a neurotoxic effect of the anticancer agent oxaliplatin on neuronal voltage-gated sodium channels. J Neurophysiol 2001; 85:2293–7. 161. Jackson DV, Wells HB, Atkins JN et al. Amelioration of vincristine neurotoxicity by glutamic acid. Am J Med 1988; 84:1016–22. 162. Thompson SW, Davis LE, Kornfeld M et al. Cisplatin neuropathy. Cancer 1984; 54:1269–75. 163. Shaffer SD, Post JD, Close LG. Ototoxicity of low and moderate dose cisplatin. Cancer 1985; 56:1934–9. 164. Jones EM, White AJ. Mental health and acquired hearing impairment: a review. Br J Audiol 1990; 24:3–9.

Cancer chemotherapy in the older patient

859

165. Rubin EH, Andersen JW, Berg DT et al. Risk factors for high-dose cytarabine neurotoxicity: an analysis of a Cancer and Leukemia Group B trial in patients with acute myeloid leukemia. J Clin Oncol 1992; 10:948–953. 166. Damon LE, Mass R, Linker CA. The association between high-dose cytarabine neurotoxicity and renal insufficiency. J Clin Oncol 1989:7:1563–8. 167. Kornblau SM, Cortes-Franco J, Estey E. Neurotoxicity associated with fludarabine and cytosine arabinoside chemotherapy for acute leukemia and myelodysplasia. Leukemia 1993; 7:378–83. 168. Rai KR, Peterson BL, Appelbaum FR et al. Fludarabine compared with chlorambucil as primary therapy of chronic lymphocytic leukemia. N Engl J Med 2000; 14:1799–801. 169. Schagen SB, Van Dam FSAM, Muller MJ et al. Cognitive deficit after postoperative adjuvant chemotherapy for breast carcinoma. Cancer 1999; 85:640–50. 170. Brezden CB, Phillps KA, Abdollel M et al. Cognitive function of breast cancer patients receiving adjuvant chemotherapy. J Clin Oncol 2000; 18:2695–701. 171. O’Reilly S, Moiseyenko V, Bell D et al. A randomized phase two study of Xeloda (capecitabine) versus paclitaxel in breast cancer patients failing previous anthracycline therapy. Proc Am Soc Clin Oncol 1998; 17:627a. 172. O’Shaughnessy J, Moiseyenko V, Bell DY et al. A randomized phase II study of Xeloda (capecitabine) versus CMF as front-line chemotherapy of breast cancer in women aged greater than 55 years. Proc Am Soc Clin Oncol 1998; 17:398a. 173. Felius S, Gonzalez-Baron M, Espinosa E et al. Uracil and tegafur modulated with LV: an effective regimen with low toxicity for the treatment of colorectal carcinoma in the elderly. Cancer 1997; 79: 1884–9. 174. Pazdur R, Donillard J-Y, Skillings JR et al. Multicenter phase III study of 5 fluorouracil or UFTTM in combination with leucovorin in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 1999; 18:1009a. 175. Carmichael J, Popiela T, Raditon D et al. Randomized comparative study of Orzel (UFT plus leucovorin) versus parenteral 5-fluorouracil plus leucovorin in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 1999; 18:1015a. 176. Ota K, Tagnchi T, Kimara K et al. Report on national pooled data and cohort investigation of UFT in phase II study. Cancer Chemother Pharmacol 1988; 22:333–8. 177. Richaret E, Mickienwiez E, Lerzo G et al. UFT plus leucovorin in advanced breast cancer: preliminary results in heavily pretreated patients. Proc Am Soc Clin Oncol 1999; 19:869a. 178. Phillis NC. Oral etoposide: Drug Intell Clin Pharmacol 1988; 22: 860–3. 179. Ando M, Minami H, Uger DR et al. Pharmacological analysis of etoposide in elderly patients with lung cancer. Clin Cancer Res, 1999; 5:1690–5. 180. Souhami RL, Spiro SG, Rudd RM et al. Five days oral etoposide treatment for advanced small cell lung cancer (SCLC): randomized comparison with intravenous chemotherapy. J Natl Cancer Inst 1997; 89:1892–3. 181. Ozols RF. Oral etoposide for the treatment of recurrent ovarian cancer. Drugs 1999; 58(Suppl 3):43–9. 182. Beale P, Judson I, Moore S et al. Effect of gastric pH on the relative oral bioavailability and pharmacokinetics of temozolomide. Cancer Chemother Pharmacol 1999; 44:389–94. 183. Middleton MR, Grob JJ, Aaronson N et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced malignant melanoma. J Clin Oncol 2000; 18:158–66. 184. Christodoulou C, Bafaloukos D, Kosmidis P et al. Phase II study of temozolomide in heavily pretreated cancer patients with brain metastases. Ann Oncol 2001; 12:249–54. 185. Vokes EE, Rosenberg RK, Jahanzeb M et al. Multicenter phase II study of weekly oral vinorelbine for stage 4 non-small cell lung cancer. J Clin Oncol 1995; 13:637–44. 186. Kalland JR. an update of satraplatin, the first oral available platinum anticancer drug. Exp Opin Invest Drugs 2000; 9:1373–82.

Comprehensive Geriatric Oncology

860

187. Malongre MM, Beijnen JH, Schellens JH. Oral delivery of taxanes. Invest New Drugs 2001; 19:155–62. 188. Gelderblom HA, De Jong MG, Spaneboom A et al. Oral topoisomerase I inhibitors in adults: present and future. Invest New Drugs 1999; 17:401–15. 189. Carmichael J. The role of gemcitabine in the treatment of other tumors. Br J Cancer 1998; 78(Suppl 3):21–5. 190. Sorio R, Robieux I, Galligioni E et al. Pharmacokinetics and tolerance of vinorelbine in elderly patients with metstatic breast cancer. Eur J Cancer 1997; 33:301–3. 191. Akerley W, Glantz M, Choy H et al. Phase I trial of weekly paclitaxel in advanced lung cancer. J Clin Oncol 1998; 16:153–8. 192. Hainsworth JD, Burris HA, Erland JB et al. Phase I trial of docetaxel administered by weekly infusion in patients with advanced refractory cancer. J Clin Oncol 1998; 16:2164–8. 193. Ranson MR, Carmichael J, O’Byrne K et al. Treatment of advanced breast cancer with sterically stabilized liposomal doxorubicin: results of a multicenter phase II trial. J Clin Oncol 1997; 15: 3185–91. 194. Balducci L, Stanta G. Cancer in the frail patient: a coming epidemic. Hematol Oncol Clin North Am 2000; 14:235–50. 195. Balducci L, Extermann M. Management of the frail person with advanced cancer. Crit Rev Oncol Hematol 2000; 33:143–8. 196. Fried LP, Tangen CM, Walston J et al. Frailty in older adults: evidence for a phenotype. J Gerontol Med Sci 2001; 56:M146–56. 197. Sheehan DC, Forman WB. Symptomatic management of the older person with cancer. Clin Geriatr Med 1997; 13:203–20. 198. Howell A. Tamoxifen versus the newer SERMs: What is the evidence? Ann Oncol 2000; 11(Suppl 3):255–65. 199. Gams R. Phase III trial of toremifene versus tamoxifen. Oncology (Huntingt) 1997; 11:23–8. 200. Holly K, Valavaara R, Blanco G et al. Safety and efficacy results of a randomized trial comparing toremifene and tamoxifen in patients with node-positive breast cancer. J Clin Oncol 2000; 18: 3487–94. 201. Bergman L, Beelen MLR, Gallee MPV et al. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Lancet 2000; 356:881–7. 202. Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for prevention of breast cancer: report from the National Adjuvant Breast and Bowel Project. J Natl Cancer Inst 1998; 90:1371– 88. 203. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet 1998; 351:1451–67. 204. Fisher B, Dignam J, Wolmark N et al. Tamoxifen in the treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B24 randomized controlled trial. Lancet 1999; 353: 1993–2000. 205. Agnusdei D, Liu-lerage S, Augendre-Ferrant B. Results of international clinical trials with raloxifene. Ann Endocrinol (Paris) 1999; 60:342–6. 206. Cummings SR, Eckert S, Kruger KA et al. The effects of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. JAMA 1999; 281:2189–97. 207. Howell A, Osborne CK, Morris C et al. ICI 187,780 (Faslodex): development of a ‘new’ pure antiestrogen. Cancer 2000; 89:817–23. 208. Goss PE, Strasser K. Aromatase inhibitors in the treatment and prevention of breast cancer. J Clin Oncol 2001; 19:881–94. 209. Bonneterre J, Thurlimann B, Robertson JFR. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability Study. J Clin Oncol 2000; 18:3748–57.

Cancer chemotherapy in the older patient

861

210. Nabholtz A, Buzdar A, Pollak M et al. Anastrozole is superior to tamoxifen as first line therapy for advanced breast cancer in post menopausal women: results of a North American multicenter randomized trial. J Clin Oncol 2000; 18:3758–67. 211. Mouridsen H, Gershanovich M, Sun Y et al. Superior efficacy of letrozole versus tamoxifen as first line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Study Group. J Clin Oncol 2001; 19: 2596–606. 212. Lonning PE, Bajetta E, Murray R et al. Activity of exemestane in metastatic breast cancer after failure of non-steroidal aromatase inhibitors: a phase II trial. J Clin Oncol 2000; 18:2234– 44. 213. Clemett D, Lambe HM. Exemestane: a review of its use in postmenopausal women with advanced breast cancer. Drugs 2000; 59:1279–96. 214. Stuart NS, Warwick J, Blackledge GR et al. A randomised phase III cross-over study of tamoxifen versus megestrol acetate in advanced and recurrent breast cancer. Eur J Cancer 1996; 32A:1888–92. 215. Ingle JN, Ahmann DL, Green SJ et al. Randomized clinical trial of diethylstilbestrol versus tamoxifen in postmenopausal women with advanced breast cancer. N Engl J Med 1981; 304:16– 21. 216. Goldhirsch A, Gelber RD. Endocrine therapies of breast cancer. Semin Oncol 1996; 23:494– 505. 217. Balducci L, Pow-Sang J, Firedland J. Prostate cancer. Clin Geriatr Med 1997; 13:283–306. 218. Yeh SS, Wu SY, Levine DM et al. The correlation of cytokine levels with body weight after megestrol acetate treatment in geriatric patients. J Gerontol A Biol Sci Med Sci 2001; 56:M48– 54. 219. Bridgewater JA, Rustin GJ. Management of non-epithelial ovarian tumours. Oncology 1999; 57:89–98. 220. Cook T, Sheridan WP. Development of GnRH antagonists to prostate cancer: new approaches to treatment. Oncologist 2000; 5:162–8. 221. Dressr GK, Spence JD, Bailey DG. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet 2000; 38:41–57. 222. Iversen P, Melezinek I, Scmidt A. Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function. BJU Int 2001; 87:47–56. 223. Caubet TF, Tosteson TD, Dong EW et al. Maximum androgen blockade in advanced prostate cancer: a meta-analysis of published randomized controlled trials using non-steroidal antiandrogens. Urology 1997; 49:71–8. 224. Prostate Cancer Early Collaborative Trials Group. Maximum androgen blockade in advanced prostate cancer: an analysis of randomized trials. Lancet 2000; 355:1491–8. 225. Eisenberger M, Blumenstein BA, Crawford Ed et al. Bilateral orchiectomy with or without flutamide for metastatic breast cancer. N Engl J Med 1998; 339:1036–42. 226. Burns EA, Goodwin IS. Immunological changes of aging. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:158–70. 227. Witt PL, Lindner DJ, D’Cunha J et al. Pharmacology of interferons: induced proteins, cell activation and antitumor activity. In: Cancer Chemotherapy and Biotherapy (Chabner BA, Longo DL, eds). Philadelphia: Lippincott-Raven, 1996:585–608. 228. Bukowski RM, Mclain D, Finke JH. Clinical pharmacokinetics of interleukin 1: interleukin 2: interleukin 4: tumor necrosis factor and macrophage colony-stimulating factor. In: Cancer Chemotherapy and Biotherapy (Chabner BA, Longo DL, eds). Philadelphia: Lippincott-Raven, 1996:609–38. 229. Hehlmann R, Heimpel H, Hasford J et al. Randomized comparison of interferon oc with busulfan and hydroxyurea in chronic myelogenous leukemia. Blood 1994; 84:4064–77.

Comprehensive Geriatric Oncology

862

230. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. Interferon α2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. N Engl J Med 1994; 330:820–6. 231. Ohnishi K, Ohno R, Tomonaga M et al. A randomized clinical trial comparing interferon oc with busulfan for newly diagnosed chronic myelogenous leukemia in chronic phase. Blood 1995; 86:906–16. 232. Andreyev HJN, Scott-Mackie P, Cunningham D et al. Phase II study of continuous infusion fluorouracil and interferon α-2b in the palliation of malignant neuroendocrine tumors. J Clin Oncol 1995; 13:1486–92. 233. Kirkwood JM, Struderman MH, Ernstoff MS et al. Interferon α-2b adjuvant therapy of high risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group trial EST 1684. J Clin Oncol 1996; 14:7–17 234. Jonasch E, Kumar UN, Linette EP et al. Adjuvant high dose interferon α2b in patients with high risk melanoma. Cancer J Sci Am 2000; 6:139–45. 235. Multnai PS, Grossbard ML. Monoclonal antibody based therapies for hematological malignancies. J Clin Oncol 1998; 16:3691–710. 236. Grillo-Lopez AJ. Rituximab: the first decade (1993–2003). Expert Rev Anticancer Ther 2003; 3:767–79. 237. Cobleigh MA, Vogel CL, Tripathy D et al. Multinational study of the efficacy and safety of humanized anti HER2 monoclonal antibody in women who have HER2 overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999; 17:2639–48. 238. Feldman AM, Lorell BH, Reis SE. Trastuzumab in the treatment of metastatic breast cancer antitumor therapy versus cardiotoxicity. Circulation 2000; 18:102:272–4. 239. Colombat P, Salles G, Brousse N et al. Rituximab (antiCD20 monoclonal antibody) as single first line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation. Blood 2001; 97:101–6 240. Grillo-Lopez AJ, White CA, Dallaire BK et al. Rituximab, the first monoclonal antibody approved for the treatment of lymphoma. Curr Pharmacol Biotechnol 2000; 1:1–9 241. Czuczman MS, Grillo-Lopez AJ, White CA et al. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric antiCD20 monoclonal antibodies and CHOP chemotherapy. J Clin Oncol 1999; 17:268–76. 242. Coiffier B, Lepage E, Herbrecht R et al. Mabthera (rituximab) plus CHOP is superior to CHOP alone in elderly patients with diffuse large cell lymphoma. Blood 2000; 96:223a. 243. O’Brien SM, Kantarjian A, Thomas DA et al. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol 2001; 19:2165–70. 244. Owen RG, Johnson SA, Morgan GJ. Walsdenstrom’s macroglobulinemia: laboratory diagnosis and treatment. Hematol Oncol 2000; 18:41–9. 245. Osterborg A, Dyer MJ, Bunjes D et al. Phase II multicenter study of human CD52 antibody in previously treated chronic lymphocytic leukemia. European Study Group of CAMPATH-1H treatment in chronic lymphocytic leukemia. J Clin Oncol 1997; 15:1567–74. 246. Sedman AD, Fornier MN, Esteva FJ et al. Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol 2001; 19:2587–95. 247. Norton L, Slamon D, Leyland-Jones B et al. Overall survival advantage to simultaneous chemotherapy plus the humanized anti HER2 monoclonal antibody herceptin in HER2overexpressing (HER2+) metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 1999; 18:127a. 248. Burstein HJ, Kuter I, Campos SM et al. Clinical activity of trastuzumab and vinorelbine in women with HER2 overexpressing breast cancer. J Clin Oncol 2001; 19:2722–30. 249. Anonymous. Trastuzumab and capecitabine for metastatic breast cancer. Med Lett Drugs Ther 1998; 40:106–8.

Cancer chemotherapy in the older patient

863

250. Nordoy T, Kolstad A, Tuck MK et al. Radioimmunotherapy with iodine-131 tositumomab in patients with low-grade non-Hodgkin’s B cell lymphoma does not induce acquired humoral immunity against common antigens. Clin Immunol 2001; 100:40–8. 251. Wun T, Kwon DS, Tuscano JM. Radioimmunotherapy: potential as a therapeutic strategy in non-Hodgkin’s lymphoma. BioDrugs 2001; 15:151–62. 252. Sievera EL, Aplebaum FR, Spielberger RT et al. Selective ablation of acute myeloid leukemia using antibody targeted chemotherapy: a phase I study of an anti CD33 chalicheamicin immunoconjugate. Blood 1999; 93:3678–84. 253. Siegel RS, Pandolfino T, Guitart J et al. Primary cutaneous T cell lymphoma: review and current concepts. J Clin Oncol 2000; 18: 2908–25. 254. Morin MJ. From oncogene to drug: development of small molecule tyrosine kinase inhibitors as antitumor and antiangiogenic agents. Oncogene 2000; 19:6574–83. 255. Jacobson JM. Thalidomide: a remarkable comeback. Expert Opin Pharmacother 2000; 1:849– 63. 256. Drucker BJ, Sawyers CL, Kantarjian H et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in blast crisis of chronic myeloid leukemia and acure lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001; 344: 1038–42. 257. Joensuu H, Roberts PJ, Sarlomo-Rikala M et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with metastatic gastrointestinal stromal tumor. N Engl J Med 2001; 344:1052–6. 258. Barker AJ, Gibson KH, Grundy W et al. Studies leading to the identification of ZD1839 (Iressa), an oral selective epidermal growth factor tyrosine kinase inhibitor targeted to the treatment of cancer. Bioorg Med Chem Lett 2001; 11:1911–14. 259. La Vecchia C, Lucchini F, Negri E, Levi F. Cancer mortality in the elderly 1960–98: a worldwide approach. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:29–37. 260. Balducci L, Extermann M. Assessment of the older patient with cancer. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:223–35. 261. Repetto L, Venturino A, Gianni W. Prognostic evaluation of the older cancer patient. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:309–19. 262. Balducci L, Extermann M. A practical approach to the older person with cancer. Curr Prob Cancer 2001; 16:6–75. 263. Extermann M, Balducci L, Lyman GH. What threshold for adjuvant therapy in older breast cancer patients? J Clin Oncol 2000; 18:1709–17. 264. Monfardini S, Ferrucci L, Fratino L et al. Validation of a multidimensional evaluation scale for use in elderly cancer patients. Cancer 1996; 77:395–401. 265. deBono JS, Tolcher AW, Rowinsky EK. Farnesyltransferase inhibitors and their potential in the treatment of breast carcinoma. Semin Oncol 2003; 30(Suppl 16):79–93.

40 Hematopoietic stem cell transplantation in the older patient Karen K Fields, Benjamin Djulbegovic Introduction In recent years, the use of hematopoietic stem cell transplantation (HSCT), with cells derived from blood or bone marrow, has resulted in durable remissions for patients with a variety of hematologic and non-hematologic malignancies.1–5 Apparent cures have been achieved in 50–60% of patients with acute myeloid leukemia (AML) in first remission and chronic myeloid leukemia (CML) in chronic phase.6 Cure rates for adult patients with aplastic anemia range from 60% to 80% following allogeneic HSCT.7,8 Additionally, in some diseases, prospective randomized clinical trials comparing standard therapy with high-dose therapy followed by allogeneic or autologous HSCT has demonstrated advantages in overall and disease-free survival for transplanted patients, suggesting that, in appropriate patients and diseases, transplantation is the standard of care.9,10 Successful HSCT is largely influenced by the incidence of transplant-related complications. Increasing age has been associated with an increased risk of morbidity and mortality following standard therapies, and consequently this limits the use of more aggressive therapies, such as HSCT, in older patients.11–13 Presently, many centers restrict transplantation to patients up to 65 years of age, although a recent trend among transplant centers with a focus on high-dose therapy and HSCT for patients with multiple myeloma to include patients up to and beyond the age of 70 may influence national trends among other diseases.14 Analysis of studies of standard therapy in patients older than 60 with AML suggests that these patients may tolerate intensive doses of chemotherapy well, and older patients frequently undergo induction and consolidation chemotherapy following the diagnosis of AML.15,16 The risks and benefits of these therapies are discussed in subsequent chapters in this volume. Although response rates and long-term disease-free survival rates do not appear to be as great as in the younger age group, it does appear that those older patients who do achieve complete remission may have remission durations comparable to those of the younger group. It is therefore reasonable to assume that some older patients may benefit from HSCT with potential cure of their disease. Consequently, several transplant centers have actively explored the use of allogeneic and autologous HSCT in older patients.17–19 Recent advances in supportive care, such as the availability of hematopoietic growth factors and other manipulations to shorten the period of aplasia following myeloablation, the use of peripheral blood stem cells, and the use of alternative conditioning regimens, have decreased the mortality and morbidity associated with

Hematopoietic stem cell transplantation in the older patient

865

transplantation and broadened the indications for HSCT, especially in the older patient population. This chapter will explore the issues related to the use of HSCT in the older patient. Initially, we shall review the rationale and recent trends related to the use of high-dose therapy followed by HSCT using allogeneic or autologous stem cells derived from the blood or marrow. This review will include a focus on the stem cell source, the use of related and unrelated donors, and recent trends in decreasing the treatment-related toxicity of the conditioning regimen, especially in the allogeneic setting. Differences in treatment-related toxicity in the older patient compared with the younger patient will then be described, including the evaluation of the older patient as a candidate for highdose therapy and autologous or allogeneic HSCT. Finally, differences in clinical outcomes among older patients compared with younger patients will be explored. Background Principles of HSCT The original goals of HSCT were to deliver curative-intent doses of chemotherapy with or without the addition of radiation therapy. For most diseases, the doses necessary to achieve this goal would result in lethal marrow damage. Stem cells derived from bone marrow or peripheral blood provide rescue from this dose-limiting side-effect, thus enabling the clinician to escalate the doses of chemotherapy or radiation therapy beyond marrow toxicity to the next level of toxicity, the non-hematologic dose-limiting toxicity. For example, thiotepa, a mechlorethamine-like alkylating agent, has been given in the non-transplant setting in doses up to 60mg/m2, with myelosuppression as the main doselimiting side-effect.20 However, when autologous stem cell rescue is provided, the maximum tolerated dose of thiotepa given alone or in combination has been found to be up to 1200mg/m2, with mucositis and, in some reports, central nervous system (CNS) toxicity constituting the main non-hematologic dose-limiting toxicities.21,22 Unfortunately, although the delivery of high-dose therapy is possible with HSCT, not all malignancies can be cured in this setting. Dose escalation has been associated with increased response rates in some hematologic and non-hematologic malignancies.23,24 However, in some diseases, the doses necessary to achieve complete tumor cell kill exceed the non-marrow lethal doses of chemotherapy or radiation therapy. Therefore, some cancers remain incurable despite our ability to provide maximum tolerable doses. In recent years, the need for high-dose conditioning regimens has been challenged.25–28 Experience with donor lymphocyte infusions (DLI) in patients with relapsed leukemia following allogeneic transplant29–31 suggests that the delivery of high-dose therapy to achieve maximum tumor cell kill is not as important for the achievement of long-term remission as is the curative potential of the adoptive immunotherapy associated with a graft-versus-tumor effect. Less intensive conditioning regimens directed at immunosuppression with the goal of allowing the development of bone marrow chimerism (mixed donor-host engraftment) rather than at tumor cell kill can be associated with decreased treatment-related toxicity, thus allowing older patients or patients with

Comprehensive Geriatric Oncology

866

underlying organ dysfunction to tolerate the acute affects of allogeneic transplant and enabling a larger population of patients to become allogeneic HSCT candidates. Thus, our understanding of the role of high-dose therapy and the concept of adoptive immunotherapy in the context of allogeneic HSCT remains in evolution. High-dose therapy continues to provide a mechanism for decreasing overall tumor burden, and, in autologous transplantation, remains the only mechanism for potential cure of the underlying malignancy. In the future, combinations of high-dose therapy with autologous stem cell rescue to achieve minimal disease states followed by non-myeloablative allogeneic transplant in diseases known to be susceptible to a graft-versus-tumor effect may become a new strategy for managing a variety of malignancies. Additionally, new insights into the mechanisms of the immune response and isolation of the specific effector cells mediating a graft-versus-tumor effect may obviate the need for high-dose therapy and its concomitant toxicities. Increasing utilization of HSCT in the older patient The largest body of data related to outcomes following both allogeneic and autologous HSCT comes from the International Blood and Marrow Transplant Registry (IBMTR) and the Autologous Blood and Marrow Transplant Registry (ABMTR). More than 450 transplant centers from around the world voluntarily report consecutive cases of transplant to these registries, with extensive details related to treatment and outcomes, thus providing a large repository of demographic and outcomes data. Worldwide, the number of transplants performed and the indications for transplants have continued to increase annually until recently, when the use of high-dose therapy and autologous stem cell rescue in the treatment of breast cancer declined.32,33 Figures 40.1 and 40.2 illustrate the trends in allogeneic and autologous HSCT by recipient age. As can be seen, in both settings, there has been a steady increase in the number of older patients transplanted. Currently, the majority of patients undergoing autologous HSCT are over the age of 50—a dramatic reversal from a decade ago. These data suggest that age itself is no longer a primary barrier for consideration of a patient for transplant. Increasing numbers of transplants performed in the older patient are more likely related to advances in supportive care, decreasing treatment-related toxicity, and the application of HSCT in a variety of new diseases. The stem cell transplant process The transplant process consists of four distinct phases: the pretransplant phase, the conditioning regimen, the stem cell transplant, and post-transplant care. The pretransplant phase includes evaluation to identify appropriate diseases for HSCT and patients capable of tolerating the therapy, as well defining the source of stem cells to be used. This phase is critical in the elderly patient for defining the appropriateness of HSCT in this high-risk population. Anticancer therapy may be indicated prior to transplant to decrease the overall tumor burden as well as to identify patients with chemosensitive disease prior to transplant, given that patients of all ages with diseases refractory to standard therapy usually have a poor outcome following HSCT. The type of transplant—

Hematopoietic stem cell transplantation in the older patient

867

autologous versus allogeneic—is determined based on the underlying disease and the anticipated ability of the patient to tolerate the proposed therapy. Age and performance status play an important role in determining the ultimate treatment plan. The source of stem cells must be identified prior to transplant. In the patient undergoing autologous HSCT, harvesting and cryopreservation of the stem cell graft are necessary prior to the administration of high-dose therapy. In recent years, there has been a dramatic shift from the use of stem cells derived from the bone marrow to stem cells derived from the peripheral blood, with

Figure 40.1 Recent trends in allogeneic HSCT based on age as reported by the IBMTR/ABMTR for patients with acute myeloid leukemia, acute lymphoblastic leukemia, and chronic myeloid leukemia transplanted from 1989 to 2000.

Comprehensive Geriatric Oncology

868

Figure 40.2 Recent trends in autologous HSCT based on age as reported by the IBMTR/ABMTR for patients with acute myeloid leukemia, acute lymphoblastic leukemia, nonHodgkin lymphoma, Hodgkin lymphoma, and multiple myeloma transplanted from 1989 to 2000. several randomized trials demonstrating shortened periods of aplasia and decreased treatment-related mortality following the use of peripheral blood stem cells (PBSC).34,35 Techniques to prime (mobilize) patients for harvesting PBSC have specific implications in the older population. Currently, PBSC are harvested following priming with hematopoietic growth factors alone or in combination with chemotherapy rather than in a resting, ‘unprimed’ state. Although few prospective studies have been performed evaluating the role of chemotherapy in the mobilization regimen, one recent randomized trial suggested that there were no differences among engraftment of neutrophils or platelets, resource utilization, treatment-related mortality, tumor cell contamination, overall survival, or progression-free survival in patients with lymphoma undergoing autologous PBSC harvesting following either chemotherapy plus filgrastim (recombinant human granulocyte colony-stimulating factor, G-CSF) or filgrastim alone.36 Given the increased risks of side-effects associated with chemotherapy administration in the older population in general, PBSC mobilization with hematopoietic growth factors alone represents an opportunity to decrease pretransplant morbidity and, possibly, decrease overall transplant-related toxicities. More randomized trials to evaluate the role of priming chemotherapy in the overall treatment strategy are needed before discarding this component of the treatment plan in the older patient population. It is important to note

Hematopoietic stem cell transplantation in the older patient

869

that the chemotherapy priming regimen is frequently administered with the goal of treating the underlying malignancy as well as as a mobilization regimen. For patients undergoing allogeneic HSCT, it is necessary to identify a potential donor. In the older population, the majority of transplants performed use HLA-matched or mismatched sibling donors. Very few unrelated-donor transplants have been performed in the older patient population, and transplants from alternative sources such as umbilical cord stem cells are exceedingly rare.37,38 One potential rate-limiting factor for HLAmatched sibling transplants in this patient population is the fact that the older patient will likely have older siblings with concomitant premorbid medical conditions that may remove them from the donor pool. Specific attention to risks such as those due to anesthesia or, in donors undergoing PBSC harvesting, venous access is necessary in the evaluation of these older potential blood or marrow donors. The conditioning regimen is disease-specific and may include chemotherapy alone or in combination with radiation therapy or other immunosuppressive agents. As previously noted, the conditioning regimen serves to decrease tumor burden with its antitumor effects and, especially in the allogeneic setting, provides the immunosuppressive effects necessary for engraftment. The conditioning regimen is generally administered over less than 1 week, depending upon the treatment modalities employed. Supportive care during the delivery of the conditioning regimen is related to the acute toxicities commonly seen during this phase of treatment. Nausea and vomiting are common during this phase of treatment and generally require continuous administration of combination antiemetic regimens consisting of serotonin (5-hydroxytrytamine) receptor (5-HT3) antagonists with or without the use of high-dose steroids.39,40 The side-effects of high-dose steroids are well known, and, in the elderly patient population, high-dose steroids can be associated with increased toxicities, including hyper-glycemia, hypertension, fluid and electrolyte disturbances, and acute CNS system and psychiatric disturbances. Additionally, salvage antiemetic regimens including the phenothiazines, benzodiazepines, and other drugs may be associated with an increased incidence of unacceptable toxicities in the older patient population. Thus, attention to the potential toxicities associated with the supportive antiemetic regimens in this population is of importance in decreasing the risk of unacceptable side-effects. Additionally, certain chemotherapy drugs commonly administered in the high-dose setting may have unique toxicity profiles in the elderly patient. For example, cyclophosphamide is a frequent component of both autologous and allogeneic conditioning regimens because of its antitumor activity as well as its immunosuppressive potential. In the high-dose setting, doses range up to 100mg/kg. At these doses, cyclophosphamide has been associated with severe hyponatremia, which is especially prominent in the older population.41 Thus, careful monitoring of electrolytes and the need for meticulous sodium and fluid management is necessary to avoid potentially lifethreatening toxicity; aggressive sodium replacement with the associated fluid burden can be difficult to manage in this patient population. Another unique toxicity of high-dose cyclophosphamide and other alkylating agents is the risk of acute hemorrhagic cystitis.42,43 Although there are limited data to suggest that this toxicity is increased in the older patient population, preventing this side-effect may have significant consequences in the older patient. The standard methods employed to decrease the risk of hemorrhagic cystitis, including hyper-hydration with vigorous intravenous hydration or continuous

Comprehensive Geriatric Oncology

870

bladder irrigation administered via large-bore triple-lumen bladder catherization, can result in unacceptable toxicities in the elderly patient population, such as profound fluid and electrolyte disturbances or increased morbidity associated with bladder instrumentation. Thus, the administration of mesna, which has also been demonstrated to decrease the risk of hemorrhagic cystitis, may be more appropriate in this patient population.44 In addition to these examples, other known toxicities of standard-dose therapy or radiation therapy in the elderly patient may be exacerbated in the high-dose setting. Alternatively, although specific toxicities associated with the conditioning regimen themselves may not be increased in older patients, the associated supportive care treatments may add additional management challenges to this fragile patient population. The stem cell transplant itself consists of an intravenous infusion of thawed previously cryopreserved or fresh stem cells, usually administered over 1 hour or less. Acute toxicities associated with the infusion of stem cells are uncommon, but can be lifethreatening. In the allogeneic transplant setting, the donor is HLA-matched and the degree of matching is extensively evaluated prior to transplant; thus, acute transfusion reactions are unlikely. The potential for an ABO or Rh mismatch still exists, since ABO compatibility is not a prerequisite for defining a suitable donor. In the case of an Rh or major ABO mismatched transplant, the stem cell product is red cell depleted and washed during processing to decrease the

Figure 40.3 Causes of death following allogeneic HSCT as reported by the IBMTR/ABMTR from 1994 to 1999. GVHD, graft-versus-host disease. potential for a transfusion reaction. However, despite pretransplant typing and appropriate processing, allogeneic transplantation can rarely be associated with profound allergic reactions, including anaphylaxis, transfusion-related acute lung injury,45 and fluid

Hematopoietic stem cell transplantation in the older patient

871

overload/pulmonary edema, any of which could have devastating side-effects in the older patient. In the autologous HSCT, dimethylsulfoxide (DMSO) is generally used in the cryopreservation of stem cells. DMSO is associated with a unique toxicity profile, which may be especially problematic in the older patient population.46,47 In addition to the frequent nausea and vomiting associated with the infusion of DMSO, other potentially life-threatening complications can be seen, including hypertension, hypotension, and cardiac arrhythmias consisting mainly of bradyarrhythmias, CNS complications, and fluid retention. Occasional anaphylaxis is also seen. Aggressive monitoring of vital signs and attention to fluid balance during and after the infusion of the stem cell product is essential in the management of these patients. The post-transplant phase begins following the infusion of stem cells, and continues through hematologic and immunologic recovery. The immediate post-transplant phase is dominated by acute toxicities secondary to the consequences of chemotherapy and/or radiation. In the critically ill transplant patient, factors associated with an increased mortality rate in the acute post-transplant period include endotracheal intubation, allogeneic transplant compared with autologous transplant, and, at the onset of critical illness, the presence of active infections or gastrointestinal bleeding, increased respiratory rate, increased heart rate, and elevated serum bilirubin.48 Data published by the ABMTR and the IBMTR illustrate the most frequent causes of treatment failure seen in the allogeneic and autologous transplant settings (Figures 40.3 and 40.4).33 Chronic (longterm) treatment-related toxicity is related to the chronic toxicities of the anticancer

Figure 40.4 Causes of death following autologous HSCT as reported by the IBMTR/ABMTR from 1994 to 1999.

Comprehensive Geriatric Oncology

872

therapy, to chronic immunosuppression, and, in the case of allogeneic HSCT, to chronic graft-versus-host disease (GVHD). Unfortunately, in some patients and regardless of age, chronic ongoing treatment-related mortality and morbidity can occur following both autologous and allogeneic transplant. Selecting the appropriate patient: pretransplant evaluation of the older patient Pretransplant evaluation is critical, not only in defining diseases appropriate for HSCT, but also for predicting the ability of the patient to tolerate the procedure. In the pretransplant evaluation, a variety of screening tests are undertaken, with attention being paid to performance status, major organ function, infection status, and psychosocial issues. In general, a workup of major organ function includes an evaluation of cardiac, pulmonary, renal, and hepatic function, with due attention to the patient’s medical history as well as to quantifiable laboratory assessments. In the older patient, comorbid diseases may limit the ability to tolerate high-dose therapy or the consequences of immunosuppression and other transplant-specific toxicities. Additional attention to underlying health status is critical in this population. Key components of the cardiac workup include a thorough history and physical examination to rule out signs and symptoms of specific cardiac problems such as coronary artery disease, congestive heart failure, uncontrolled cardiac arrhythmias, and clinically significant valvular disease. Determination of prior anticancer therapies is important, with specific assessment of cumulative doses of anthracyclines and related agents and determination of prior chest wall irradiation doses and fields of radiation. Cardiac workup also includes measurement of left ventricular ejection fraction (LVEF) with echocardiography or nuclear medicine methods. Uncontrolled cardiac problems or decreased cardiac function manifested as an LVEF<50% are generally considered contraindications to high-dose therapy and autologous or traditional allogeneic transplant. Treatment of specific problems may allow some patients to proceed with transplantation. Evaluation of pulmonary function includes a thorough history and physical examination, with specific attention being paid to smoking history, other environmental exposures, and prior therapy, including prior radiation therapy. Specific pulmonary illnesses, including chronic obstructive bronchitis and reactive airway disease, must be identified and treated as appropriate. Pulmonary function tests focusing specifically on forced vital capacity and diffusion capacity are traditionally used to determine transplant eligibility. Additionally, interventions such as smoking cessation may decrease morbidity and mortality in the post-transplant period. Adequate renal function is critical for tolerance of high-dose therapy and HSCT. Many drugs used in high-dose conditioning regimens are renally excreted. In addition, potentially nephrotoxic drugs such as cyclosporine and antibiotics such as aminoglycosides and amphotericin derivatives are important elements of supportive care. A thorough history and physical examination, with atten- tion being paid to prior doses of nephrotoxic drugs such as platinum derivatives, is important. Measurement of 24-hour creatinine clearance serves as the standard for deter- mining transplant eligibility. Although autologous transplants have been performed successfully in patients with

Hematopoietic stem cell transplantation in the older patient

873

underlying renal failure,49 transplantation in this setting should only be undertaken at centers with a specific interest in this area. Assessment of hepatic function is also important. Many chemotherapeutic agents are metabolized in the liver or associated with direct hepatic toxicity, especially in the high-dose setting. Generally, patients are considered ineligible if they have a total serum bilirubin or serum aminotransferases of more than 2–2.5 times normal, unless the abnormalities are due to the underlying malignancy. A past history of severe hepatic dysfunction, including uncontrolled viral hepatitis, can also be associated with an increased risk of post-transplant morbidity and mortality, including an increased risk of veno-occlusive disease of the liver.50 Although limited prospective data are available to determine the utility of specific measures of major organ function as outlined above, at least one center has retrospectively evaluated the predictive value of the standard elements of the pretransplant evaluation.51 These investigators evaluated 100-day non-relapse mortality in 383 patients undergoing autologous and allogeneic HSCT. The overall 100-day nonrelapse mortality rate was 6%. Univariate analysis demonstrated that the following factors were associated with an increased risk of toxic death: a decreased forced expiratory volume in first second (FEV1), allogeneic transplant compared with autologous transplant, a decreased diffusion capacity, an elevated serum creatinine of greater than 1.1mg/dl, an Eastern Cooperative Oncology Group (ECOG) Performance Status of greater than 0, a preparative regimen containing total body irradiation compared with chemotherapy alone, the use of bone marrow rather than peripheral blood stem cells, and a semm alanine aminotransferase (ATL) of greater than 50IU/l. Approaching statistical significance were the presence of an underlying hematologic disorder compared with a solid tumor, a serum bilirubin of greater than 1.1mg/dl, an abnormal LVEF, and the absence of use of hematopoietic growth factors following transplant. Multivariate analysis demonstrated that transplant type, performance status, serum creatinine, and serum bilirubin were independent predictors of early toxic mortality. In addition to excluding major organ dysfunction, it is critical that a thorough evaluation of infection risks be performed prior to proceeding with HSCT and the associated consequences of immunosuppression. For obvious reasons, uncontrolled infections of any kind prohibit transplant in any patient. Additionally, specific prior infections such as resistant bacterial infections, fungal infections, and certain viral infections (such as HIV disease or viral hepatitis associated with severe hepatic dysfunction) could preclude transplant. Other potential transplant exclusions include uncontrolled psychiatric disorders and uncontrolled neurologic diseases. In the elderly patient, specific attention to comorbid medical conditions is necessary to determine the appropriateness of high-dose therapy. Age itself is not an exclusion for HSCT. However, determination of the patient’s underlying physiologic function is critical in predicting the ability to tolerate HSCT. Tolerance and outcomes following HSCT in the older patient Allogeneic HSCT

Comprehensive Geriatric Oncology

874

Few published data are available to evaluate differences in tolerance and outcome based on age in patients undergoing allogeneic HSCT. The largest body of data is from the IBMTR/ABMTR. Data reported to the IBMTR between 1983 and 1993 include information from 198 patients over the age of 50 receiving HLA-identical sibling bone marrow transplant for leukemia reported by 75 teams worldwide. Table 40.1 lists the characteristics of these patients. The oldest patient reported at that time was a 73-year-old

Table 40.1 Characteristics of patients aged over 50 receiving HLA-identical sibling bone marrow transplants for leukemia between 1983 and 1993 and reported to the IBMTR by 75 teams worldwide Variable

Number evaluable

Diagnosis: Acute lymphoblastic leukemia Acute myeloid leukemia Chronic myeloid leukemia

9 (5%) 48 (24%) 141 (71%)

Disease state at transplant: Early

124 (64%)

Intermediate

32 (16%)

Advanced

38 (20%)

Karnofsky score pretransplant: ≥90%

154 (78%)

<90%

44 (22%)

Acute graft-versus-host disease (among 179 patients surviving ≥21 days with engraftment)

61 (34%)

Chronic graft-versus-host disease (among 144 patients surviving ≥90 days with engraftment)

67 (46%)

female undergoing syngeneic transplantation for a diagnosis of CML. As illustrated, the most common indication at that time for allogeneic HSCT in patients over the age of 50 was CML. The majority of patients transplanted had less advanced disease and a good performance status—factors predictive of an improved post-transplant outcome. The incidences of acute and chronic GVHD, (34% and 46%, respectively) are comparable to those expected in a younger population. Figures 40.5–40.8 illustrate differences in treatment-related mortality by age based on disease for patients reported to the IBMTR/ABMTR.33 As can been seen, no differences in tolerance for the patients greater than age

Hematopoietic stem cell transplantation in the older patient

875

Figure 40.5 One-year treatmentrelated mortality rate following allogeneic HLA-matched sibling HSCT for patients with early-stage leukemia defined as first remission or first chronic phase transplanted from 1996 to 1999 based on age.

Figure 40.6 One-year treatment-related mortality rate following allogeneic HLAmatched sibling HSCT for patients

Comprehensive Geriatric Oncology

876

with intermediate-stage leukemia defined as greater than second remission or second chronic phase transplanted from 1996 to 1999 based on age.

Figure 40.7 One-year treatmentrelated mortality rate following allogeneic HLA-matched sibling HSCT for patients with late-stage leukemia defined as relapse or blast crisis transplanted from 1996 to 1999 based on age.

Hematopoietic stem cell transplantation in the older patient

877

Figure 40.8 One-year treatmentrelated mortality rate following unrelated-donor HSCT for patients in first remission or first chronic phase transplanted from 1996 to 1999 based on age. Table 40.2 Transplant-related outcomes for patients aged over 50 receiving HLA-identical sibling bone marrow for leukemia between 1983 and 1993 and reported to the IBMTR by 75 teams worldwide 2-year probability (±95% confidence interval) (%) Disease state

Number evaluable

Early Not early

Relapse rate

Survival

LFS

124

14±8

61±9

59±9

70

52±18

23±10

19±10

LFS, leukemia-free survival.

55 years are seen following allogeneic HSCT for leukemia with either an HLA-identical sibling or with an unrelated donor. Table 40.2 illustrates leukemia-free survival for patients over the age of 50 with early-stage leukemia compared with patients with advanced leukemia as reported by the IBMTR/ABMTR. There are few specific reports on allogeneic HSCT in the elderly patient. The transplant center at the University of Washington in Seattle published one of the original

Comprehensive Geriatric Oncology

878

papers addressing allogeneic HSCT in the older population.17 In 1986, they reported the results of 63 patients aged 45–68 years who had undergone bone marrow transplantation for various hematologic disorders. Of these patients, 24 underwent syngeneic transplants and 39 underwent allogeneic transplant from an HLA-matched sibling or other relative. Seven patients were aged 60 or older. The oldest patient in this series, aged 68, successfully received a syngeneic transplant for a diagnosis of AML, dying of relapse 237 days after transplant. In this series, the actuarial disease-free survival rate for patients undergoing syngeneic transplantation was 20% at 7 years. The main causes of death in this group were leukemic relapse and interstitial pneumonitis. For patients undergoing allogeneic transplantation, the actuarial disease-free survival rate at 7 years was 11%. Deaths in this group were most frequently attributed to cytomegalovirus (CMV) pneumonia and septicemia. The actuarial incidence of acute GVHD in patients over the age of 50 was 79%, compared with an incidence of 30% in patients aged 45–50 years treated at the same institution during the same time period. Analysis of these data suggested that older patients with CML were more likely to benefit from allogeneic HSCT than older patients with acute leukemia. This was attributed to the amount of prior therapy in patients with acute leukemia. In addition, in this series, patients with acute leukemia were more likely to have been transplanted with advanced disease. These investigators concluded that allogeneic transplants should be considered in patients over the age of 45, especially in patients with good performance status and early-stage disease. Patients with CML leukemia and preleukemia were considered to be good candidates for HSCT. An update of patients receiving allogeneic bone marrow transplantation for the treatment of CML at the Fred Hutchinson Cancer Research Center in Seattle evaluated 328 patients older than age 10 treated between 1983 and 1994, which included 87 patients aged 40–50 and 57 patients aged 50–60.52 Adverse factors associated with a significantly poorer survival in this group included age between 40 and 50 and age greater than 50, with relative risks compared with patients less than 30 years of age of 2.84 and 2.66, respectively. An additional risk factor included the time from diagnosis to treatment: patients transplanted more than 2 years following diagnosis fared significantly worse than patients transplanted less than 1 year following diagnosis. However, the predicted survival of patients between the ages of 50 and 60 was not worse than that of patients between the ages of 40 and 50. Of note, 3 of 5 patients in the series transplanted at age 60 remained in remission between 18 and 24 months following transplant. The authors concluded that age itself is not a valid reason to deny patients curative-intent therapy by bone marrow transplantation. Few other centers have reported experience with allogeneic HSCT in the older patient. Beelen and co-workers53 evaluated 20 allogeneic HSCT patients with acute leukemia and CML transplanted in the fifth decade of life, compared with 32 similar patients transplanted between the ages of 30 and 39. They found that standard-risk patients, defined as patients in first chronic phase of CML or with acute leukemia in first remission, with HLA-identical sibling donors, had a higher probability of survival than poor-risk advanced-stage patients in both age groups, although the differences were not statistically significant. Older patients with advanced disease at the time of transplant, however, had an actuarial survival that was statistically inferior to that of younger patients. The cumulative incidence of acute and chronic GVHD was 27% in patients who

Hematopoietic stem cell transplantation in the older patient

879

received bone marrow from an HLA-identical sibling—an incidence similar to that seen in younger patients. The most frequent cause of death was interstitial pneumonitis, the incidence of which did not differ statistically from the incidence in younger patients. The authors concluded that allogeneic bone marrow transplantation could be regarded as firstline therapy for patients with acute leukemia in first remission and patients in the first chronic phase of CML. Transplanters at the Johns Hopkins Oncology Center in Baltimore reported the outcomes in 14 patients aged 50–55 who received allogeneic bone marrow transplants for a variety of diagnoses.54 The actuarial disease-free survival rate at 3 years was 31%, compared with an actuarial disease-free survival rate of 48% in patients aged 20–49 treated concurrently on the same protocols; this difference was statistically significant (p=0.05). Of the 14 older patients, there were 9 transplant-related deaths, including 5 due to refractory GVHD and 1 due to relapse. The authors concluded that allogeneic bone marrow transplantation in the older patient is associated with a high risk of transplantrelated mortality, and suggested that future clinical trials in older patients should focus on the treatment or prevention of GVHD. Although several other centers have reported their experiences with allogeneic HSCT in older patients, the majority of patients transplanted in these studies were younger than 45.55–58 Only a handful of patients reported in these studies were over the age of 50. In general, the older patients reported in these series tended to do well—a finding that was generally attributed to improved GVHD prophylaxis. In summary, there are few data available in the literature concerning the role of standard allogeneic HSCT in the older patient. Data from the largest transplant registry, the IBMTR/ABMTR, suggest that patients over the age of 55 have similar leukemia-free survival and transplant-related outcomes as compared with younger patients. The majority of older patients reported to this registry tended to have less advanced disease, a diagnosis of CML leukemia rather than acute leukemias, and a good performance status. Although some centers have reported an increased risk of GVHD in older patients, this is not universal. The problem of GVHD is associated with an increased risk of transplantrelated morbidity and mortality in all age groups, and efforts to modulate the incidence and severity of GVHD could be expected to improve treatment-related outcomes for all patients undergoing allogeneic HSCT, including older patients. The incidence of infectious complications, specifically interstitial pneumonitis, appears to be increased in older patients compared with younger patients in some series. At present, standard allogeneic HSCT should be limited to good-risk patients, such as those with aplastic anemia, acute leukemia in first remission, CML in first chronic phase, or preleukemic states. Patients with a poor performance status or advanced disease, or heavily pretreated patients, should not be considered candidates for standard allogeneic bone marrow transplantation but may be candidates for newer interventions, such as non-myeloablative allogeneic transplants as discussed later in this chapter. Potential candidates should be referred to centers with specific interest in allogeneic transplantation in the older patient. Autologous HSCT Autologous HSCT has been used more frequently than allogeneic HSCT in the older patient population given the lower toxicity profile associated with this type of transplant.

Comprehensive Geriatric Oncology

880

However, in some diseases, survival advantages are demonstrated following allogeneic transplantation in comparison with autologous transplantation. For example,

Figure 40.9 One-year transplantrelated mortality rate following autologous HSCT for non-Hodgkin lymphoma and Hodgkin lymphoma in second remission or first relapse for patients transplanted from 1996 to 1999 based on age. clinical outcomes following allogeneic HSCT for the treatment of multiple myeloma demonstrate long-term disease-free survival consistent with potential cures (most likely due to a graft-versus-myeloma effect); however, the treatment-related mortality rate following allogeneic HSCT for multiple myeloma is reported to be as high as 40%, prohibiting the routine use of allogeneic transplantation in this disease.59,60 In acute leukemia, as well, the risk of relapse is higher following autologous HSCT; however, the risks of treatment-related mortality remain substantial following allogeneic HSCT, thus resulting in similar overall survival rates for autologous and allogeneic transplantation.61,62 Given these circumstances, the clinician is more likely to offer the older patient autologous rather than allogeneic HSCT, risking decreased potential curability in favor of increased tolerability. The disease-specific indications for autologous HSCT may also account for the increasing use of autologous transplantation in the older population. For example, certain diseases may be more prominent in the older population. As an example, prospective randomized trial data demonstrating a survival advantage in patients undergoing autologous HSCT compared with standard therapy with

Hematopoietic stem cell transplantation in the older patient

881

a diagnosis of multiple myeloma parallels the increased incidence of autologous transplantation in older patients.63 The majority of reports of autologous HSCT in older patients focus on tolerance of high-dose therapy rather than on outcomes. Figure 40.9 illustrates the treatment-related mortality rate for patients undergoing autologous HSCT for non-Hodgkin lymphoma (NHL) based on age as reported by the IBMTR/ABMTR.33 At the H Lee Moffitt Cancer Center, Tampa, Florida, we retrospectively compared older patients with younger patients treated as part of a phase I/II dose-escalation trial of high-dose ifosfamide, carboplatin, and etoposide to determine if toxicities differed by age among patients treated on the same regimen.64 Of a total of 168 patients treated in the trial, only 11 were aged 55–59. The transplant-related morality rate was 9% in the younger patients, compared with no transplant-related deaths in the oldest patient group (a difference that was not statistically significant). Engraftment and time to discharge following transplant did not vary by age. The risk of developing WHO grade III/IV hemorrhagic cystitis was significantly greater in the older patients, despite the use of mesna in all patients. There was a trend (although not a significant one) toward an increased risk of WHO grade III/IV mucositis and peripheral neuropathy also noted in the older patients. No other differences in organspecific toxicities were noted based on age. Data such as these suggest that older patients tolerate high-dose therapy as well as younger patients, although there may be an increased incidence of some organ-specific side-effects related to individual high-dose regimens. To determine if older patients derived the same benefits in terms of response and overall survival as younger patients, we compared treatment outcomes for all patients undergoing autologous HSCT over a 5-year period at our center, specifically focusing on toxicity and survival differences.65 In this series of patients, 458 had received autologous HSCT for a variety of diagnoses, 45 of whom were between the ages of 55 and 65. Several different high-dose regimens were used to treat a variety of malignancies in these patients; the majority (48%) of patients had a diagnosis of high-risk or metastatic breast cancer. The transplant-related mortality rates for all patients were similar: 16% among patients aged 18–55, compared with 24% in the older group (not significantly different). In patients younger than 55, the event-free survival rate, overall survival rate, and risk of relapse at 2 years were 33%, 47%, and 59%, respectively. However, in patients older than 55, the event-free survival rate, overall survival rate, and risk of relapse at 2 years were 12%, 18%, and 82%, respectively. These differences were statistically significant, and suggested that although older patients tolerate high-dose therapy as well as younger patients, the risk of relapse may be greater in older patients following high-dose therapy for certain malignancies. The reasons for these differences still remain to be clarified, and prospective trials are needed to define the role of autologous HSCT in the older patient population, but these findings may be due to inherent differences in tumor biology or immune reconstitution following transplantation in older patients compared with younger patients. Studies evaluating the effect of age frequently focus on patients with multiple myeloma. The University of Arkansas has reported the oldest cohort of patients with multiple myeloma to undergo autologous HSCT.66 A total of 70 patients over the age of 70 (median age 72; range 70–82.6) were included in the analysis. Of these patients, 44% received tandem transplants. The 3-year overall and event-free survival rates were

Comprehensive Geriatric Oncology

882

projected to be 31%±10% and 20%±9%, respectively. Of note, the first 25 patients received a conditioning regimen of single-agent melphalan, 200mg/m2, which was associated with an excessive mortality rate of 16%. All subsequent patients received 140mg/m2 of melphalan, with no apparent decrease in efficacy but improved tolerance, leading the authors to conclude that the lower dose was more appropriate in the older patient population. Tandem transplant appeared to positively effect outcomes, with improvements in median overall and event-free survivals. Another study of patients with multiple myeloma compared outcomes in 17 patients aged 65–74 (median 67) with matched pairs under the age of 65 undergoing transplant at the same center, and demonstrated that post-transplant median overall survival was similar in the two groups (3.59 years versus 3.01 years; p=0.92), and there were no significant differences in relapse rates, myelotoxicity, or overall tolerance among the matched cohorts.67 The University of Nebraska reported its experience with autologous HSCT in patients over the age of 60 with NHL and Hodgkin lymphoma.19 Between November 1984 and October 1991, seven patients aged 60–68 with NHL underwent high-dose therapy and autologous bone marrow transplantation; there were four transplant- related deaths and only one patient survived beyond 1 year. Between March 1992 and November 1993, 14 patients aged 60–67 with NHL and 1 patient aged 63 with Hodgkin lymphoma underwent autologous HSCT. Five patients received autologous bone marrow and 10 received PBSC. Although two patients experienced significant morbidity, no transplant-related deaths were seen in this group, and patients were discharged a median of 20 days post transplant. Overall survival and progression-free survival were similar to those seen in younger patients with lymphoma transplanted at the same institution during the same interval. Hematopoietic growth factors were not routinely available for use post transplant prior to 1992; however, following 1992, all patients received hematopoietic growth factors, which was felt to have accounted for some of the differences in transplantrelated mortality. The authors concluded that selected patients over the age of 60 tolerate high-dose chemotherapy, and that, therefore, older patients should not be excluded from high-dose protocols. The University of Washington more recently reported outcomes following autologous HSCT for 53 patients with NHL aged 60 and older (median age 62 years; range 60.3– 67.7 years).68 The 4-year overall survival, progression-free survival, and treatment-related mortality rates were 33%, 24%, and 22%, respectively. On multivariate analysis, chemosensitive disease was found to be a positive predictor of outcome, with a 4-year overall survival rate of 39%. Factors associated with reduced treatment-related mortality included the treatment regimen (a regimen containing cyclophosphamide, etoposide, and total body irradiation was superior to other regimens), suggesting that the selection of the conditioning regimen in this population is critical as well. Several other centers have reported outcomes for older patients with a variety of hematologic malignancies undergoing autologous HSCT that suggest similar tolerability and efficacy when compared with younger patients undergoing similar procedures.69–72 From these data, it appears that patients over the age of 60 are likely to tolerate and benefit from myeloablative therapy with autologous HSCT. Elderly patients with adequate stem cell reserves and physiologic organ function should not be excluded from high-dose therapy trials solely on the basis of chronological age. The increased risks of

Hematopoietic stem cell transplantation in the older patient

883

coexisting conditions, such as coronary artery disease or pulmonary disease, would be more likely to limit the use of autologous HSCT than age itself. Strategies to decrease treatment-related toxicity in patients undergoing HSCT Advances in supportive care Over the past several years, treatment-related morbidity and mortality following HSCT have continued to decrease. Multiple explanations for this exist, including a shift from offering this form of therapy to patients with end-stage, refractory disease and associated poor performance statuses, to offering it to patients with earlier disease. Continued recognition of factors predictive of a poor transplant-related outcome has also resulted in improved patient selection. Significant changes in technology and supportive care have also influenced outcomes. One of the most significant changes in recent years associated with decreased treatment-related toxicity with subsequent increased utilization has been the change in the source of stem cells from bone marrow to peripheral blood. These data were addressed earlier in the chapter. Other examples of significant changes in supportive care associated with decreased treatment-related toxicity include the use of hematopoeitic growth factors and the use of prophylactic antibiotics. Hematopoeitic growth factors in the early post-transplant period following both allogeneic and autologous HSCT have resulted in shortened periods of aplasia, with concomitant decreases in treatment-related costs.73–76 Although the use of prophylactic antibiotics has become standard over the past decade, few randomized trials have been performed to assess the value of this intervention.77,78 These interventions have been demonstrated to decrease the frequency of positive blood cultures in patients with neutropenic fevers as well as changing the spectrum of infections seen in this patient population. Fewer gram-negative and gram-positive infections can be seen, with no increase in morbidity or mortality from other infections. In addition, new antifungal agents and new antiviral agents provide the opportunity for treatment and prevention of a variety of infections that have, in the past, resulted in significant transplant-related toxicity.79,80 Non-myeloablative transplants Traditionally, it has been believed that allogeneic HSCT provides a potential cure of the underlying malignancy due to the delivery of high-dose therapy and that the infusion of allogeneic stem cells merely serves as a supportive measure to allow the administration of myeloablative treatment without producing permanent aplasia. Recently, however, apparent cures have been observed in patients with advanced hematologic malignancies who had failed several lines of aggressive chemotherapy or had recurrent disease following standard allogeneic HSCT with adoptive immunotherapy using donor lymphocyte infusions (DLI) only.26,80,81 This observation suggests that the efficacy of allogeneic HSCT in many of the hematologic malignancies is more likely related to a graft-versus-leukemia effect than to the effects of high-dose therapy.26,82 In this setting,

Comprehensive Geriatric Oncology

884

less dose-intensive regimens are required to achieve donor engraftment and the mechanism of engraftment is based on the development of tolerance in the host over a prolonged period of time.26,28 In turn, the use of this approach has been extended to older patients and those with pre-existing organ dysfunction—patients currently excluded from allogeneic HSCT. Several studies have shown that these less intense regimens (alternatively called non-myeloablative regimens or ‘mini’ allogeneic transplants) are associated with decreased treatment-related toxicities as well as a trend toward a decrease in the incidence of acute GVHD. Although this technology is relatively new and clinical experience is limited, an extensive review of the literature found that transplant-related mortality, the incidence of acute and chronic GVHD, relapse rates, and 1-year survival were within acceptable ranges for patients undergoing non-myeloablative allogeneic transplants for a variety of hematologic malignancies.83 Recently, a systematic review synthesizing the totality of research evidence on the topic was published indicating that the treatment-related mortality rate of non-myeloablative treatment was about 15%.84 Of note, 15% of the patients in these trials were over the age of 60 (30 of a total of 199 patients), with 7 of the 29 surviving older patients remaining in complete remission at reported follow-up times ranging from 5 to 15 months. The use of this technology in patients with solid tumors is less extensive.85 Although promising, the lack of comparative data, the extreme heterogeneity of the studies, the short follow-up, and the relatively small number of patients studied preclude any firm recommendations regarding the net benefits of nonmyeloablative allogeneic HSCT, especially in the older patient population. However, this approach does offer the potential for less toxic regimens delivered with curative intent in the older patient population. Conclusions The available data suggest that older patients undergoing HSCT, both allogeneic and autologous, generally tolerate therapy as well as younger patients. In many diseases, progression-free survival is comparable to that of younger patients following both allogeneic and autologous HSCT. There remains a paucity of data in patients undergoing transplantation over the age of 60, and therefore continued evaluation of this group of patients is necessary to define the role of high-dose therapy in the older patient. In the allogeneic transplant setting, recent advances in prophylaxis and treatment of GVHD have allowed clinicians to consider older patients as transplant candidates. Continuing improvements in supportive care, including the development of hematologic growth factors and new antibiotics, will also enable transplanters to consider a wider variety of patients for both allogeneic and autologous HSCT. The future limiting factors in determining transplant eligibility are likely to be performance status and organ function, although differences in tumor biology or host immune defects associated with aging could ultimately limit the use of this type of therapy in the elderly population. Elderly patients with a good performance status and early-stage disease should be referred to transplant centers with a specific interest in HSCT in the older patient. Such centers are more likely to have access to the continuing developments in the field of supportive care and novel therapies. Careful selection of patients with diseases likely to

Hematopoietic stem cell transplantation in the older patient

885

benefit from high-dose therapy (i.e. acute leukemias in first remission, first chronic phase of CML, and early-stage breast cancer) is essential to ensure the cost-effective use of this potentially expensive therapy. Yet, as the proportion of older patients in the population continues to grow, so does the need to provide innovative approaches to their care. References 1. Bortin MM, Horowitz MM, Gale RP. Current status of bone marrow transplantation in humans: report from the International Bone Marrow Registry. Nat Immunol Cell Growth Regul 1980; 7:334–50. 2. Champlin R, Gale RP. Acute myelogenous leukemia: recent advances in therapy. Blood 1987; 69:1551–62. 3. Thomas ED. The use and potential of bone marrow allograft and whole-body irradiation in the treatment of leukemia. Cancer 1982; 50:1449–54. 4. Dicke KA, Spitzer G, Jagannath S, Evinger-Hodges (eds). Autologous Bone Marrow Transplantation. Proceedings ofthe Fourth International Symposium, Houston, 1989. 5. Cheson BD, Lacerna L, Leyland-Jones B et al. Autologous bone marrow transplantation: current status and future directions. Ann Intern Med 1989; 110:51–6. 6. Thomas ED, Blume KG, Forman SJ. Hematopoietic Stem Cell Transplantation, 2nd edn. Malden, MA: Blackwell Science, 1999. 7. Bortin MM, Gale RP, Rimm AA. Allogeneic bone marrow transplantation for 144 patients with severe aplastic anemia. JAMA 1981; 245:1132. 8. Camitta BM, Storb R, Thomas ED. Aplastic anemia: pathogenesis, diagnosis, treatment and prognosis. N Engl J Med 1982; 306:645. 9. Attal M, Harousseau JL, Stoppa AM et al. Randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med 1996; 335:91–7. 10. Philip T, Guglielmi C, Hagenbeek A et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 333:1540–5. 11. Applebaum FR, Dahlberg S, Thomas ED et al. Bone marrow transplantation or chemotherapy after remission induction for adults with acute nonlymphoblastic leukemia. Ann Intern Med 1984; 101: 581. 12. Bross DS, Tutschka PJ, Farmer ER et al. Predictive factors for acute graft-versus-host disease in patients transplanted with HLA-identical siblings. Blood 1984; 63:12–15. 13. Storb R, Prentice RL, Sullivan K et al. Predictive factors in chronic graft-versus-host disease in patients with aplastic anemia treated by marrow transplantation from HLA-identical siblings. Ann Intern Med 1983; 98:461. 14. Kyle, RA. Management of patients with multiple myeloma: emphasizing the role of high dose therapy. Clin Lymphoma 2001; 2:21–8. 15. Foon KA, Sigelboim J, Yale C, Gale RP. Intensive chemotherapy is the treatment of choice from elderly patients with acute myelogenous leukemia. Blood 1981; 58:467. 16. Reiffers J, Raynal F, Broustet A. Acute myeloblastic leukemia in elderly patients. Cancer 1980; 45:2816. 17. Klingemann HG, Storb R, Fefer A et al. Bone marrow transplantation in patients aged 45 years and older. Blood 1986; 67:770–776. 18. Vesole DH, Jagannath S, Tricot G et al. High-dose intensive therapy with autologous transplantation (AT) in multiple myeloma (MM) patients over age 60. Proc Am Soc Clin Oncol 1995; 14:939a.

Comprehensive Geriatric Oncology

886

19. Stewart D, Bierman P, Anderson J et al. High dose chemotherapy (HDC) with autologous hematopoietic rescue in patients (pts) age 60 and over. Proc Am Soc Clin Oncol 1994; 13:1260a. 20. Edwards MS, Levin VA, Seger ML et al. Phase II evaluation of thiotepa for treatment of central nervous system tumors. Cancer Treat Rep 1979; 63:1419–21. 21. Fields KK, Elfenbein GJ, Perkins JB et al. Two novel high-dose treatment regimens for metastatic breast cancer—ifosfamide, carboplatin, plus etoposide and mitoxantrone plus thiotepa: outcomes and toxicities. Semin Oncol 1993; 20(Suppl 6):59–66. 22. Lazarus HM, Reed MD, Spitzer TR et al. High-dose IV thiotepa and cryopreserved autologous bone marrow transplantation for therapy of refractory cancer. Cancer Treat Rep 1987; 71:689– 95. 23. Armstrong DK, Davidson NE. Dose intensity for breast cancer. Oncology 2001; 15:701–8. 24. Savarese DM, Hsieh C, Stewart FM. Clinical impact of chemotherapy dose escalation in patients with hematologic malignancies and solid tumors. J Clin Oncol 1997; 15:2981–95. 25. Vastag B. A brief history of the brief history of low-dose transplants. J Natl Cancer Inst 2000; 92:1201. 26. Storb R, Yu C, Sandmaier BM et al. Mixed hematopoietic chimerism after marrow allografts: transplantation in the ambulatory care setting. Ann NY Acad Sci 1999; 872:375–6. 27. Carella AM, Champlin R, Slavin S et al. Ongoing trials in humans. Bone Marrow Transplant 2000; 25:345–50. 28. McSweeney P, Storb R. Establishing mixed chimerism with immunosupressive, minimally myelosupressive conditioning: preclinical and clinical studies. Hematology. Education Program Book. Washington, DC: American Society of Hematology, 1999:396–405. 29. Levine JE, Braun T, Penza S et al. Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advance myeloid malignancies after allogeneic stem-cell transplantation. J Clin Oncol 2002; 20:405–12. 30. Storb R, Yu C, Sandmaier BM et al. Mixed hematopoietic chimerism after marrow allografts: transplantation in the ambulatory care setting. Ann NY Acad Sci 1999; 872:375–6. 31. Champlin R, Khouri I, Giralt S. Use of nonmyeloablative preparative regimens for allogeneic blood stem cell transplantation: induction of graft-vs-malignancy as treatment for malignant diseases. J Clin Apheresis 1999; 14:45–9. 32. Horowitz MM. Uses and growth of hematopoietic cell transplantation. In: Hematopoietic Cell Transplantation, Vol II (Forman SJ, Blume KG, Thomas ED, eds). Malden, MA: Blackwell Science, 1999:12–18. 33. Report on state of the art in blood and marrow transplantation. IBMTR/ABMTR Newsletter 2002; 9:1–11. 34. Shea TC. Introduction: Current issues in high-dose therapy and stem cell support. Bone Marrow Transplant 1999; 23(Suppl 2):S1–5. 35. Korbling M, Anderlini P. Peripheral blood stem cell versus bone marrow allotransplantation: Does the source of hematopoietic stem cells matter? Blood 2001; 98:2900–08. 36. Narayanasami U, Kanteti R, Morelli J et al. Randomized trail of filgrastim versus chemotherapy and filgrastim mobilization of hematopoietic progenitor cells for rescue in autologous transplantation. Blood 2001; 98:2059–64. 37. Laughlin MJ, Barker J, Bambach B et al. Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors. N Engl J Med 2001; 344:1815–22. 38. McGlave PB, Shu XO, Wen W et al. Unrelated donor marrow transplantation for chronic myelogenous leukemia: 9 years’ experience of the National Marrow Donor Program. Blood 2000; 95:2219–25. 39. del Giglio A, Soares HP, Caparroz C, Castro PC. Granisetron is equivalent to ondansetron for prophylaxis of chemotherapy-induced nausea and vomiting: results of a meta-analysis of randomized controlled trials. Cancer 2000; 89:2301–8.

Hematopoietic stem cell transplantation in the older patient

887

40. Tsukada H, Hirose T, Yokoyama A, Kurita Y. Randomized comparison of ondansetron plus dexamethasone with dexamethasone alone for the control of delayed cisplatin-induced emesis. Eur J Cancer 2001; 37:2398–404. 41. Berghmans T. Hyponatremia related to medical anticancer treatment. Support Care Cancer 1996; 4:341–50. 42. deVries CR, Freiha FS. Hemorrhagic cystitis: a review. J Urol 1990; 143:1–9. 43. Efros MD, Ahmed T, Coombe N, Choudhury MS. Urologic complications of high-dose chemotherapy and bone marrow transplantation. Urology 1994; 43:355–60. 44. Shepherd JD, Pringle LE, Barnett MJ et al. Mesna versus hyperhydration for the prevention of cyclophosphamide-induced hemorrhagic cystitis in bone marrow transplantation. J Clin Oncol 1991; 9: 2016–20. 45. Silliman CC. Transfusion-related acute lung injury. Transf Med Rev 1999; 13:177–86. 46. Alessandrino P, Bernasconi P, Caldera D et al. Adverse events occurring during bone marrow or peripheral blood progenitor cell infusion: analysis of 126 cases. Bone Marrow Transplant 1999; 23: 533–7. 47. Hoyt R, Szer J, Grigg A. Neurological events associated with the infusion of cryopreserved bone marrow and/or peripheral blood progenitor cells. Bone Marrow Transplant 2000; 25:1285–7. 48. Price KJ, Thall PF, Kish SK et al. Prognostic indicators for blood and marrow transplant patients admitted to an intensive care unit. Am J Respir Crit Care Med 1998; 15:876–84. 49. Ballester OF, Tummala R, Janssen WE et al. High-dose chemotherapy and autologous peripheral blood stem cell transplantation for patients with multiple myeloma and renal insufficiency. Bone Marrow Transplant 1997; 20:653–6. 50. Richardson P, Guinan E. Hepatic veno-occlusive disease following hematopoietic stem cell transplantation. Acta Haematol 2002; 106: 57–68. 51. Goldberg SL, Klumpp TR, Magdalinshi AJ, Mangan KF. Value of the pretransplant evaluation in predicting toxic day-100 mortality among blood stem cell and bone marrow transplant recipients. J Clin Oncol 1998; 16:3796–802. 52. Clift RA, Buckner CD, Storb R et al. The influence of patient age on the outcome of transplantation during chronic phase (CP) of chronic myeloid leukemia (CML). Blood 1995; 86:616a. 53. Beelen DW, Quabeck K, Mahmood HK et al. Allogeneic bone marrow transplantation for acute leukemia or chronic myeloid leukemia in the fifth decade of life. Eur J Cancer Clin Oncol 1987; 23: 1665–71. 54. Miller CB, Kennedy MJ, Santos GW, Jones RJ. Bone marrow transplantation (BMT) in patients over the age of fifty. Proc Am Soc Clin Oncol 1992; 11:1138a. 55. Copelan EA, Kapoor N, Berliner M, Tutschka PJ. Bone marrow transplantation without totalbody irradiation in patients aged 40 and older. Transplantation 1989; 48:65–8. 56. Elfenbein GJ, Winton E, Lazarus H et al. Improved outcome for older patients receiving allogeneic bone marrow transplants for chronic myelogenous leukemia. Proc Am Soc Clin Oncol 1989; 30: 235. 57. Ramond E, Ash R, Doukas M et al. Allogeneic bone marrow transplantation (BMT) in older patients (PTS) with Philadelphia chromosome positive P1+ chronic myelogenous leukemia (CML). Proc Am Soc Clin Oncol 1985; 4:158. 58. Blume KG, Forman SJ, Nademantee AP et al. Bone marrow transplantation for hematologic malignancies in patients aged 30 years or older. J Clin Oncol 1986; 4:1489–92. 59. Bensinger WI, Maloney D, Storb R. Allogeneic hematopoietic cell transplantation for multiple myeloma. Semin Hematol 2001; 38:243–9. 60. Reynolds C, Ratanatharathorn V, Adams P et al. Allogeneic stem cell transplantation reduces disease progression compared to autologous transplantation in patients with multiple myeloma. Bone Marrow Transplant 2001; 27:801–7.

Comprehensive Geriatric Oncology

888

61. Singhal S, Powles R, Treleaven J et al. Long-term outcome of adult acute leukemia patients who are alive and well 2 years after autologous blood or marrow transplantation. Bone Marrow Transplant 1999; 23:875–9. 62. Carlo-Stella C, Mangoni L, Caramatti C et al. High-dose therapy in acute leukemia. Leuk Lymphoma 1997; 26(Suppl 1):61–7. 63. Attal M, Harousseau JL. Randomized trial experience of the Intergroupe Francophone du Myelome. Semin Hematol 2001; 38:226–30. 64. Partyka JB, Fields KK, Perkins JB et al. The effects of age on tolerance of high dose ifosfamide, carboplatin, and etoposide and autologous stem cell rescue: morbidity and mortality. Proc Am Soc Clin Oncol 1996; 15:A506. 65. Fields KK, Ballester OF, Goldstein SC et al. Age effects in patients undergoing autologous bone marrow or peripheral blood stem cell transplantation. Proc Am Soc Clin Oncol 1996; 15:A505. 66. Badros A, Barlogie B, Siegel E et al. Autologous stem cell transplantation in elderly multiple myeloma patients over the age of 70 years. Br J Haematol 2001; 114:600–7. 67. Sirohi B, Powles R, Treleaveren J et al. Myeloma: the role of autologous transplantation in patients with multiple myeloma aged 65 years and over. Bone Marrow Transplant 2000; 25:533–9. 68. Gopal AK, Gooley TA, Golden JB et al. Efficacy of high-dose therapy and autologous hematopoietic stem cell transplantation for non-Hodgkin’s lymphoma in adults 60 years of age and older. Bone Marrow Transplant 2001; 27:593–9. 69. Leger CS, Bredseon C, Kearns B et al. Autologous blood and marrow transplantation in patients 60 years and older. Biol Blood Marrow Transplant 2000; 6(2A):204–210. 70. Jantunen E, Mahlamaki E, Nousiainen T. Feasibility and toxicity of high-dose chemotherapy supported by peripheral blood stem cell transplantation in elderly patients (≥60 years) with nonHodgkin’s lymphoma: comparison with patients <60 years treated within the same protocol. Bone Marrow Transplant 2000; 26:737–41. 71. de la Rubia J, Sasaverdra S, Sanz GF et al. Transplant-related mortality in patients older than 60 years undergoing autologous hematopoietic stem cell transplantation. Bone Marrow Transplant 2001; 27:21–5. 72. Olivieri A, Capelli D, Montanari M et al. Very low toxicity and good quality of life in 48 elderly patients autotransplanted for hematological malignancies: a single center experience. Bone Marrow Transplant 2001; 11:1189–95. 73. Bishop MR, Tarantolo SR, Geller RB et al. A randomized, double-blind trial of filgrastim (granulocyte colony-stimulating factor) versus placebo following allogeneic blood stem cell transplantation. Blood 2000; 96:80–5. 74. Jansen J, Thompson EM, Hanks S et al. Hematopoietic growth factor after autologous peripheral blood transplantation: comparison of G-CSF and GM-CSF. Bone Marrow Transplant 1999; 23:1251–6. 75. Tarella C, Castellino C, Locatelli F et al. G-CSF administration following peripheral blood progenitor cell (PBPC) autograft in lymphoid malignancies: evidence for clinical benefits and reduction of treatment costs. Bone Marrow Transplant 1998; 21:401–7. 76. Bolwell B, Goormastic M, Dannley R et al. G-CSF post-autologous progenitor cell transplantation: a randomized study of 5, 10, and 16 µg/kg/day. Bone Marrow Transplant 1997; 19:215–19. 77. Meisenberg B, Gollard R, Brehm T et al. Prophylactic antibiotics eliminate bacteremia and allow safe outpatient management following high-dose chemotherapy and autologous stem cell rescue. Support Care Cancer 1996; 4:364–9. 78. Bow EJ, Mandell LA, Louie TJ et al. Quinolone-based antibacterial chemoprophylaxis in neutropenic patients: effect of augmented gram-positive activity on infectious morbidity. National Cancer Institute of Canada Clinical Trials Group, Ann Intern Med 1996; 125:183–90.

Hematopoietic stem cell transplantation in the older patient

889

79. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. Recommendations of CDC, the Infectious Diseasees Society of America, and the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2000; 6:659–734. 80. Marr KA, Seidel K, Slavin MA et al. Prolonged fluconazole prophylaxis is associated with persistent protection against candidiasis-related death in allogeneic marrow transplant recipients: long-term follow-up of a randomized, placebo-controlled trial. Blood 2000; 96:2051– 61. 81. Slavin S, Nagler A, Naparstek E et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998; 91:756–63. 82. Champlin R, Khouri I, Giralt S. Use of nonmyeloablative preparative regimens for allogeneic blood stem cell transplantation: induction of graft-vs-malignancy as treatment for malignant diseases. J Clin Apheresis 1999; 14:45–9. 83. Djulbegovic B, Seidenfeld J, Lacevic M, Bonnell C. ‘Mini-transplants’ in hematologic malignancies: a synthesis of available evidence. Blood 2000; 96:353b. 84. Djulbegovic B, Seidenfeld J, Bonnell C, Kumar A. Nonmyeloablative allogeneic stem cell transplantation for hematologic malignancies: a systematic review. Cancer Control 2003; 10:17–41. 85. Childs R, Chernoff A, Conentin N et al. Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheralblood stem-cell transplantation. N Engl J Med 2000; 343:750–8.

41 Polypharmacy in the senior adult patient Mary E Corcoran Introduction In the past, when an apothecary compounded medications, polypharmacy referred to the mixing of many drugs in one prescription.1,2 Today, polypharmacy is predominantly defined as the concurrent use of several different medications, including more than one medication from the same drug classification. There are situations in which multiple drug regimens are justified. For example, congestive heart failure and hypertension are situations that frequently affect the older adult (>65 years of age), and commonly involve a multitude of medications. However, there are many instances where excessive and unnecessary medications are used. The senior adult population comprises approximately 12% of the total population.3 The number of senior adults is projected to reach 39.3 million by the year 2010.4 Approximately 30% of all prescription medications are utilized by the senior adult, with an unknown percentage of non-prescription medications taken.3 As the number of senior adults increases, and researchers discover and test new medications to prevent and treat medical problems, polypharmacy will continue to flourish. A risk is involved with the administration of any medication, and that risk may be heightened when the patient is a senior adult. The usefiilness of a drug, its side-effects, and any potential interactions need to be clearly defined before addition to a medication regimen. In 1984, Simonson5 suggested that polymedicine was a more appropriate term than polypharmacy for the excessive and unnecessary use of medications. Seven features are noted: • use of medications that have no apparent indication; • use of duplicate medications; • concurrent use of interacting medication; • use of contraindicated medication; • use of inappropriate dosage; • use of drug therapy to treat adverse reactions; • improvement following discontinuation of medications. The Healthy People 2000 conference identified polypharmacy by older people with chronic health problems as the principal safety issue in the coming years.4

Polypharmacy in the senior adult patient

891

Development of polypharmacy (Table 41.1) Four out of five elderly patients have at least one chronic illness and experience a vast array of symptoms.6 The likelihood of an elder adult experiencing a chronic illness increases rapidly with age. Elderly (aged over 65) patients are prescribed twice as many medications as are younger patients.7 The trend for multiple medications continues through age 80.8 There seems to be a sex specificity, since the mean number of medications taken by an older woman is higher than that taken by an older man.9 Polypharmacy may also be attributed to the fact that senior adults seek medical advice more often than young adults. The senior adult’s perception is that medication is the answer to alleviating symptoms and/or disease states. Nolan and O’Malley8 noticed that 35% of office visits by those aged more than 85 resulted in a prescription of three or more medications. The senior adult is often targeted by the mass media in the promotion of new medications and those medications that are given over-the-counter status. The phenomenon of treating with ‘natural products’ advocated and sold by health food stores and the advertisement of such products may unintentionally harm the senior adult. These products, which are advertised as ‘natural’, can often interact with prescribed medications and exacerbate existing health conditions. For example,

Table 41.1 Development of polypharmacy • Number of chronic illnesses increases with age • Multiple medications • A ‘pill for every ill’ • Advertisement industry • Non-prescription drug availability • Self-treatment • Hoarding of old medications • Cost of prescription products • Multiple prescribers • Multiple sources for medication • Lack of knowledge about own medications and medical condition

iron products inhibit the absorption of tetracyclines, quinolones, and anti-hypertensive agents. When iron is given with thyroxine replacement therapy, it increases the serum concentration of thyrotropin (thyroid-stimulating hormone, TSH) and thereby increases the signs and symptoms of hypothyroidism.10 Calcium products inactivate tetracycline, and should not be given with antibiotics. Calcium should be used cautiously in those seniors receiving cardiac glycosides owing to the interaction between these two classes of drug—arrhythmias may occur if these agents are given together. The term ‘natural

Comprehensive Geriatric Oncology

892

product’ may tend to imply ‘safe product’ to the senior adult, when in fact it may not be safe, depending on the overall condition of the elder individual.11 The danger in the use of ‘natural’ products by the senior adult lies in the lack of information disclosed to the health professional. When medical histories are taken, sideeffects, interactions, and exacerbations of already-apparent disease processes may be attributed to other causes. The senior adult may or may not perceive the use of non-prescription products as medication and may take these products without knowledge of the possibility of interactions with prescribed medications. With the volume of medications formerly obtained via prescription being given non-prescription status, the potential for polypharmacy increases. Home remedies, nutritional supplements, vitamins, and alcohol have the potential for interactions—not only with prescribed medications, but also with each other.12 At least one-half of the most commonly prescribed medications for the elderly have the potential to interact with alcohol.13 Of the 79 initial patients interviewed by the Senior Adult Oncology Program at the H Lee Moffitt Cancer Center and Research Center in Tampa, Florida, 42% were taking non-prescription items, but did not report these products as medication on their 3-day medication history. An average of 4.4 medications per patient was reported; 3.2 were via prescription, and 1.2 were nonprescription items taken on a daily basis (Figure 41.1). Of the daily non-prescription items, 62% were classified as vitamins and nutritional supplements, 18% analgesics, 12% laxatives, and 8% antacids and others (Figure 41.2). Cough and cold remedies may also cause problems for seniors with high blood pressure, diabetes, and/or coronary artery disease. The approval of cimetidine as a nonprescription item should warrant an element of caution to the senior adult. Cimetidine reduces the hepatic metabolism of some prescription items: warfarin, phenytoin, propranolol, theophylline, terfenadine, some tricyclic antidepressants, and some benzodiazepines. By reducing hepatic metabolism, cimetidine decreases elimination and increases the blood concentrations of these medications. Clinically important effects that are considered to be adverse events occur. For example, the

Polypharmacy in the senior adult patient

893

Figure 41.1 Medications per patient: total 4.4.

Comprehensive Geriatric Oncology

894

Figure 41.2 Non-prescription medications. concomitant administration of cimetidine with phenytoin and theophylline leads to increased side-effects from these medications,14 which may lead to decreased dosages. Once the cimetidine is discontinued or if it is taken on a irregular basis, subtherapeutic levels may result. The hoarding of old medications poses a potential for polypharmacy with senior adults.15 ‘Saving medication for later use’ seems to be a common explanation given by individuals questioned as to why they did not take all their medication as prescribed.16 The fixed income of many senior adults is an issue that cannot be ignored and may potentiate an elder adult’s ‘need’ to hoard medications. These situations are also compounded by the sharing of medications among friends and family members. Unfortunately, the doctor’s visit may be the result of the inability of senior adults to treat symptoms themselves by using ‘hoarded’ medication or the medications of family members. With the increase in number of chronic illnesses reported with advancing age, the number of physicians seen by the senior adult may increase.17 This may lead to many physicians prescribing a multitude of medications in order to achieve the same therapeutic endpoint. If these physicians do not have access to the primary medical record, therapy may be initiated without the full scope of a patient’s medication history. With each additional physician seen by the senior adult, the probability of duplicate medication and other polypharmacy issues increases exponentionally The lack of a

Polypharmacy in the senior adult patient

895

‘primary care’ physician with the ability to orchestrate all physicians seen by one patient increases the possibility of polypharmacy. Multiple prescribers for the senior adult are not limited to physicians. Health food store personnel, pharmacists, dieticians, nurses, friends, and family members all may influence the medication practices of the elder adult. Recommendations may be made without full knowledge of the disease process, symptoms, or concomitant illness that the elder person is experiencing. Another component that adds to the development of polypharmacy is the practice of multiple sources of prescription medications. The senior adult may go from pharmacy to pharmacy looking for the best price on a medication and may not transfer all medications to that particular store. The development of the linking of pharmacies via a common computer is utilized in several of the large drugstore chains. This linkage is beneficial to the senior adult who travels from one pharmacy in a chain to another pharmacy in that chain. Each pharmacy within a particular chain has access to a complete record of all prescriptions filled by that chain for a particular senior. However, this system breaks down when the senior adult uses several different chains or sources for medication that do not have a common computer source. Lack of knowledge about medications and the corresponding medical condition for the medication may also lead to polypharmacy. Psychosocial aspects of an elder adult’s ability to learn about medications has been documented.18 Education of a patient is vital to the treatment of their medical condition. Lack of knowledge may or may not be attributed to the information resources available to the senior adult. Presentation of information must correspond to the physical limitations of patients and their education level. Beyond age 65, one in four people is affected by hearing loss or significant tinnitus.19,20 Medication information is often presented in small print, making it difficult to read. A slowing of the cognitive process occurs with age, thereby corresponding to a decline in memory and learning procedures.21 The level of education may be such that the patient does not understand what the therapeutic endpoint in their therapy is, or why the medication is being given. Arenas of polypharmacy There are three major arenas in which polypharmacy has been documented: community settings, extended care facilities, and hospital settings. Each arena has its own special characteristics that add to the incidence of polypharmacy. Research is ongoing in each particular area and is currently being reported in a number of venues. The rate of prescribing in the ambulatory community setting is lower than in either the extended care facility or the institutionalized setting.22 Ambulatory patients are healthier than institutionalized patients. Research done in this arena in specific populations dealing with specific disease states or medication groups has shown a lower rate of prescribing. Two studies involving the use of prescription and non-prescription drugs are presented in Table 41.2.23,24 These studies show that, regardless of study parameters, the categories of medications most frequently used in the senior population are very similar. Shimp et al17 studied potential medication-related problems in non-institutionalized elderly, and concluded that the total number of medications, the number of those

Comprehensive Geriatric Oncology

896

prescribed, and the number of medical problems experienced had relationships with the number of potential drug-related problems experienced. Patients experiencing frequent changes in medication regimens may become unclear about which medication to continue or discontinue. The change from brand name to generic carries the potential of both medications being taken concurrently.

Table 41.2 Similarities in rankings of the most common prescription and non-prescription medication use by the senior adult in two studies23,24 Hale et al23

Vener et al24

1.

Multivitamins

1.

Vitamins

2.

Antihypertensives

2.

Analgesics

3.

Non-narcotic analgesics

3.

Cardiovascular medications

4.

Antirheumatics

4.

Antihypertensives

5.

Laxatives

5.

Anti-inflammatories

6.

Coronary vasodilators

6.

Asthma/bronchitis medications

7.

Diuretics

7.

Sedatives/hypnotics

8.

Cardiovascular medications

8.

Thyroid hormones

9.

Anticoagulants

9.

Diabetic medications

10.

Antacids

10.

Laxatives

The change from one generic product to another may also compound the issue by changes in color or appearance. These alterations may cause confusion for senior adults, who frequently identify their medications by color, shape, and size of the tablet or capsule. Approximately three-quarters of ambulatory seniors take at least one prescription medication. The number of over-the-counter medications is not well documented. Extended care facilities have a higher number of medications used than the community setting. This may be due to more accurate records and accountability for medication use, which first became mandated in the USA by Federal legislation in the early 1970s.25 This legislation required a pharmacist to perform a drug regimen review in those nursing home facilities receiving Medicare or Medicaid reimbursement. The consultant pharmacist must complete a drug regimen review (DRR) on each patient— monthly in a skilled nursing facility or nursing facility and quarterly in an intermediate care facility or mentally retarded care facility. Each patient chart must contain documentation of the date of the review and the consultant’s signature. Documentation of any medication problems and/or pertinent findings must be provided in writing to the director of nursing and the attending physician. This legislation gave rise to a multitude of studies conducted regarding the use and misuse of medication the nursing home environment. A study by Beers et al26 found that in 12 nursing homes studied, physicians

Polypharmacy in the senior adult patient

897

prescribed an average of 7.2 medications per patient, with 14% of those patients prescribed 10 or more medications. The higher number of medications prescribed to the senior adult in the nursing home setting has led to more recent Federal regulation in the USA.27 It is mandated that senior nursing home residents be free of unnecessary or inappropriately prescribed drugs. Unnecessary drugs are defined as any medication given in excessive doses, for an excessive length of time, without adequate monitoring or indication, and given regardless of adverse reactions or consequences.27 This legislation builds on previous legislation that impacts the consultant pharmacist.25 Legislation is aimed specifically at decreasing the use of long-acting benzodiazepines and psychotropic agents in the skilled nursing home setting. It has been reported that 44.9% of patients over the age of 65 in the nursing home setting have five or more medications prescribed.28 Of the medications taken in long-term care facilities, 70% can be grouped into six categories: psychotropic agents, cardiovascular agents, laxatives, analgesics, diuretics, and vitamins. A 1988 study by Carbonin et al29 studied drug use and adverse reactions in 41 medical and geriatric wards. An average of 5.1 medications was taken per patient, and this number increased with advancing age. The most common medications given during hospitalization were cardiac glycosides, loop diuretics, cardiac medications, and antiulcer medications. Interestingly, these medications are also reported among the top 10 medications in the ambulatory setting (Table 41.2). Differences in study design and samples make it difficult to draw conclusions from the reporting of adverse drug reactions (ADR) in the senior hospitalized population. Drug interactions are thought to be a leading cause of ADR.30 With the multitude of medications prescribed to the senior adult upon hospitalization, the potential for drug interactions to occur may increase. This may explain the assumption that ADR are related to the age of the individual, when they may be due to the severity of the reason for admission (e.g. congestive heart failure, an infectious process, or respiratory difficulties). As in the long-term care facility, several parameters for the reporting of adverse or possible adverse events are suggested. The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) suggests several avenues to report these events and examines the methods for reporting upon inspection of the hospital. These requirements regarding ADR have allowed for many research opportunities in the field of ADR as well as reporting the number of medications taken by hospitalized patients. Consequences of polypharmacy Adverse drug reactions ADR can be caused by a variety of factors: drug-drug interactions, inappropriate prescribing, changes in pharmacokinetics and pharmacodynamics, multiple prescribers and sources of medication, and non-compliance. Drug-drug interactions are thought to be the leading cause of ADR. An exponential, rather than linear, increase in the incidence of ADR is observed with the addition of each drug to an existing regimen.1 The potential for drug–drug interactions to be clinically significant was studied by Lipton et al.31 This

Comprehensive Geriatric Oncology

898

study reported that 48% of 236 ambulatory patients experienced a drug interaction. Only 2% of those reactions were determined to be clinically significant. The medications most commonly prescribed to senior adults have been mentioned above: it is important to note that these are also the medications that most commonly cause ADR in the senior population (Table 41.3).29,32–34 The inappropriate prescribing of medications for the elderly may also potentiate the ocurrance of ADR. Non-pharmacologic therapy such as alterations in diet, exercise, sleeping patterns, and daily activities are not as tangible as a prescription. Changes in the pharmacodynamics and pharmacokinetics of the senior adult may cause ADR to occur. These include decreased absorption,35 declining renal function,36 and reduced liver mass and metabolic clearance of medications.37

Table 41.3 Medications that cause adverse drug reactions in the senior population: similarities of different settings Hospital29

Ambulatory32 Nursing home33

US population34

Ampicillin

Aspirin

Analgesics

Antidepressants

Captopril

Digoxin

Cardiac medications

Antihypertensives

Furosemide

Ibuprofen

Central nervous system medications Antilipemics

Nifedipine

Prednisone

Gastrointestinal medications

Nitroglycerin Propranolol

Antineoplastics Gastrointestinal medications

Intentional and non-intentional compliance has been studied. If information on noncompliance is not reported by the patient to the prescriber, increases or decreases in dosages of medications may result. The ramifications are multiple. The patient may be hospitalized with an ADR secondary to the dosage of the medication, not to the medication itself. Sub-therapeutic or super-therapeutic drug levels may result. Side-effects of medication Most side-effects experienced by senior adults can be uncomfortable, but usually do not warrant discontinuation of the medication. However, the consequences of treating these side-effects may themselves lead to polypharmacy. If another medication is prescribed to negate the side-effect, there is a potential for side-effects from the new medication. This stacking of medications can become quite cumbersome, not only to the patient taking the medication, but also to the individual attempt- ing to discover the use for those medications. It is difficult to decide which medication is causing which problem when some medications have the same indications and side-effects. For example, narcotics and tricyclic antidepressants are both used in pain control and both have the potential to cause constipation. An overlapping of effects may occur with the concomitant administration of medications.

Polypharmacy in the senior adult patient

899

The perception that an occurrence is a side-effect may in fact be a misnomer. The patient may be experiencing a disease state that has not been diagnosed. Upon an accurate diagnosis, the addition of more medication may result. This would also increase the patient’s chance of more side-effects due to polypharmacy. Some side-effects of medication subside with time, but the urgency to alleviate any unwanted symptoms is strong. Cost The costs of the medication as well as of hospitalization due to medication are of great concern to the senior adult. Fixed incomes of the senior population may prohibit the purchasing of essential medications. The economic losses experienced by the senior adult due to the inaffordability of medication and subsequent hospitalization can be devastating. Higher medication costs have been linked to an increase in non-compliance. Medications that are not essential may take priority over essential medications because the cost-versus-benefit ratio is not discussed with the senior adult. Also, the cost of seeing a physician leads seniors to accept recommendations from individuals who are not actively involved in their treatment. Friends, family, salespeople, etc. have an influence on the senior adult. Recommendations from these individuals are usually free, but the potential cost of following those recommendations may be very high. The senior adult may or may not be facing the financial burden alone. Insurance companies and the healthcare system’s resources are also responsible for paying the mounting costs of addition to drug therapy. Drug-drug interactions The opportunity for drug-drug interactions increases with the addition of each medication to the drug regimen. Publicized drug interactions usually reference only one other drug and do not look at the ability of several medications to potentiate one medication. It is difficult to separate which medication is causing the interaction when this occurs. There is a potential for polypharmacy to continue when the interaction is not identified. Another medication may be added to the regimen if the drug-drug interaction causes a decrease in response for the patient. An increase in response may also occur and lead the patient to describe exacerbated side-effects of medication, which may result in hospitalization or an addition of medication to the therapy. This addition may include not only prescription medications but also self-treatment by the senior adult with non-prescription products. Non-compliance Non-compliance is the main reason for most outpatient treatment failure, as well as a cause of serious medical complications. Rates of non-compliance have been estimated as 25–59% in the elderly.35 An average of 50% non-compliance has been reported in those individuals with chronic disease.1 Non-compliance with medications has been correlated more strongly with the number of medications given than with the age of the patient.

Comprehensive Geriatric Oncology

900

Difficulty in interpreting the importance of a medication or the directions for that medication may lead the senior adult to non-compliance. A senior adult’s knowledge base, cognition, hearing acuity, vision, memory, and physical condition may affect compliance. These may be single or additive in nature. If a senior adult cannot physically open the bottle of medication, or drive to get the medication, he or she may be viewed as non-compliant. If a senior adult does not understand the directions given to him or her regarding the medication, due to hearing loss or educational level, the chances for compliance are decreased. When a patient cannot take a medication as prescribed, he or she is often labeled as non-compliant. This may lead to the prescribing of more medication to the senior adult, due to the fact that the patient is embarrassed to tell the physician about their difficulties in taking medication. Confusion about therapy may increase the patient’s non-compliance. Medication scheduling may be a causative factor in the development of non-compliance. An increased number of medications dispersed throughout the day may be so timeconsuming that the senior adult has difficulty in remembering when each medication is to be taken. The amount of time spent taking medications may actually decrease the quality of life of the patient. For example, diuretic use may prevent a senior adult from enjoying outdoor daily activities or traveling owing to the frequency of urination that often accompanies these products. Dosages may be missed and taken at a later date or time, which may result in medical problems in the future. Seniors may also play ‘catch-up’— taking two doses of a medication to make up for the one that was missed. This may be described as non-compliance and cause serious problems that may lead to hospitalization. Gebhardt et al36 reported that 60% of senior adults interviewed would discontinue a prescription drug without speaking to a physician if the medication did not appear to be working. Approximately one-half of those seniors interviewed thought that there were risks involved in taking medications. Prevention of polypharmacy The identification of polypharmacy is the first step towards prevention. The recognition of polypharmacy can be performed in numerous ways. A comprehensive baseline assessment of the senior adult is essential to aid in the recognition of situations where polypharmacy may occur.37 All aspects of the senior adult’s daily life are reviewed, and may provide insight into the physical, emotional, or educational situations that may lead to the determination that polypharmacy has occurred. The possibility of illiteracy and the subsequent psychological embarrassment of the individual may lead to polypharmacy. The medication history is another valuable tool in this determination. However, a tool is only as good as the questions asked of the senior adult. It is important to phrase questions about medication use that will allow the senior adult to expound on their experience. Open-ended questions are a very valuable tool. They allow insight into the medication habits of the senior adult and grant information that a yes/no answer will not provide. An effective evaluation allows the healthcare provider to learn from the patient. The medication history should include any past adverse reactions to medication, as well as allergies.

Polypharmacy in the senior adult patient

901

The ‘brown bag’ approach employed by Colt and Schapiro38 is a useful and valuable tool in the identification and prevention of polypharmacy. The information extracted from this approach is invaluable to the health-care practitioner. This is dependent on the instructions given to the senior adult about the brown bag. The patient needs to be informed that all products, both prescription and non-prescription, need to be brought to the office visit. The amount of medication remaining in a vial and calculations as to what should be remaining are available, and therefore a measure of compliance can be discovered. Multiple physician use and multiple pharmacy use can be determined by the labels on the prescription. Non-prescription medication use may be available. This will provide the healthcare practitioner with information about possible drug interactions, actual prescribed dosages of medications, and duplications of medications. Another valuable tool in the prevention of polypharmacy is the 3-day medication history. With this tool, the senior adult provides information on daily medication use (dosage and scheduling) for a 3-day period. The 3-day history, in combination with the brown bag, provides another measure of medication compliance in the senior adult. The education of the patient concerning medication use is one of the most important tools that the healthcare provider can use to prevent the occurrence of polypharmacy. Medication information at a level suited to the individual senior adult is imperative. The involvement of patients in their treatment options not only allows them some control over their treatment plan, but also prevents possible polypharmacy occurrences. The patient needs to be an active partner in his or her care, and will then understand the possible ramifications of non-compliance. As an active partner, the senior adult can aid the physician in the choice of medication for the disease process. For example, if fixed income is a concern for the patient, communication with the physician will allow a possible therapeutic alternative at a lower cost. This will promote compliance in the patient, as well as making the physician aware of possible problems in the future. Simplification of drug regimens is another means by which the healthcare provider can prevent polypharmacy. Single-day dosing is available for many medications, and may improve the quality of life of the senior adult by decreasing the number of medications taken on a given day.39 One medication may have many therapeutic indications, and can therefore be utilized for a number of disease states. The utilization of a pharmacotherapy consultant can aid the physician in the prevention of polypharmacy. Lipton et al31 studied the utilization of clinical pharmacists in the prescribing of medications in a geriatric population. Their results indicated that clinical pharmacists can improve geriatric prescribing by physicians in the outpatient setting. The best way to prevent polypharmacy is to change prescription habits. Prescribing medications without a diagnosis only adds to the problem of polypharmacy. The benefit of the addition of a medication to a therapeutic regimen must be weighed against the possible problems that may occur from this addition. The patient should be aware of the benefit-to-risk ratio of each additional medication. Multiple sources of prescribing and providing of medications will increase the number of medications per patient unless communication among these sources occurs. A responsible party should be designated to review all medications prescribed for the senior patient and distinguish necessary and unnecessary medications. This responsible party must also maintain accurate records of non-prescription product use. A primary file or

Comprehensive Geriatric Oncology

902

record of all medication use should be available to all practitioners as part of the detailed history of the senior adult. The use of ‘as needed’ (PRN) medication should be kept to a minimum to prevent polypharmacy, since antagonism or synergism of daily medications can occur. The frequency of use of PRN medications must be reviewed in order to prevent the misuse or overuse of these agents. The term ‘essential’ is the key to the simplification of medications taken by the senior adult. The outcome of drug therapy must be reviewed, and medications must be discontinued if they are not accomplishing the therapeutic endpoint. Also, once that therapeutic endpoint has been met, medications must be discontinued. This information should be shared with the senior adult upon addition to the therapeutic regimen. This will prevent the continuance of medications past their usefulness. The use of non-medication strategies may be effective in the treatment of symptoms experienced by the senior adult. Education of the patient concerning non-drug treatment is a step towards the prevention of polypharmacy. Health promotion for senior adults is an important asset to their quality of life. Exercise, nutrition, and a healthy lifestyle all add to a decrease in the need for medications to treat symptoms. For example, ‘stiffness’ due to arthritis may be treated with increased exercise with or without the addition of medication. Summary Polypharmacy is defined as the concurrent use of several different medications, including more than one medication from the same drug class. Unnecessary and excessive medication use is present in the senior adult population. Polypharmacy occurs in several settings, including hospital, community, and nursing facilities. The development of polypharmacy is enhanced by many factors, including multiple disease states, multiple medications, multiple prescribers, multiple sources for medication, lack of education about medication, and self-treatment. These factors may build upon each other and become additive in nature. The consequences of polypharmacy involve adverse drug reactions, drug interactions, cost to the patient, and non-compliance. Polypharmacy is often recognized after it has occurred. The key to prevention of polypharmacy is the utilization of different prevention methods and the addition of these to form a plan of action prior to the occurrence. Education of the medical community as well as the senior adult is essential to the prevention of polypharmacy. The use of the ‘essential medication only’ premise to medication treatment in the senior adult population will aid in the prevention of polypharmacy. Cost factors, therapeutic endpoints, non-drug therapy through health promotion, education, and communication between the senior adult and all prescribers involved in medical care, are all vital components of the main goal of decreased medication use in the senior adult population.

Polypharmacy in the senior adult patient

903

References 1. Colley CA, Lucas LM. Polypharmacy: the cure becomes the disease. J Gen Intern Med 1993; 8:278–83. 2. Stedman’s Medical Dictionary, 24th edn. Baltimore: Williams and Wilkins, 1984. 3. Baum C, Kennedy DL, Forbes MB et al. Drug use in the United States in 1981. JAMA 1984; 251:1293. 4. Healthy People 2000: National Health Promotion and Disease Prevention Objectives. Washington, DC: US Dept of Health and Human Services, 1990. 5. Simonson W. Medications and the Elderly: A Guide for Promoting Proper Use. Rockville, MD: Aspen Systems Corporation, 1984:33. 6. Kovar M. Health of the elderly and use of health services. Public Health Rep 1977; 92:9–19. 7. Colt HG, Shapiro AP. Drug-induced illness as a cause for admission to a community hospital. J Am Geriatr Soc 1989; 37:323–6. 8. Nolan L, O’Malley K. Prescribing for the elderly: Part I. Sensitivity of the elderly to adverse drug reactions. J Am Geriatr Soc 1989; 36: 142–9. 9. Guttman D. Patterns of legal drug use of older Americans. Addict Dis 1978; 3:337–56. 10. AHFS Drug Information 95. Bethesda, MD, 1995:922. 11. AHFS Drug Information 95. Bethesda, MD, 1995:1745. 12. Ellor JR, Kurz DJ. Misuse and abuse of prescription and nonprescription drugs by the elderly. Nurs Clin North Am 1982; 17:319. 13. Atkinson RM. Alcoholism in the elderly population. Mayo Clin Proc 1988; 63:825. 14. AHFS Drug Information 95. Bethesda, MD, 1995:2025. 15. Law R, Chalmers C. Medicines and elderly people: a general practice survey. BMJ 1976; i:565. 16. Ostrom JR, Hammerlund ER, Christiansen DB et al. Medication usage in the elderly population. Med Care 1985; 23:157. 17. Shrimp LA, Ascione FJ, Glazer HM, Atwood BF. Potential medication-related problems in non-institutionalized elderly. Drug Intell Clin Pharm 1985; 19:766–72. 18. Back KW, Sullivan DA. Self-image, medicine and drug use. Addict Dis 1978; 3:373–82. 19. National Health Review Survey. Hyattsville, MD: US National Center for Health Statistics, 1981. 20. Oyer HJ, Oyer EJ. Social consequences of hearing loss for the elderly. Allied Health Behav Sci 1979; 2:123–38. 21. Arenberg D. Memory and learning do decline late in life In: Aging: A Challenge to Science and Society, 3rd edn (Birren JE, Munnichs JMA, Thomas H, Marois M, eds). Oxford: Oxford University Press, 1983:312–22. 22. Nolan L. Prescribing for the elderly, II. Prescribing patterns: difference due to age. J Am Geriatr Soc 1988; 36:245. 23. Hale WE, May FE, Marks RG, Stewart RB. Drug use in an ambulatory elderly population: a five year update. Drug Intell Clin Pharm 1987; 21:530–5. 24. Vener AM, Krupla LR, Climo JJ. Drug usage and health characteristics in non-institutionalized retired persons. J Am Geriatr Soc 1979; 27:83–90. 25. US Federal Register 1974 (January 17); 39:2238–57. 26. Beers MH, Fingold SF, Ouslander JG et al. Characteristics and quality of prescribing by doctors practicing in nursing homes. J Am Geriatr Soc 1993; 41:802–07. 27. Elon R, Pawlson G. The impact of OBRA on medical practice within nursing facilities. J Am Geriatr Soc 1992; 40:958–63. 28. Lamy PP, Michocki RJ. Medication management. Clin Geriatr Med 1988; 4:623.

Comprehensive Geriatric Oncology

904

29. Carbonin P, Pahor M, Bernabei R, Sgadari A. Is age an independent risk factor for adverse drug reactions in hospitalized medical patients? J Am Geriatr Soc 1991; 39:1093–9. 30. Lamy PP. The elderly and drug interactions. J Am Geriatr Soc 1986; 34:586–92. 31. Lipton HL, Bero LA, Bird JA, McPhee SJ. The impact of clinical pharmacist’s consultations on physicans’ geriatric drug prescribing. Med Care 1992; 30:646–58. 32. Chrischilles EA, Segar ET, Wallace RB. Self-reported adverse drug reactions and related resource use. Ann Intern Med 1992; 117: 634–40. 33. Gerety M, Cornell JE, Plichta D, Eimer M. Adverse events related to drugs and drug withdrawal in nursing home residents. J Am Geriatr Soc 1993; 41:1326–32. 34. Burke LB, Jolson HM, Goetsch RA, Ahronheim JC. Geriatric drug use and adverse event reporting in 1990. Annu Rev Gerontol Geriatr 1992, 12:1–28. 35. Col N, Fanale JE, Kronholm P. The role of medication noncompliance and adverse drug reactions in hospitalizations of the elderly. Arch Intern Med 1990; 150:841–5. 36. Gebhardt MW, Governali JF, Hart EJ. Drug related behavior, knowledge and misconceptions among a selected group of senior citizens. J Drug Educ 1978; 8:85–92. 37. Schlarach AE, Mor-Barak ME, Katz A et al. Generation: a corporate-sponsored retiree health care program. Gerontologists 1992; 32:265–9. 38. Colt HG, Shapiro AP. Drug-reduced illness as a cause for admission to a community hospital. J Am Geriatr Soc 1989; 37:323–6. 39. Stewart RB. Noncompliance in the elderly: Is there a cure? Drugs Aging 1991; 1:163–7.

42 Diagnosis and treatment of cancer in the elderly; Cost-effectiveness considerations Gary H Lyman, Nicole M Kuderer Introduction The resources available and allocated by society for medical care are limited. Modern medical care is costly, and with the introduction of new and more expensive technologies, the demands on these resources are increasing rapidly. Many clinical decisions involve trade-offs between what is best for the individual (most effective or least harmful) and what is best for society (least costly). A systematic method is needed to appropriately evaluate medical care and healthcare technology that carries significant risk or cost to either the patient or society. Hopefully, such evaluation methods will not only reduce cost, but also improve the quality of healthcare, resulting in a more rational approach to the utilization of health-care resources. Physicians and other healthcare professionals should play a leadership role in the evaluation and appropriate use of health care resources. Nearly 1.5 million Americans will have been diagnosed with invasive cancer in 2002, and more than 550000 will have died of the disease.1 The impact of cancer and cancer treatment upon the population can be measured both clinically and economically. As shown in Figure 42.1(a), application of age-specific cancer incidence rates to the current US population suggests that approximately one-half of men and one-third of women will be diagnosed with cancer if they do not die of other causes. Figure 42.1 (b) illustrates the rapid rising in healthcare expenditures in the USA over the past three decades, totaling nearly $1.5 trillion annually. Cancer care represents approximately 10% of direct medical expenditures, mostly associated with hospitalization, physician costs, long-term care, and drug costs (Figure 42.1c). It is impossible to fully understand and measure the effect of this disease on the population, including the elderly, without measures of both its clinical and economic impact. Both intermediate measures and ultimate or long-term measures are utilized to measure healthcare outcomes related to cancer, including clinical, psychosocial, and economic dimensions. Clinical outcome may be measured in terms of the desired effectiveness or benefit along with any associated toxicity or harm that results. The favorable effect of cancer treatment is conventionally measured in terms of response and ultimately survival or the area beneath the survival curve represented by life-expectancy or the average number of years of life remaining at any given time. The gain in life-years represented by the area between survival curves is a more powerful measure for evaluating the impact of an intervention than comparing the time for a given proportion of patients to die or the proportion of patients surviving to some time point (Figure 42.2).

Comprehensive Geriatric Oncology

906

The adverse effect of cancer treatment is conventionally measured in terms of toxicity and ultimately the effect on quality of life. Health-related quality of life is commonly measured utilizing health profile measures derived from psychosocial theory, which can be either generic (albeit generalizable) or specific for given diseases, treatments, or circumstances. Quality of life can also be measured by eliciting patient preferences or utilities for various health states as derived from economic theory. The economic outcomes of cancer are generally measured as either charges or ultimately expenditures or costs. These costs include the direct costs of delivering medical care or non-medical and indirect costs associated with illness, with the latter representing some two-thirds of all costs associated with cancer care. As shown in Table 42.1, five cancers constitute over 90% of the healthcare costs associated with cancer care in the USA. Not accounted for are the substantial intangible costs associated with such issues as pain and suffering and loss of companionship, which are very real to the patient and

Table 42.1 Cancers associated with the greatest costsa • Breast cancer (24%) • Colorectal cancer (24%) • Lung cancer (18%) • Prostate cancer (17%) • Bladder cancer (8%) • All five cancers (91%) a

US National Center of Health Statistics, HCFA, 1995.

Diagnosis and treatment of cancer in the elderly

907

Figure 42.1 (a) Projected lifetime risk of developing invasive cancer for both males and females based on 2000 census and age-specific cancer incidence from the US National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results

Comprehensive Geriatric Oncology

908

(SEER) Program, 1990–2000. (b) US healthcare expenditures for 1970– 2000, from the Office of National Health Statistics, Health Care Finance Administration (HCFA). (c) US healthcare expenditures as a percentage of total expenditures (left) and as a percentage of expenditures for cancer care (right) from the Office of National Health Statistics, HCFA, and the NCI.

Figure 42.2 Gain in life-expectancy with a hypothetical intervention compared with control based on the area between two survival curves representing the probability of survival on the vertical axis and time since randomization on the horizontal axis. Also illustrated are the traditional comparative measures represented by the gain in median (50th percentile) survival time and the gain in the probability of survival (e.g. at 5 years). Adapted from Naimark et al.110

Diagnosis and treatment of cancer in the elderly

909

family but extremely difficult to quantitate or place in monetary terms. Outcome measures, which combine the clinical, psychosocial, and economic impacts of disease and its treatment, are available and have gained increasing acceptance for the comprehensive comparison of clinical strategies. Such measures are particularly useful for comparing the values of different diagnostic and therapeutic interventions. While such measures, including cost-effectiveness, are extremely valuable, they are vulnerable to misinterpretation and must be fully understood. This chapter will focus on the utilization of outcome measures and their application to the special population represented by the elderly patient with cancer. Cancer in the elderly Cancer clearly is a disease of aging, since age-specific incidence rates increase with increasing age (see Chapter 2 of this volume2). Cancer is the second leading cause of death among the elderly, accounting for nearly one-fourth of all deaths in the USA.3 Approximately 58% of all malignancies and over two-thirds of all deaths from cancer occur in individuals aged 65 and over. The median age of cancer patients at the time of diagnosis is 67, and at the time of death it is 70. Cancer incidence rates have increased 26% over the past two decades among those aged 65 and over, compared with only 10% among younger patients.3 Similarly, cancer mortality rates have increased 15% among individuals aged 65 and over, compared with a decrease of nearly 5% among younger individuals during the same time period. Lung cancer represents the leading cause of cancer-related mortality among the elderly, and has increased threefold during the last two decades among women aged 65 and over.3 There are considerable differences in both the potential for response and the risk of toxicity between older and younger individuals. The malignancies most commonly seen in the elderly are often less responsive to systemic therapies, while the frequency of comorbid illnesses, which may further complicate treatment, is greater. Likewise, the potential benefit of treatment in terms of improved life-expectancy becomes less with increasing age (see Chapter 22). Therefore, the importance of carefully balancing benefits and risks in evaluating the impact of disease and its intervention is clear. And nowhere are these issues and the consideration of healthcare costs more important and readily apparent than in the care of the elderly patient with cancer. Issues related to the quality of life and the utilization of limited resources, while always of importance, reach their greatest importance when considering cancer care in the elderly. Healthcare outcomes in cancer care A variety of measures are available to assess healthcare outcomes associated with cancer care. Effectiveness is the measurement of the clinical outcome of cancer management in the population. This must be distinguished from efficacy, which represents the outcome apparent in a sample of the population, generally in the framework of a clinical trial. Intermediate clinical outcomes such as tumor response are frequently utilized because they are available earlier and are often predictive of the ultimate outcome of interest.

Comprehensive Geriatric Oncology

910

More powerful intermediate measures include the time to relapse, time to recurrence, and time to progression of disease. Ultimately, the benefit of cancer treatment is most frequently measured in terms of overall survival or life-expectancy. Survival may be presented as actual survival, where all deaths are considered, or relative survival, where only deaths from the disease of interest are considered. Disease-free and progression-free survival, on the other hand, consider disease recurrence and progression as well as death as adverse outcomes. In seriously ill patients such as cancer patients with limited lifeexpectancy, the mortality rate may be considered as nearly constant. When the mortality rate is constant, the relationship between survival and time is described by a declining exponential function. Such a declining exponential approximation for life-expectancy (DEALE) is generally close enough for most clinical applications. Appendix 42.1 provides a brief overview of the assumptions and methods associated with utilization of the DEALE. Organ-specific toxicity can be measured along scales, which are difficult to summarize satisfactorily. Ultimately, treatment-related toxicity and symptoms related to the malignancy can be measured in terms of quality of life (QoL). Treatment and diseaserelated symptoms may be alleviated by supportive care measures, which have little or no direct effect on the patient’s malignancy. Just as survival and life-expectancy measure the quantity of clinical outcome, a measure of QoL is often sought. QoL, unfortunately, is an outcome for which there is not complete agreement on measurement or application. One approach to QoL measurement is to assess patient responses to health profile surveys assessing several specific dimensions thought to measure the various aspects of QoL (Table 42.2). Numerous instruments designed to measure QoL are available, including generic health status measures, several cancer-specific measures, and cancer site-specific measures for specific types of cancer.4,5 These measures are all limited by the lack of consensus on the specific dimensions of importance and the high variability of such measures. While easily administered in the context of a clinical trial, they are often

Table 42.2 Major quality-of-life dimensions111 1. Physical concerns (symptoms) 2. Functional ability 3. Family well-being 4. Emotional well-being 5. Treatment satisfaction 6. Sexuality/intimacy 7. Social functioning

relegated to measures of secondary importance, limiting their interpretation. Alternatively, QoL may be measured as a utility in terms of quantitative measures of patient preference for a certain outcome. Properly assessed utilities provide an opportunity to combine clinical and QoL outcome measures by adjusting actual longevity for QoL. Patient preferences may be assessed monetarily as a willingness-to-pay to achieve or avoid certain outcomes. More commonly, patient preferences are assessed as

Diagnosis and treatment of cancer in the elderly

911

an adjustment of the effectiveness of the clinical outcome measure such as survival time or life-expectancy. Such preferences may be assessed along a linear scale from 0 to 1. Alternatively, preferences can be assessed by a time trade-off method utilizing a standard reference gamble. The time in full health considered equivalent to the actual in the diseased state is a measure of QoL or quality-adjusted life-years (QALYs). The impact of QoL on

Figure 42.3 Time without symptoms of disease or toxicity of treatment (QTWIST) for a hypothetical patient, represented by the patient preference or utility on the vertical axis and time on the horizontal axis, illustrated by the following health states: induction therapy (t0 to t1), remission (t1 to t2), recurrence (t2 to t3), palliation (t3 to t4), and death (t4). Q-TWIST is the sum of the products of the time intervals and the time-specific utilities. Modified from Gelber et al.112 patients over time can also be assessment by dividing the clinical course of disease and its treatment into a finite number of healthcare states with defined length and with an associated utility weight (Figure 42.3). The sum over all health states of the product of the time spent in each state and the utility of each state will yield a summary measure

Comprehensive Geriatric Oncology

912

termed quality-adjusted time without symptoms of disease or toxicity of treatment (QTWIST).6 This provides an elegant method for the empiric measurement of qualityadjusted survival in actual clinical settings and a powerful tool for comparing patients receiving different interventions.7 While utility measures may permit the estimation of combined measures of clinical and QoL outcome, they are difficult and costly to measure, depend upon an understanding of various hypothetical scenarios, and have not found general applicability in the setting of controlled clinical trials. Clearly, more information is needed about the best way to measure QoL and how these measures change over time, as well as the perceived trade-offs between the quantity and quality of survival. The economic outcomes of cancer Measures utilized in evaluating the economic outcome of disease include charges for services, the cost of delivering care, and the revenues actually received for services. Charges are sometimes utilized as an intermediate measure of economic outcome. Although the ratio of costs to charges may be relatively constant in certain settings, charges often have an inconsistent relationship to the actual costs of care. There are many components to healthcare costs, which vary greatly in measurability and accessibility (Table 42.3). As a result, there is often little uniformity in the reporting

Table 42.3 Healthcare costs Direct • Medical: costs of delivering medical services (e.g. hospitalization, physician services, pharmaceutical) • Non-medical: costs incurred while receiving medical care (e.g. transportation, childcare) Indirect • Morbidity costs: economic value of days lost from work • Mortality costs: economic value of output lost owing to premature death Intangible • Pain and suffering • Loss of companionship

of healthcare costs in different studies.8,9 Direct costs include both the medical and nonmedical expenses associated with the diagnosis, treatment, prevention, and follow-up of patients. Such costs can be thought of as a product of the level of activity or resource utilization and the unit cost of this activity or resource in terms of man-hours or product consumed. Indirect costs represent the monetary losses to the patient, family, or society due to time lost from work due to disability or premature death from disease. Intangible costs are non-monetary, but nevertheless real social and emotional costs to the patient and family from illness. Since these are difficult to measure objectively, economic analyses

Diagnosis and treatment of cancer in the elderly

913

seldom consider the intangible costs of disease. In addition, most economic analyses do not consider the indirect costs of illness because of the effort required to extract and evaluate such information. In fact, most economic analyses are restricted to measures of the direct medical costs of disease, ignoring any additional expenses of medical care to the patient and family.10 Direct medical costs include several component costs, the proportion of which will vary with the type of illness. As shown in Figure 42.1(c) above, hospital care represents nearly one-half of all direct medical costs, making it the single largest share of direct healthcare expenditures for cancer. The next largest component of direct medical costs is physician services, representing one-fourth of expenditures. Approximately 10% of direct medical costs are allocated for medicines and nursing home care respectively. The costs of hospital care include multiple components, which will vary with the specific diagnosis and treatment. The total hospital operational costs include both the direct costs for specific service units, such as nursing care, pharmacy, blood bank, laboratory, and radiology, and indirect costs associated with support functions, including administration, engineering, janitorial, education, etc. The estimated cost of healthcare depends upon the ability to measure the effects of illness and the perspective from which costs are viewed. The perspectives on health-care costs will vary greatly between the hospital, the physician and other professional providers, the payer, the patient and family, and society as a whole. It is, perhaps, from the global perspective of society as well as the intimate perspective of the patient and family that the true total costs of illness are best understood. From a narrow perspective, the lowest cost will be associated with minimal diagnostic and therapeutic intervention. However, from a more global perspective, the importance of new effective therapeutic strategies, early detection with screening programs, and disease prevention or eradication through health education cannot be overemphasized. These will represent the ultimate answer to reducing healthcare costs while at the same time improving clinical outcomes. The cost of cancer in the elderly Approximately one-half of healthcare expenditures for cancer care are for patients aged 65 and over. As noted above, more than 90% is accounted for by five diagnoses: breast cancer (24%), colorectal cancer (24%), lung cancer (18%), prostate cancer (17%), and bladder cancer (8%).11 Perhaps the most readily available information on health-care costs associated with cancer in the elderly is based on Medicare coverage of cancer patients aged 65 and over.12 However, limitations on these data include the observations that billed charges to Medicare generally exceed actual costs and Medicare payments often do not reflect the actual costs for cancer care, which include nursing home costs and self-administered prescription medications. In a study from the Health Care Financing Administration (HCFA), Medicare payments for all covered services by site and stage over the first 17 years after diagnosis were studied for patients aged 65 and over with cancer of the lung, breast, prostate, colon, or bladder.13 Medicare payments for cancer were not uniform in this study, but varied by site, age at diagnosis, and time throughout the course of disease. Medicare payments from diagnosis to death correlate with patient survival, and are highest among those with bladder cancer ($57629) and lowest for those

Comprehensive Geriatric Oncology

914

with lung cancer ($29184). Higher total payments were seen among those diagnosed at an early stage, while the highest average annual payment was observed in those diagnosed at later stages of disease. The highest average Medicare payments were seen during the initial 6 months following diagnosis and during the final 6 months before death. The lowest average payments were found during the interval of continuing care and monitoring. Efforts to diagnose disease early through cancer screening may increase total lifetime Medicare costs by increasing survival. Thus, screening and prevention strategies must be evaluated by virtue of their ability to improve life-expectancy and QoL at an acceptable cost. Similar changes in cancer care costs in those aged 65 and over have been reported for members of a health maintenance organization diagnosed with colon, prostate, or breast cancer.14 The greatest average cost was found during the final 6 months of life, followed by the initial 6 months following diagnosis. The costs of initial and terminal care were generally somewhat less among the elderly than among younger individuals. While the total costs of continuing care were higher among the elderly, the net cost of cancer care after deducting the age- and sex-specific costs observed for noncancer patients was actually lower among the elderly. Economic analyses Economic analyses must consider the clinical outcome as well as the economic outcome or cost.15,16 Economic

Table 42.4 Economic analysis: types of studies Methodology

Cost unit

Effect unit

Cost-of-illness

Monetary

Cost-minimization

Monetary

Equal

Cost-effectiveness

Monetary

LYSa

Cost-utility

Monetary

QALYb

Cost-benefit

Monetary

Monetary

a

Life-years saved. Quality-adjusted life-years.

b

analyses are seldom needed or of value when both an improved clinical outcome and reduced cost are evident or when both a worse clinical outcome and increased cost are found. Economic analyses are called for and of greatest value when the clinical outcome is improved but the cost is increased. The most efficient program will be the one with the lowest cost per unit of benefit. Economic analyses are also of value when the cost is greatly reduced, but the clinical outcome is not as good. The most efficient program would be the one with the greatest benefit per unit cost. There are different types of economic analyses based on the available data and the purpose to which the analysis will be applied (Table 42.4). Perhaps the most common type of economic study involves an analysis of administrative databases collected on the

Diagnosis and treatment of cancer in the elderly

915

basis of healthcare payer. These are often called cost-of-illness studies, and seek to describe the individual and total costs defining the economic burden of disease. Commonly utilized measures include the incidence and prevalence of disease, measures of disease severity (including mortality), and direct and indirect costs (including avoidable costs or the value of resources used, as well as willingness-to-pay—reflecting what society or an individual would pay to avoid an illness). Such studies ultimately attempt to estimate and compare the resource consequences of disease and treatment. Cost-minimization studies attempt to compare the costs of alternative strategies assumed to have similar clinical outcomes. Commonly utilized measures include the net cost or average cost for equivalent outcomes or the difference (margin) in such outcomes between treatment alternatives. Such an analysis seeks to identify the strategy associated with the lowest cost. Cost-effectiveness studies compare strategies that may have both different clinical effects and different associated costs. Commonly employed measures include the difference (margin) in cost per unit effect, the difference (margin) in effectiveness per unit of cost, and the marginal cost-effectiveness or cost-effectiveness ratio, represented by the marginal cost divided by the marginal effectiveness (e.g. increase in cost per lifeyear gained). The average cost-effectiveness may also be presented. The goal of such a study is to define the approach with the greatest effectiveness for the least cost. Cost-utility studies compare strategies that may have both different clinical effects adjusted for patient preference or utility and different associated costs. Commonly employed measures include the difference (margin) in cost per unit utility, the difference (margin) in quality-adjusted effectiveness per unit of cost, and the marginal cost-utility or cost-utility ratio, represented by the marginal cost divided by the marginal utility (e.g. increase in cost per QALY gained). The goal of such a study is to define the approach with the greatest quality-adjusted effectiveness associated with the least cost. Cost-benefit studies compare strategies with different outcomes using common monetary units. Commonly employed measures include the net cost-benefit (e.g. in dollars) and the cost-benefit ratio (in units). Such studies are severely limited by the requirement that outcomes as well as costs must be assigned a monetary value. Such economic studies may involve retrospective analyses of specific population cohorts based on disease or other criteria. Increasing interest has developed over the past several years in either retrospective or prospective economic analyses of cancer clinical trials. One of the most valuable methods for performing economic analyses in the evaluation of cancer care involves decision analytic models. Decision analytic models require the specification of a model structure where decision (choice) points represent the focus of analysis.17 Modeling requires the explicit consideration of all decision points as well as their relationship to chance events and outcomes. This is generally schematized in the form of a decision tree where each branching point represents a chance or decision point and the leaves represent endpoints or outcomes. Analysis of such models also requires the specification of initial estimates for the probability of each event and the value of each outcome. These estimates may be based on experience, expert opinion, or data available from the clinical literature (evidence). Decision models can be analyzed in a variety of ways. The simplest analysis involves calculating the expected value of each choice at a decision point by a process of folding

Comprehensive Geriatric Oncology

916

back the tree. Folding back involves multiplying the assigned outcome value of each branch by the probability of that outcome and summing over all of the branches of the immediately preceding chance event. This sum represents the expected value of that event. The expected value now becomes the outcome value, and the process is repeated by multiplying this value by its probability. When a decision point is reached, the choice associated with the greatest expected value is the preferred choice. One of the greatest strengths of decision analysis is the ability to vary any of the assumed probabilities and outcome values as well as the model structure over a range of reasonable estimates in order to determine how such changes alters the expected value of the choices and the optimal decision. In such sensitivity analyses, a threshold value of the variable may be found at which the expected value of two choices are exactly equal. Threshold analysis can be further elaborated by varying two or more variables simultaneously in order to define a threshold function or family of threshold functions. Decision models are particularly suited to economic analyses by permitting the simultaneously consideration of more than one type of outcome measure (e.g. clinical outcomes and economic outcomes). In addition, costs and benefits can be modified by procedures to incorporate considerations of QoL. Such procedures permit economic analyses based on cost-benefit, cost-minimization, cost-effectiveness, and cost-utility functions. In the most basic scenario involving one disease and a choice between treatmertt or no treatment, there are four possible outcomes. Ideally, one would initiate treatment when the disease is present and withhold treatment when the disease is absent. Under realistic clinical conditions of uncertainty, however, treatment may be initiated when the disease is not present and treatment may be withheld when the disease is present. The expected value of each treatment strategy depends upon both the disease prevalence and the utility of each possible outcome. Clearly, the decision choice associated with the greatest expected value is the preferred one. The threshold prevalence of disease for choosing the optimal treatment strategy relates to the ratio of benefits and costs reflected in the utilities incorporated into the model. As the ratio of benefits to costs increases, the threshold changes so as to increase the indications for treatment (see Chapter 22 and Appendix 42.2). Cost-effectiveness analysis The majority of clinical investigations report outcome measured in terms of clinical benefit or quality-adjusted benefit. When clinical effectiveness is not an issue, an economic outcome such as cost may be the preferred measure of interest. In most realistic clinical circumstances, however, the measurement of both clinical and economic outcomes offers a more accurate and valuable summary of the impact of disease and treatment on the patient, family, and society. There are a variety of economic analyses that combine measures of clinical and economic outcome together into a single measure of benefit and cost, including cost-effectiveness and cost-utility analyses.18 These measures differ substantially from one another in makeup and application, and are sometimes confused with one another.19 There is increasing concern for an improved

Diagnosis and treatment of cancer in the elderly

917

understanding of these methods, including the proper utilization and reporting of such economic analyses.20 Cost-benefit analysis is conducted by converting clinical benefits into the same economic measure as costs in order to combine them in a single term. This approach requires placing an economic value on the clinical outcome measure such as survival or life-expectancy. Obviously, the measure of value for life or the willingness to pay to avoid certain events will vary with ability to pay among different socioeconomic groups. The most commonly utilized combined measure is that of cost-effectiveness. This approach measures the added clinical benefit of one approach over another (marginal benefit) and the added cost of that strategy over the other (marginal cost). Costeffectiveness combines these two measures into a summary measure, which can be either cost-based or effectiveness-based. The cost-based measure is most commonly utilized, and calculates the added cost per unit of clinical benefit, for example cost in dollars per year of life gained (marginal cost-effectiveness). The effectiveness-based measure calculates the amount of added benefit per unit of economic outcome, for example years of life gained per dollar. Cost-effectiveness is most often utilized to compare management strategies based on this common measure. The measures of clinical outcome can be adjusted for QoL by assigning a utility value to different health outcome states. A cost-utility analysis can be conducted in the same fashion as a cost-effectiveness analysis by utilizing a quality-adjusted outcome measure such as QALYs as the clinical outcome of interest. By measuring the added quality-adjusted benefit (marginal benefit) and the added cost of a clinical strategy (marginal cost), the cost per unit of quality-adjusted clinical benefit can be calculated, for example cost in dollars per QALY gained (marginal cost-utility). In order to better understand the concepts associated with cost-effectiveness and costutility analysis, it is useful to refer to the adaptation known as the cost-effectiveness plane, illustrated in Figure 42.4. By convention, the vertical axis on the plane represents the incremental cost, while the horizontal axis represents the incremental effectiveness or utility. Any combination of incremental cost and effectiveness in the upper left corner, associated with increased cost and decreased benefit, should lead one not to accept a new approach, while a combination in the lower right corner, associated with reduced cost and increased benefit, should lead to always adopting a new intervention. In the other two corners, the choice is not as clear, and will vary based on the adoption of an acceptance line determined by an acceptable ratio of incremental cost and incremental benefit. Above the line, the change in benefit is not worth the change in cost, while below the line, the new treatment is favored because of the comparative increased effectiveness or decreased cost. The complexity associated with the application of these analyses is illustrated by recognizing that the values of the incremental benefit and cost are estimates and (like most

Comprehensive Geriatric Oncology

918

Figure 42.4 The cost-effectiveness plane represented by the change in cost or incremental cost on the vertical axis and the change in effectiveness (incremental effectiveness) on the horizontal axis for a hypothetical treatment. Treatment is always acceptable when it is associated with an increase in effectiveness and a reduction in cost (lower right rectangle). Treatment is never acceptable when it is associated with an increase in cost and a reduction in effectiveness (upper left rectangle). Treatment may or may not be acceptable when associated with either an increase in both effectiveness and cost or a decrease in both cost and effectiveness, depending upon the maximum acceptable costeffectiveness ratio represented by the diagonal line. The point estimate of the cost effectiveness ratio is represented by a point on the cost-effectiveness plane. Both effectiveness and cost

Diagnosis and treatment of cancer in the elderly

919

contributions to the estimate have associated variability represented by confidence limits. The confidence limits on both effectiveness and cost define the confidence box. The confidence box represents a conservative estimate of the joint distribution of effectiveness and cost, which more reasonably would be represented by an ellipse defining the covariance of the measures. Modified from Grieve.113 estimates) have considerable uncertainty associated with them, illustrated by the associated confidence limits. Since both cost and effectiveness are free to vary (although they are often correlated), the variance structure of the estimated cost-effectiveness ratio is often complex in reality. For simplicity, the variance or confidence limits of each separate measure are often thought of as defining a ‘confidence box’. Such a measure of uncertainty is often overly conservative, but much easier to define in practice than that determined by the joint distribution of the two variables. It should be evident, however, that the variability of these measures adds an additional degree of complexity to the decision whether a given estimate of cost-effectiveness should lead to the application or avoidance of a new technology. It is often necessary and appropriate to adjust changes in the cost or benefit measures for factors related to time or other criteria. The most common adjustment consid- ered is related to cost discounting due to the frequent preference for delaying present costs to the future. Appen- dix 42.3 provides a brief description of cost discounting between present and future costs. In a similar fashion, future benefits can be adjusted to the present for comparison purposes based on the usual preference for immediate benefit. It is important to note that summary measures of cost-effectiveness and cost-utility are marginal measures and do not provide information on the absolute amount of benefit or cost. Therefore, a strategy can potentially appear superior in terms of cost-effectiveness or cost-utility and yet have substantially lower absolute effectiveness or utility. In other words, a strategy may have substantially lower cost and appear more cost-effective, even though it may have substantially lower clinical benefit. It is important, therefore, to measure both the absolute as well as the marginal measures of benefit and cost in such analyses. When properly estimated and presented, such methods are of value in objectively comparing strategies competing for limited resources. Cost-effectiveness studies in elderly cancer patients A wide variety of studies have been performed assessing the cost-effectiveness of cancer interventions, including screening and prevention strategies, diagnostic approaches,

Comprehensive Geriatric Oncology

920

therapy for early-stage and advanced disease, and supportive measures during treatment and at the end of

Figure 42.5 Bar chart illustrating the comparative estimated costeffectiveness of several interventions for the treatment of cancer from various studies. ABMT, autologous bone marrow transplantation; AML, acute myeloid leukemia; Adj CMF, adjuvant cyclophosphamide/methotrexate/ 5fluorouracil; CAE, cyclophosphamide/ doxorubicin/etoposide; NSCLC, nonsmall cell lung cancer; Adj IFN, adjuvant interferon-α; HL, Hodgkin lymphoma. Modified from Smith et al.114 life (Figure 42.5). Few studies, however, have specifically focused on the elderly patient with cancer. Nevertheless, each of these areas raises unique issues related to the care of the elderly and the risks and benefits of specific interventions.21 Cancer screening and early diagnosis Economic assessments of screening and diagnostic procedures are inherently more difficult than those of therapeutic interventions.22 Economic analyses of cancer screening

Diagnosis and treatment of cancer in the elderly

921

programs for several malignancies have been conducted. Decision analytic models have proven to be efficient and effective methods of economic analysis in order to develop guidelines for screening programs.23 These models are generally based on available incidence data, knowledge of the natural history of the disease, and available information on test performance and cost. The results of an economic evaluation of cancer screening clearly depend upon the perspective of the analysis.24 The elderly present both unique opportunities as well as important obstacles to the application of currently available screening methods.25–30 The increasing prevalence of most cancers among the elderly increases the predictive value of positive screening tests in this population. Many of the malignancies affecting the elderly are asymptomatic in their earliest phases, with patients coming to medical attention only after the onset of symptoms, when they already have advanced disease. Early diagnosis by effective screening methods may permit treatment when curative potential is reasonably high. Alternatively, the limited life-expectancy of the elderly and the frequency of comorbid conditions complicate and limit the value of effective treatment (see Chapter 22). It is precisely this type of complex trade-off of benefits and risks that calls for the application of cost-effectiveness analysis in clinical and public health decision-making. The relative 5-year survival rate for cervical cancer in women aged 65 and over is approximately 50%, compared with 65% in women under 65.3 Despite marked reductions in mortality from cervical cancer in younger patients, there has been no decrease in mortality in women aged over 70.31 The high frequency of abnormal smears and the high incidence of invasive cervical cancer among elderly women appear to relate to a lack of screening in this population. Compliance with recommended screening practice in women over 70 has been found to be only about one-half that among younger women. In 1990, Papanicolau smear screening for cervical cancer was adopted as a preventive health service covered by Medicare. While there is substantial evidence that cervical cancer screening is effective, few studies have included a sufficient number of elderly women to draw definitive conclusions. A study by the US Office of Technology Assessment of the cost-effectiveness of cervical cancer screening concluded that screening the elderly will not save money, but the cost per additional year of life saved is quite low.32 Utilizing a decision analysis format based on a Markov model, the impact of screening women aged 65–109 was studied.33 Triennial screening was found to reduce mortality from cervical cancer by 75% at a cost of $2254 per year of life saved. Annual screening resulted in an increase in cost to $7345 per year of life saved. These results were critically dependent upon the quality of the Papanicolau smear. Screening was most efficiently applied to women who had not had regular screening, and was least efficient in those who had demonstrated consistently negative cervical cytologies. While limiting the analysis to women up to age 75, Eddy34 demonstrated that there was little difference in clinical outcome, but large increases in cost as the frequency of cervical screening changed from every 4 years to every year. This led to screening guide-lines calling for a reduced frequency of screening if several annual screens were negative. The potential for more cost-effective methods for cervical cancer screening in the elderly appear promising with emerging technologies.35 The cost-effectiveness of the various screening modalities for cervical cancer has recently been compared.36 Medicare provides coverage for cervical cytology screening in average-risk women once every 24 months. In high-risk individuals

Comprehensive Geriatric Oncology

922

and those with a previous abnormal smear, coverage for screening every 12 months is provided. The incidence of colorectal cancer increases dramatically with increasing age, although age-specific survival with this disease has remained relatively constant. The early stages of the disease may be entirely asymptomatic, resulting in the majority of patients having advanced disease at presentation. When diagnosed at an early, asymptomatic stage of disease, the vast majority of patients may be cured with available treatments. Screening for fecal occult blood has been shown to reduce mortality from colorectal cancer in a population aged 50–80.37 However, the cost-effectiveness of this approach continues to be debated.38–41 Screening by fecal occult blood testing (FOBT) has low sensitivity and low specificity. Sigmoidoscopy has been shown to increase the likelihood of detecting early-stage disease.42 Screening colonoscopy is highly sensitive and specific, but very expensive. A cost-effectiveness model developed by the Office of Technology Assessment found that annual FOBT would detect 17% of cancers at a cost of $35000 per year of life saved.43 Screening schedules that included periodic sigmoidoscopy would prevent a greater population of cancers, but would cost between $43000 and $47000 per year of life saved. Although costly, colorectal cancer screening with periodic sigmoidoscopy appears to be a reasonably cost-effective preventive strategy in the elderly.44 However, one-time screening with FOBT and sigmoidoscopy fails to find advanced colonic neoplasms in one-fourth of cases.45 Colonoscopy every 3–5 years for high-risk individuals based on personal and family histories may be the most effective and cost-effective screening method.46 An economic analysis comparing various colorectal screening procedures has recently been reported.47 Care provides coverage for average-risk individuals for annual FOBT, sigmoidoscopy every 4 years, or colonoscopy every 10 years. For individuals over age 50 at high risk for colon cancer, coverage is provided for screening colonoscopy every 2 years. The risk of breast cancer increases rapidly with increasing age, with more than 75% of breast cancers occurring in women aged 50 or over. While previous studies suggested that elderly women with breast cancer fared poorly because of less aggressive management, several recent studies have demonstrated that elderly women actually experience a greater survival than younger women when treated in a similar fashion.48 Breast cancer screening incorporating breast self-examination, physical examination, and periodic mammography have been shown to be effective at diagnosing patients at an earlier stage of disease, resulting in a greater potential for curability.49 There remain many unresolved issues related to the cost-effectiveness of breast cancer screening among the elderly, including the frequency of screening, the type of screening, and the value of screening in the very elderly. There are also many barriers to the universal utilization of breast cancer screening among the elderly, including cost, education, anxiety, and physician compliance. Currently, the American Cancer Society and the US National Cancer Institute recommend monthly breast self-examination, yearly physician examination, and annual mammography over the age of 50. Randomized trials provide greater evidence for the effectiveness of breast cancer screening than for screening of any other cancer. Over the past three decades, eight major randomized trials of breast cancer screening with mammography have been analyzed.50 These studies have demonstrated a mortality reduction in women aged 50–69 of approximately 30%. A meta-analysis of screening mammography concluded that screening mammography of women aged 50–74

Diagnosis and treatment of cancer in the elderly

923

reduced the risk of mortality by more than 25%.51 Numerous cost-effectiveness studies of breast cancer screening have been conducted.52–54 The estimated cost-effectiveness of breast cancer screening has varied between $20000 and $50000 per year of life gained.55 The cost-effectiveness of breast cancer screening recruitment strategies has also been evaluated, revealing that personal strategies were more cost-effective than public strategies.56 Decision analysis models have shown that the cost per year of life saved by breast cancer screening decreases with increasing age to somewhat less than $30000 per year of life saved in the 65–70-year age group, after which it increases with increasing age, approaching $50000 per year of life saved in the 80–85-year age group.57 A decision analysis model generated to look at the effects of comorbid conditions found net benefits from breast cancer screening after adjustment for changes in long-term QoL in elderly women of all ages.58 However, data on the effectiveness of breast cancer screening remain very limited in women aged 75 and over. There are many outstanding questions concerning the application of breast cancer screening in very elderly women.59–62 Medicare provides coverage for women of average risk for a clinical breast examination every 24 months and for film or digital mammography annually. Prostate cancer is the most frequently diagnosed cancer in men in the USA and the second leading cause of cancer mortality after lung cancer.3 Prostate cancer is primarily a disease of older men, with a median age at diagnosis of 77 and an age-specific incidence of over 1% annually above the age of 75. Prostate cancer is often asymptomatic unless advanced disease is present. An analysis of benefit and risk is complicated by two clinical features of prostate cancer. First, while the prevalence of prostate cancer is extremely high in elderly men, many cases do not metastasize and cause life-threatening symptoms. Second, the therapeutic options for localized prostate cancer, including surgical resection and radiation therapy, are not completely effective and are associated with considerable morbidity. Utilizing generous assumptions about the effectiveness of primary therapy, a cost-effectiveness analysis based on data from the American Cancer Society National Prostate Cancer Detection Project concluded that the combination of digital rectal examination (DRE) and prostate-specific antigen (PSA) represents an economical and ethical screening method for prostate cancer.63 In other studies utilizing a decision analytic model, DRE alone was not found to reduce mortality at any age. Screening with either PSA or transrectal ultrasound (TRUS) was found to increase life-expectancy, but actually decreased quality-adjusted life-expectancy.64 All strategies were found to increase costs, and selecting only high prevalence subpopulations did not improve the benefit of screening.65,66 Debate continues over the value and cost-effectiveness of prostate cancer screening in elderly men.67 Medicare provides coverage for DRE and PSA annually for men aged 50 and over. Cancer treatment and supportive care The cost-effectiveness of treatment strategies for cancer has only received attention in recent years. The levels and distribution of costs of cancer treatment vary considerably between cancer types, and much of this variability remains unexplained.68 Smith et al69 have presented an excellent review of cost-effectiveness studies of cancer treatment based on decision analytic models. Relatively few studies have specifically addressed the cost-effectiveness of early-stage disease in elderly cancer patients. Without consideration

Comprehensive Geriatric Oncology

924

of age, breast-conserving surgery has been shown to yield better quality-adjusted survival than mastectomy,70 and at no greater cost.71 Adjuvant chemotherapy in premenopausal women has been shown to add benefit for all women at acceptable costs of from $4500 to $22000 per QALY gained.72,73 Adjuvant chemotherapy appears to prolong the survival of older women to a lesser extent than younger women. A cost-effectiveness analysis of adjuvant chemotherapy in women aged 60–80 with lymph node-positive breast cancer estimated costs per QALY gained that ranged from $28200 for a 60-year-old to $57100 for an 80-year-old.74 A study of the cost-effectiveness of adjuvant therapy for stage III colorectal cancer without regard to age estimated costs per year of life saved as between $2000 and $5000.75 Hormonal suppression therapy has been shown to be reasonably costeffective in elderly men with prostate cancer.76 Several cost-effectiveness studies of firstline leukemia and lymphoma therapy have also been presented, but with little direct attention to the elderly population.77–79 There have been several cost-effectiveness analyses of treatment for advanced cancer. Few of these, however, have specifically addressed the elderly population. Cost-effectiveness in terms of incremental costs per year of life gained has generally been estimated in the range of $20000–50000 for standard-dose therapy.80–85 Similarly, cost-effectiveness studies of high-dose therapy with autologous bone marrow support have yielded cost estimates of $25000–100000 per year of life gained.86–87 Decision analytic methods have also been utilized to address the costs associated with the use of supportive care technologies in patients undergoing cancer treatment.88–91 The colony-stimulating factors are a good example of a new technology finding a defined role in the management of elderly patients with cancer receiving systemic chemotherapy.89,92,93 Extensive reviews of the economics of the hematopoietic growth factors have been provided, helping to define their role in clinical practice guidelines.94–97 In a meta-analysis of colony-stimultating factors utilized therapeutically, eight randomized controlled trials were identified of patients with solid tumors or non-Hodgkin lymphoma (NHL).98 Summary estimates demonstrated a 64% reduction in the odds of neutropenia for more than 5 days and a 52% reduction in the proportion of patients hospitalized beyond 10 days (p<0.001). In addition, a meta-analysis has been presented of neutropenic complications as well as growth factor use in elderly patients with NHL or in acute leukemia.93 The risk of febrile neutropenia in elderly patients with NHL receiving CHOP-like regimens varied from 25% to 40%. Prophylactic growth factor use was associated with a reduction in risk of febrile neutropenia of approximately 50% in elderly patients with NHL. In a study of adjuvant breast cancer treatment among approximately 20000 women in the USA, increasing age was a significant independent predictor in a multivariate model of risk of febrile neutropenia and reduced dose intensity.99 The colony-stimulating factors have been the subject of a number of economic analyses comparing treatment options based on differences in resource utilization or cost. Clinical decision models have been very useful in such analyses by studying the trade-off between the added cost of growth factor use and any reduction in risk or duration of febrile neutropenia.100–101 The colony-stimulating factors have demonstrated both clinical and economic benefit in the support of patients receiving cancer chemotherapy. Recently published studies have confirmed and extended the role of these agents to the supportive management of elderly patients with cancer.

Diagnosis and treatment of cancer in the elderly

925

There has been little systematic appraisal of the cost-effectiveness of palliative care for patients near the end of life, regardless of age.102–104 There is now great interest in incorporating not only QoL measures but also economic outcome measures into prospective randomized clinical trials, particularly in the elderly patient with cancer.105–

109

Conclusions Cancer care is associated with both clinical and economic outcomes of interest. There is increasing interest in measuring the impact of cancer and cancer treatment on both the quantity and quality of survival. Methods are available to evaluate management strategies based on both the clinical and economic outcomes of cancer. These methods have only recently been introduced into the study of cancer care in the elderly. Over the next decade, we can anticipate a great increase in our understanding of the effectiveness and costs of cancer screening, treatment, and supportive care among the elderly. This should greatly aid both clinical and health planning to provide optimal quality and cost-effective care to the elderly patient with cancer. References 1. Jemal A, Thomas A, Murray T, Thun M. Cancer statistics 2002. CA Cancer J Clin 2002; 52:23– 47. 2. Lyman GH. Essentials of clinical decision analysis: a new way to think about cancer and aging. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:11–25. 3. Miller BA, Ries LAG, Hankey BF et al (eds). SEER Cancer Statistics Review: 1973–1990. Bethesda, MD: NIH Publication No. 93–2789, 1993. 4. Cella DF, Bonomi AE. Measuring quality of life: 1995 update. Oncology 1995; 9:47–60. 5. Ganz PA. Impact of quality of life outcomes on clinical practice. Oncology 1995; 9:61–5. 6. Gelber RD, Goldhirsch A, Cavelli F. Quality-of-life-adjusted evaluation of adjuvant therapy for operable breast cancer. Ann Intern Med 1991; 114:621–8. 7. Weeks J. Measurement of utilities and quality-adjusted survival. Oncology 1995; 9:67–70. 8. Brown ML. The national economic burden of cancer: an update. J Natl Cancer Inst 1990; 82:1811–14. 9. Schuette HL, Tucker TC, Brown ML et al. The costs of cancer care in the United States: implications for action. Oncology 1995; 9: 19–22. 10. Vincenzino JV. Health care costs: market forces and reform. Oncology 1995; 9:367–372. 11. Brown ML, Fintor L. The economic burden of cancer. In: Cancer Prevention and Control. New York: Marcel Dekker, 1995. 12. Maker MS, Kessler LC. Site-specific treatment costs in cancer. In: Cancer Care and Cost. Chicago: Health Administration Press, 1989. 13. Riley GF, Potosky AL, Lubitz JD, Kessler LG. Medicare payments from diagnosis to death for elderly cancer patients by stage at diagnosis. Med Care 1995; 33:828–41. 14. Taplin SH, Barlow W, Urban N et al. Stage, age, comorbidity and direct costs of colon, prostate and breast cancer care. J Natl Cancer Inst 1995; 87:417–26. 15. Schulman KA, Yabroff KR. Measuring the cost-effectiveness of cancer care. Oncology 1995; 9:523–33.

Comprehensive Geriatric Oncology

926

16. Lyman GH, Djulbegovic B. Understanding economic analyses. Evidence-Based Oncol 2001; 2:2–5. 17. Parker SG, Kassirer JP. Decision analysis. N Engl J Med 1987; 316: 250–8. 18. Detsky AS, Naglie IG. A clinician’s guide to cost-effectiveness analysis. Ann Intern Med 1990; 113:147–54. 19. Udvarhelyi IS, Colditz GA, Rai A, Epstein AM. Cost-effectiveness and cost-benefit analyses in the medical literature: Are the methods being used correctly? Ann Intern Med 1992; 116:238– 44. 20. Task Force in Principles for Economic Analysis of Health Care Technology. Economic analysis of health care technology. Ann Intern Med 1995; 122:61–70. 21. Lyman GH, Kuderer N, Balducci L. Cancer care in the elderly: cost and quality of life considerations. Cancer Control 1998; 5:347–54. 22. Mushlin AJ, Ruchlin HS, Callahan MA. Cost effectiveness of diagnostic tests. Lancet 2001; 358:1353–5. 23. Walker LC, Covinsky KE. Cancer screening in elderly patients: a framework for individualized decision making. JAMA 2001; 285: 2750–56. 24. Mansley EC, McKenna MT. Importance of perspective in economic analyses of cancer screening decisions. Lancet 2001; 358: 1169–73. 25. Freer CB. Screening the elderly. BMJ 1990; 300:1447–8. 26. Oddone EZ, Feussner JR, Cohen HS. Cancer screening older patients for cancer saves lives. Clin Geriatr Med 1992; 8:51–67. 27. List ND. Problems in cancer screening in the older patient. Oncology 1992; 6:25–30. 28. Samet JM, Hunt WC, Lerchen ML, Goodwin JS. Delay in seeking care for cancer symptoms: a population-based study of elderly New Mexicans. J Natl Cancer Inst 1988; 80:432–38. 29. Suarez L, Lloyd L, Weiss N et al. Effect of social networks on cancer-screening behavior of older Mexican-American women. J Natl Cancer Inst 1994; 86:775–9. 30. List ND, Kucuk O. Approaches to and effectiveness of current cancer interventions in the elderly. Oncology 1992; 6:31–8. 31. Power EJ. Pap smears, elderly women and Medicare. Cancer Invest 1993; 11:164–8. 32. Muller C, Mandelblatt J, Schacter CJ et al. Costs and Effectiveness of Cervical Cancer Screening in Elderly Women. Washington, DC: Office of Technology Assessment, 1990. 33. Fahs MC, Mandelblatt J, Schechter C, Muller C. Cost effectiveness of cervical cancer screening for the elderly. Ann Intern Med 1992; 117:520–7. 34. Eddy DM. Screening for cervical cancer. Ann Intern Med 1990; 113: 214–16. 35. Solomon D. Screening for cervical cancer: prospects for the future. J Natl Cancerlnst 1993; 85:1018–19. 36. van den Akker-van Marle ME, van Ballegooijen M, van Oortmarssen GJ et al. Costeffectiveness of cervical cancer screening: comparison of screening policies. J Natl Cancer Inst 2002; 94:193–204. 37. Mandel JS, Bond JH, Church TR et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. N Engl J Med 1993; 328:1365–71. 38. Lang CA, Ransohoff DF. Fecal occult blood screening for colorectal cancer: Is mortality reduced by chance selection for screening colonoscopy? JAMA 1994; 271:1011–13. 39. Helm JF, Russo MW, Biddle AK et al. Effectiveness and economic impact of screening for colorectal cancer by mass fecal occult blood testing. Am J Gastroenterol 2000; 95:3250–8. 40. Gyrd-Hansen D. Fecal occult blood tests. A cost-effectiveness analysis. Int J Technol Assess Health Care 1998; 14:290–301. 41. Whynes DK, Neilson AR, Walker AR, Hardcastle JD. Fecal occult blood screening for colorectal cancer: Is it cost-effective? Health Econ 1998; 7:21–9. 42. Winawer SJ, Flehinger BJ, Schottenfeld D, Miller DG. Screening for colorectal cancer with fecal occult blood testing and sigmoidoscopy. J Natl Cancer Inst 1993; 85:1311–18.

Diagnosis and treatment of cancer in the elderly

927

43. Wagner JL, Herdman RC, Wadha S. Cost-effectiveness of colorectal cancer screening in the elderly. Ann Intern Med 1991; 115: 807–17. 44. Eddy DM. Screening for colorectal cancer. Ann Intern Med 1990; 113:373–84. 45. Lieberman DA, Weiss DG. One-time screening for colorectal cancer with fecal occult-blood testing and examination of the distal colon. N Engl J Med 2001; 345:555–560. 46. Sonnenberg A, Delco E. Cost-effectiveness of a single colonoscopy in screening for colorectal cancer. Arch Intern Med 2002; 162: 163–8. 47. Vijan S, Lwang EW, Hofer TP, Hayward RA. Which colon cancer screening test? A comparison of costs, effectiveness and compliance. Am J Med 2001; 111:593–601. 48. Lyman GH, Lyman S, Balducci L et al. Age and the risk of breast cancer recurrence. Cancer Control 1996; 3:421–7. 49. Sharpiro S, Venet W, Strax P et al. Ten-to-14-year effect of screening on breast cancer mortality. J Natl Cancer Inst 1982; 69: 349–355. 50. Fletcher SW, Black W, Harris R et al. Report of the International Workshop on Screening for Breast Cancer. J Natl Cancer Inst 1993; 85:1644–56. 51. Kerlikowski K, Grady D, Rubin SM et al. Efficacy of screening mammography: a metaanalysis. JAMA 1995; 273:149–54. 52. Eddy DM. Screening for breast cancer. Ann Intern Med 1989; 111: 389–99. 53. Okubo I, Glick H, Frankin H et al. Cost-effectiveness analysis of mass screening for breast cancer in Japan. Cancer 1991; 67: 2021–29. 54. Brown ML. Sensitivity analysis in the cost-effectiveness of breast cancer screening. Cancer 1992; 69:1963–7. 55. Mushlin AI, Fintor L. Is screening for breast cancer cost-effective? Cancer 1992; 69:1957–62. 56. Hurley SF, Jolley DJ, Livingston PM et al. Effectiveness, cost and cost-effectiveness of recruitment strategies for a mammography screening program to detect breast cancer. J Natl Cancer Inst 1992; 84:855–63. 57. Brown ML. Economic considerations in breast cancer screening of older women. J Gerontol 1992; 47:51–8. 58. Mandelblatt JS, Wheat ME, Manane R et al. Breast cancer screening for elderly Women with and without comorbid conditions: a decision analysis model. Ann Intern Med 1992; 116:722–30. 59. Constanza ME. Issues in breast cancer screening in older women. Cancer 1994; 74:2009–15. 60. Nattinger AB, Goodwin JS. Screening mammography for older women: a case of mixed messages. Arch Intern Med 1992; 152: 922–5. 61. Kerlikowske K, Salzmann P, Phillips KA et al. Continuing screening mammography in women aged 70 to 79 years: impact on life expectancy and cost-effectiveness. JAMA 1999; 282:2156– 63. 62. Torgerson DJ, Gosden T. Clinical and economic arguments favour extension to upper age limit for breast screening. BMJ 1998; 316: 1829. 63. Lettrup PJ, Goodman AC, Mettlin CJ. The benefit and cost of prostate cancer early detection. CA Cancer J Clin 1993; 43:134–49. 64. Krahn MD, Mahoney JE, Eckman MH et al. Screening for prostate cancer: a decision analytic view. JAMA 1994; 272:773–80. 65. Krahn MD, Coombs A, Levy IG. Current and projected annual direct costs of screening asymptomatic men for prostate cancer using prostate-specific antigen. AMAJ 1999; 160:49–57. 66. Homberg H, Carlsson P, Lofman O, Varenhorst E. Economic evaluation of screening for prostate cancer: a randomized population based programme during a 10-year period in Sweden. Health Policy 1998; 45:133–47. 67. Chodak GW. Screening for prostate cancer: the debate continues. JAMA 1994; 272:813–14. 68. Chirikos T. Cancer economics: on variations in the costs of treating cancer. Cancer Control 2002; 9:59–66. 69. Smith TJ, Hillner BE, Desch CE. Efficacy and cost-effectiveness of cancer treatment: rational allocation of resources based on decision analysis. J Natl Cancer Inst 1993; 85:1460–74.

Comprehensive Geriatric Oncology

928

70. Verhoef LC, Stalpers LJ, Verbeck AL et al. Breast-conserving treatment or mastectomy in early breast cancer: a clinical decision analysis with special reference to the risk of local recurrence. Eur J Cancer 1991; 27:1132–7. 71. Warren JL, Brown ML, Pay MP et al. Costs of treatment for elderly women with early-stage breast cancer in fee-for-service settings. J Clin Oncol 2002; 20:307–16. 72. Beck JR, Pauker SG. The Markov process in medical prognosis. Med Decis Making 1983; 3:419–58. 73. Smith, TJ, Hillner BE. The efficacy and cost-effectiveness of adjuvant therapy of early breast cancer in pre-menopausal women. J Clin Oncol 1993; 11:771–6. 74. Desch CE, Hillner BE, Smith TJ, Retchin SM. Should the elderly receive chemotherapy for node-positive breast cancer? A cost-effectiveness analysis examining total and active lifeexpectancy outcomes. J Clin Oncol 1993; 11:777–82. 75. Brown ML, Nayfield SG, Shibley LM. Adjuvant therapy for stage III colon cancer: economics returns to research and cost-effectiveness of treatment. J Natl Cancer Inst 1994; 86:424–30. 76. Bayoumi AM, Brown AD, Garber AM. Cost-effectiveness of androgen suppression therapies in advanced prostate cancer. J Natl Cancer Inst 2000; 92:1731–9. 77. Djulbegovic B, Hollenberg J, Woodcock TM et al. Comparison of different treatment strategies for diffuse large cell lymphomas: a decision analysis. Med Decis Making 1991; 11:1–8. 78. Rutherford CJ, Deforges JF, Barnett HI et al. The decision between single- and combinedmodality therapy in Hodgkin’s disease. Am J Med 1982; 72:63–70. 79. Lobo PJ, Powles RL, Hanrahan A et al. Acute myeloblastic leukemia—a model for assessing value for money for new treatment programs. BMJ 1991; 302:323–6. 80. Rees GJG. Cost effectiveness in oncology. Lancet 1985; ii: 1405–8. 81. Glimelius B, Hoffman K, Graf W et al. Cost effectiveness of palliative chemotherapy in advanced gastrointestinal cancer. Ann Oncol 1995; 6:267–74. 82. Goodwin PJ, Feld R, Evans WK, Pater J. Cost-effectiveness of cancer chemotherapy: an economic evaluation of a randomized trial in small-cell lung cancer. J Clin Oncol 1988; 6:1537–47. 83. Smith TJ, Hillner BE, Neighbors DM et al. Economic evaluation of a randomized clinical trial comparing vinorelbine, vinorelbine plus cisplatin, and vindesine plus cisplatin for non-small cell lung cancer. J Clin Oncol 1995; 13:2166–73. 84. Hillner BE, McLeod DG, Crawford ED, Bennett CL. Estimating the cost-effectiveness of total androgen blockade with flutamide in Ml prostate cancer. Urology 1995; 45:633–40. 85. Jaakkimainen L, Goodman PJ, Pater J et al. Counting the costs of chemotherapy in a National Cancer Institute of Canada randomized trial of non-small cell lung cancer. J Clin Oncol 1990; 8:1301–9. 86. Hillner BE, Smith TJ, Desch CE. Efficacy and cost-effectiveness of autologuous bone marrow transplantation in metastatic breast cancer: estimates using decision analysis while awaiting clinical trial results. JAMA 1992; 267:2055–61. 87. Desch CE, Lasala MR, Smith TJ et al. The optimal timing of autologous bone marrow transplantation in Hodgkin’s disease patients following a chemotherapy relapse. J Clin Oncol 1992; 10:200–9. 88. Lyman GH, Lyman CG, Sanders RA, Balducci L. Decision analysis of hematopoietic growth factor use in patients receiving cancer chemotherapy. J Natl Cancer Inst 1993; 85:488–93. 89. Lyman GH, Balducci L. A cost analysis of hematopoietic colony-stimulating factors. Oncology 1995; 9:85–91. 90. Glaspy JA, Bleecker G, Crawford J et al. The impact of therapy with filgrastim (recombinant granulocyte colony-stimulating factor) on the health care costs associated with cancer chemotherapy. Eur J Cancer 1993; 29A:S23–30. 91. Balducci L, Hardy CL, Lyman GH. Hematopoietic growth factors in the older cancer patient. Curr Opin Hematol 2001; 8:170–87.

Diagnosis and treatment of cancer in the elderly

929

92. Lyman GH, Kuderer NM, Djulbegovic B. Prophylactic granulocyte colony-stimulating factor in patients receiving dose intensive cancer chemotherapy: a meta-analysis. Am J Med 2002; 112: 406–11. 93. Lyman GH, Balducci L, Agboola Y. Use of hematopoietic growth factors in the older cancer patient. Oncol Spectrum 2001; 2:414–21. 94. Lyman GH, Kuderer N, Greene J, Balducci L. The economics of febrile neutropenia: implications for the use of colony-stimulating factors. Eur J Cancer 1998; 34:1857–64. 95. Lyman GH, Kuderer NM, Balducci L. Granulopoiesis stimulating agents: economic impact on the management of febrile neutropenia. Curr Opin Oncol 1998; 10:291–98. 96. Lyman GH, Kuderer NM, Balducci L. Economic analyses of the use of the colony-stimulating factors: an update. Curr Opin Hematol 1999; 6:145–51. 97. Balducci L, Hardy CL, Lyman GH. Hempoietic reserve in the older cancer patient: clinical and economic considerations. Cancer Control 2000; 7:539–47. 98. Crawford J, Ozer H, Stoller R et al. Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med 1991; 325:164–70. 99. Lyman GH, Crawford J, Dale D et al, for the ANC Study Group. Clinical prediction models for febrile neutropenia (FN) and relative dose intensity (RDI) in patients receiving adjuvant breast cancer chemotherapy. Proc Am Soc Clin Oncol 2001; 20:394A. 100. Lyman, GH. A novel approach to maintain planned dose chemotherapy on time: a decision making tool to improve patient care. Eur J Cancer 2000; 36:S15–21. 101. Silber JH, Fridman M, Shpilsky A et al. Modeling the cost-effectiveness of granulocyte colony-stimulating factor use in early-stage breast cancer. J Clin Oncol 1998; 16:2435–44. 102. Tchekmedyian NS. Costs and benefits of nutrition support. Cancer Oncol. 1995; 9:79–84. 103. Emanuel EJ, Emanuel LL. The economics of dying: the illusion of cost savings at the end of life. N Engl J Med 1994; 330:540–4. 104. Bailes JS. Cost aspects of palliative cancer care. Semin Oncol 1995; 22:64–6. 105. Portenoy RK. Issues in the economic analysis of therapies for cancer pain. Oncology 1995; 9:71–7. 106. Bennett CL, Armitage JL, Buchner D, Gulati S. Economic analysis in phase III clinical cancer trials. Cancer Invest 1994; 12:336–42. 107. Simes RJ. Risk benefit relationships in cancer clinical trials: the ECOG experience in nonsmall-cell lung cancer. J Clin Oncol 1985; 3:462–72. 108. Lyman GH. Methodological issues related to health economic analysis in controlled clinical trials. In: Handbook of Statistics in Clinical Oncology (Crowley J, ed). New Year: Marcel Dekker, 2001: 291–320. 109. Lyman GH. The economics of randomized controlled trials. Curr Oncol Rep 2001; 3:396–403. 110. Naimark D, Naglie G, Detsky AS. The meaning of life expectancy: What is a clinically significant gain? J Gen Intern Med 1994; 9: 702–7. 111. Cella DF, Tulsky DS, Gray G et al. The Functional Assessment of Cancer Therapy scale: development anf validation of the general measure. J Clin Oncol 1993; 11:570–9. 112. Gelber RD, Goldirsch A, Cole BF. Evaluation of effectiveness: Q-TWiST. The International Breast Cancer Study Group. Cancer Treat Rev 1993; 19(Suppl A):73–84. 113. Grieve AP. Issues for statisticians in pharmaco-economic evaluation. Statist Med 1998; 17:1715–23. 114. Smith TJ, Hillner BE, Desch CE. Efficacy and cost-effectiveness of cancer treatment: rational allocation of resources based on decision analysis. J Natl Cancer Inst 1993; 85:1460–74.

Comprehensive Geriatric Oncology

930

Appendix 42.1: Declining exponential approximation for lifeexpectancy (DEALE) When the mortality rate is constant, the relationship between time and survival can be described as a declining exponential function. If S0 is the number of patients alive at diagnosis (t= 0), S is the number of patients alive at some time T in the future (t=T), and β is the mortality rate, then this relationship can be described as follows. S/S0=e−βt ln(S/S0)=−βt β=−t−1 ln(S/S0) This model has two major advantages over other models in terms of computational simplicity. First, the life-expectancy, which is the average number of years of life remaining, is 1/β, and therefore β=1/life-expectancy. If t is the median survival time, then β=0.693/t. Second, an individual’s total mortality rate is the sum of an individual’s agespecific (AS) mortality rate and the mortality rate due to disease (D). Thus, βtotal=βAS+βD or βD=βtotal−βAS If the mortality rate associated with a certain cancer is known, then this information can be utilized to estimate the total life-expectancy of an individual even if direct observational data are not available. In addition, if the patient has more than one disease impacting on longevity, then the contributions of comorbid conditions may be incorporated into the estimate of overall life-expectancy. For example, if we need to know the life expectancy (LE) of 65-year-olds with a certain cancer (CA), but only have information on 50-year-olds with the same cancer that 25% survive to 5 years, then, for 50-year-olds with cancer,

If the LE of 50-year-olds without disease is 30 years, then β50= 0.033. Therefore, βCA=0.277–0.033=0.244. If the LE for 65-year-olds without cancer is 20 years, then β65=0.05. We can then calculate the results for the 65-year-old with cancer as ßtotal=ß65+ßCA =0.05+0.244=0.294 and life-expectancy=1/0.294=3.40 years

Diagnosis and treatment of cancer in the elderly

931

If the patient also has coronary artery disease (CAD) with a mortality rate of 10%, then the result for a 65-year-old with cancer and coronary artery disease is βtotal+βCA+βCAD =0.05+0.244+0.10=0.394 and life-expectancy=1/0.394=2.54 years

Appendix 42.2: Decision model threshold analysis based on benefits and costs Each possible outcome in a realistic clinical situation can be considered to have a certain value or utility (U) and a certain probability of disease (p). The expected values (EV) of the treatment and no treatment strategies are therefore EVtreatment=pUtreat/disease+(1–p)Utreat/no disease EVno treatment=pUno treat/disease+(1−p)Uno treat/no disease The treatment strategy associated with the greatest expected value should be chosen in order to optimize the likelihood of the best result. The benefits and costs can be derived from utility estimates as follows: benifit of treatment=Utreat/disease−Uno treat/disease cost of treatment=Uno treat/no disease−Utreat/no disease A sensitivity analysis could be conducted comparing the expected value functions as the probability of disease is varied. Most often, however, we are interested in determining the threshold probability, at which point the expected value of the treatment strategies are equal, i.e. EVtreatment=EVno treatment or pUtreat/disease−(1−p)Utreat/no disease =pUno treat/disease−(1−p)Uno treat/no disease Solving for p,

It is evident from this relationship that as the ratio of benefit to cost increases, the threshold probability of disease decreases. Above the threshold probability of disease,

Comprehensive Geriatric Oncology

932

treatment will be associated with a greater expected value and will therefore be the favored strategy. The indications for treatment therefore broaden as the ratio of benefit to cost increases. Appendix 423: Cost discounting based on future and present costs Cost discounting is based on the preference to delay present costs to some future time. The cost discount is the difference between future cost and present cost. The cost discount rate (CDR) is the cost discount as a proportion of the present cost:

If the CDR is known, then future costs can be converted into costs referable to the present as follows:

so

If the discounting is conducted over several (n) years, then the present value is given by

43 Guidelines for the management of the older cancer patient Lodovico Balducci Introduction Guidelines for the diagnosis and management of diseases are becoming increasingly more common for a number of reasons, including the following:1 • Simplification of the practice of medicine, in an increasingly more complex context due to rapid accrual and diffusion of new information. • Quality assurance in the practice of medicine and nursing. • Determination of the level of evidence supporting different diagnostic and treatment strategies. The level of evidence is classified according to the criteria of the US Preventive Service Task Force2 (Table 43.1). It should be underlined that promotion of evidence-based practice does not necessarily discourage time-honored practices developed prior to the evidence rules: for example, no reasonable person would recommend to quit operating on acute appendicitis because there have been no randomized controlled clinical trials supporting appendectomy. Rather, an evidencebased analysis is helpful in identifying diagnostic and therapeutic approaches that need a second look because of questionable value. The National Cancer Center Network (NCCN) is a body involving 14 comprehensive cancer centers in the USA, and has endeavored to issue guidelines for the

Table 43.1 Levels of evidence I

Based on two or more randomized controlled clinical trials

II-1

Based on one randomized clinical trial or on well-performed cohort studies

II-2

Based on retrospective clinical studies

II-3

Based on personal experience or anecdotal reports

II-4

Based on authoritative opinion

III

No supportive evidence whatsoever

management of common malignancies, which are reviewed every 3 years.3 In 1999, the NCCN gathered a panel of experts to study guidelines for the management of the older cancer patient.4 The mandate of this panel was to establish whether specific treatment guidelines are necessary for older individuals affected by cancer. The panel issued

Comprehensive Geriatric Oncology

934

guidelines related to assessment and management. In this chapter, the evidence on which the guidelines are based is reviewed, and comments are made on possible modifications suggested by emerging evidence. Geriatnc assessment The elements of the Comprehensive Geriatric Assessment (CGA) are reviewed in Chapter 19 of this volume.5 The NCCN listed a number of potential benefits of the geriatric assessment (Table 43.2), which may be summarized into two categories: • recognition of conditions that may interfere with cancer treatment and are potentially reversible; • estimate of life-expectancy and tolerance of chemotherapy.

Table 43.2 NCCN guidelines related to the management of older cancer patients • All cancer patients aged 70 and older should undergo some form of geriatric assessment • Colony-stimulating factors should be use to support prophylactically persons aged 65 and over receiving moderately toxic chemotherapy (e.g. CHOP or CA) • Patient’s hemoglobin should be kept at 12g/dl or higher with erythropoietin • Doses of chemotherapy should be adjusted to the renal function of patients aged 65 and older • Acute myeloid leukemia in patients aged 70 and over should be managed in a cancer center • Capecitabine should be used preferentially in lieu of intravenous fluorinated pyrimidines

Table 43.3 Value of the CGA according to the NCCN • Assessment of comorbidity, which may render older individuals more susceptible to the complications of chemotherapy. Many comorbid conditions may be reversed or ameliorated, and chemotherapy may be safer in these circumstances • Assessment of socioeconomic conditions that may prevent compliance with chemotherapy or enhance the risk of complications. There include inadequate transportation, inadequate home caregiver, and inability to achieve timely help in the case of serious complications • Assessment of functional dependence that may affect the tolerance of complications from cytotoxic agents • Recognition of frailty, a condition in which most functional reserve is exhausted, and the aim of treatment is palliation. • Assessment of emotional and cognitive conditions, such as depression and memory disorders, which may interfere with comprehension and acceptance of treatment plans • Some gross estimate of life-expectancy, based on functional status, comorbidity, cognition, and presence or absence of geriatric syndromes. In general, this estimate is critical before instituting treatments whose benefits may be seen only years later, such as adjuvant treatment for breast

Guidelines for the management of the older cancer patient

935

cancer or colorectal cancer, primary treatment of prostate cancer, or the use of chemotherapy in myelodysplasia

In addition, the NCCN recognized that the CGA allows adoption of a much needed common language in the assessment of older individuals (Table 43.3). The benefits of this common language are self-evident, and include proper stratification of patients in prospective trials according to life-expectancy, functional reserve, comorbidity, and social support, meaningful retrospective reviews of cancer treatment based on the same criteria, and quality assurance. Evidence supporting the recommendations Recognition of conditions that may interfere with cancer treatment and are potentially reversible Two cohort studies support this statement (evidence level II–1). Extermann et al6 reported on 200 patients treated in the Senior Adult Oncology Program (SAOP) at the H Lee Moffitt Cancer Center in Tampa, Florida, who had undergone CGA at the time of the initial visit. Significant comorbidity was detected in approximately 70% of patients, malnutrition, depression, and dementia in approximately 20%, some degree of functional dependence in approximately 70%, and polypharmacy in more than 50%. The majority of these findings would have been missed without the CGA. Similar findings were reported by Repetto et al7 among Italian patients aged 65 and over. Neither study documented a definitive benefit in the detection of socioeconomic conditions interfering with cancer treatment through the CGA. This benefit was documented by Extermann and colleagues in a pilot study involving 15 women aged 70 and older with breast cancer, 50% of whom presented need for a caregiver to administer antineoplastic treatment. Estimate of life-expectancy and treatment tolerance A number of cohort studies have correlated functional status,8–11 cognitive decline,12–15 depression,16–21 comorbidity 22–24 falls,25 incontinence,26 delirium,27 failure to thrive,28 and neglect and abuse29–31 with the life-expectancy of older individuals (evidence level II-1). It is not clear, however, how these conditions may be integrated into the estimate of lifeexpectancy. A reasonable approach would involve a modification of the old DEALE formula32 in which mortality according to functional status, cognitive decline, depression, and geriatric syndrome is added, in addition to the mortality rate from individual comorbid conditions. A potential pitfall with this approach, which has not been validated in clinical practice, is the possibility that the effect of different conditions overlap. At present, it is safe to say that the CGA allows an estimate of mortality related to specific abnormalities, but not a global estimate of life-expectancy. Appropriately, the NCCN panel did not make any comments about the potential benefits of the geriatric assessment in terms of survival, function preservation, or prevention of hospitalization, because there are no data on these subjects in older cancer

Comprehensive Geriatric Oncology

936

patients. It should be mentioned, however that a number of randomized controlled studies (level I evidence) in the general geriatric population have established that the CGA: • Reduces the rate of functional decline and of admission to assisted living facilities.33–39 • Reduces the complications of hospitalization, including in-hospital delirium.40 • Reduces the rate of hospital readmission after discharge.33–39 • Reduces the risk of falls.41 • May improve patient survival, although this finding is controversial.33,42–44 Early small studies reviewed by Stuck et al44 suggested an improvement of survival for inpatient geriatric assessment. However, a large

Table 43.4 Taxonomy of age45 Type

Description

Rehabilitative needs

Primary

• Fully independent

Health and function maintenance

• Negligible comorbidity Intermediate

• May be dependent in one or more IADL • Less than three comorbid conditions; intermediate comorbidity scores

Secondary or frailty

Classical definition—one or more of the following:

May be rehabilitated to some extent

Prevention of further functional deterioration

• ADL dependence • One or more geriatric syndromes • Three or more comorbid conditions Alternative definition—at least three of the following: • Unintentional weight loss of 10% or more of original body weight over 1 year • Self-reported exhaustion • Decreased grip strength • Slow movements • Difficulty in initiating movements Near death

Life-expectancy of 3 months or less; no treatment available

No rehabilitation

ADL, Activities of Daily Living; IADL, Instrumental Activities of Daily Living.

randomized trial could not confirm this benefit.33 Survival may still be improved in special patient categories, such as postsurgical patients.42 While it may not be legitimate to conclude from these studies that the CGA prolongs the survival of older cancer patients, it is reasonable to assume that the CGA may prevent

Guidelines for the management of the older cancer patient

937

functional decline and hospitalization for these patients, as it does for the general older population. New evidence supporting changes in the present recommendations Attempting a taxonomy of aging In 1999, Hamerman45 proposed a taxonomy of aging in four subgroups, distinguished by their susceptibility to rehabilitation and residual functional reserve (Table 43.4). This taxonomy allows for the first time a subdivision of older cancer patients into categories of different life-expectancy and tolerance to treatment that could be inserted in a treatment algorithm. At the same time, two conditions have become better defined since the original guidelines were issued, namely frailty and vulnerability. The classical definition of frailty46 should be complemented in the new set of guidelines by an alternative definition proposed by Fried et al47 that appears to be more comprehensive and may detect frailty even when the criteria of the classical definition are not fulfilled. The construct of vulnerability48 (Tables 43.5 and 43.6) is of special interest with regard to cancer patients for at least two reasons:

Table 43.5 Vulnerability scale Element of assessment

Score

Age: •

75–84

1

•

≥85

3

Self-reported health: •

Good or excellent

0

•

Fair or poor

1

ADL/IADL—needs help in: •

Shopping

1

•

Money management

1

•

Light housework

1

•

Transferring

1

•

Bathing

1

Activities—needs help in: •

Stooping, crouching or kneeling

1

•

Lifting or carrying 10lb

1

•

Writing or handling small objects

1

Comprehensive Geriatric Oncology

938

•

Reaching or extending arm above shoulder

1

•

Walking one-quarter mile

1

•

Heavy housework

1

Table 43.6 Vulnerability scores, functional decline, and survival Score

Risk of functional decline or death (%)

1–2

11.8

≥3

49.8

1–3

14.8

≥4

54.9

• It allows better qualification of Hamerman’s intermediate group, to which the majority of older cancer patients belong. • It provides a reasonable screening instrument to recognize those patients who most may benefit from a full assessment. It appears reasonable, in a new set of guidelines, to recommend that the CGA be used to construct a classification of the older person according to Hamerman’s criteria and to integrate vulnerability into this taxonomy. Laboratory assessment of aging A number of potential biochemical markers of aging have emerged. Aging has been constructed as the accumulation of inflammatory damages, leading to increased concentration of inflammatory cytokines in the circulation and to a prevalently catabolic status.49 It has been known for a long time that the concentration of interleukin-6 (IL-6) is increased in a number of aging-related conditions, from osteoporosis to Alzheimer dementia.50,51 A study has shown that the simultaneous increase of IL-6 and D-dimer in the circulation marks frailty.52 While the sensitivity of this finding is very high, no information exists concerning its specificity. Another condition that may be overlapping with frailty, namely somatopause,53 is marked by simultaneous increases in IL-6 and tumor necrosis factor (TNF) in the circulation and reduced production of growth hormone. These laboratory findings are of extreme interest, and the measurement of IL-6 in the circulation should probably be included in any clinical trial related to the assessment of aging. At present, the value of these findings in clinical practice remains to be established. Value of physical performance tests A number of physical performance tests predict the risk of disability, functional decline, and death.54–57 It is reasonable to expect that some of these tests may be useful in identifying older individuals in need of a more complete assessment.

Guidelines for the management of the older cancer patient

939

At present, there is not sufficient evidence to recommend that any of these tests be routinely included in the assessment of the older person with cancer. Use of screening tests to establish which patients may benefit from a full assessment Conscious of the impact of the CGA on a busy oncology practice, the NCCN suggested that some form of screening test be used to identify patients who may benefit from a full assessment. At that time, it was found that the instrument proposed by Lachs et al58 might have been the most suitable for this purpose. Since the guidelines were issued, two new findings have emerged: • Recognition of vulnerability through a 13-item questionnaire (Table 43.5).48 • The feasibility and value of self-reported geriatric assessment. Ingram et al59 reported that more than two-thirds of older veterans with cancer were able and willing to fill a lengthy questionnaire related to function, comorbidity, emotional, and social status, sent to their home prior to the clinic visit. These findings present new opportunities to streamline the assessment of the older person. Seemingly, the Vulnerability Questionnaire (VES13) may substitute for the Lachs questionnaire. The work of Ingram et al59 indicates the possibility of gathering information without overtaxing the time of a limited clinic. In the meantime, it is reasonable to study the use of physical performance tests as screening instruments for a more complex assessment. Treatment-related recommendations Dose adjustment according to the glomerular filtration mte in persons aged 65 and older The basis of this recommendation is twofold: • There is a consistent decline in the glomerular filtration rate (GFR) with age (see Chapter 18 of this volume60). • It has been demonstrated by Gelman and Taylor61 that reducing the doses of methotrexate and cyclophosphamide according to the GFR in women aged 65 and over with metastatic breast cancer reduces the toxicity but not the effectiveness of chemotherapy (level of evidence II-1). This is a problematic recommendation for several reasons, however: • The implementation itself is problematic because, with the exception of carboplatin, there is no reliable way to predict the AUC (area under the curve) of different drugs based on the GFR exclusively. This is especially true for agents that have active metabolites excreted through the kidney, such as idarubicin and daunorubicin. The formula of Kinzel and Dorr62 is recommended for this purpose, but has not been validated by wide clinical experience.

Comprehensive Geriatric Oncology

940

• The determination of the GFR itself is less than accurate. The formula of Cockroft and Gault63 may be more practical and accurate than 24-hour urine collection, but is not very precise, especially for low GFR values. Other formulae, such as the Levin formula, although more accurate, are cumbersome to use.64 • Individual pharmacokinetics vary, at least partly owing to pharmacogenomics.65 An initial dose adjustment may be reasonable for vulnerable patients, with the provision of dose escalation if no toxicity is seen after the first treatment. Use of colony-stimulating factors after age 65 for patients receiving moderately toxic chemotherapy (e.g. CHOP or CA) This recommendation is supported by the following data: • In seven prospective studies of lymphoma in patients aged 60 and older, treated with CHOP (cyclophos-phamide, doxorubicia, vincristine, and prednisone) or CHOP-like combination chemotherapy, the rate of grade 4 neutropenia was consistently higher than 50%, the risk of neutropenic infections varied between 20% and 47%, and the risk of infectious death varied between 5% and 15% (Table 43.7).66–73 Of special interest, the study of Gomez et al70 showed that two-thirds of infectious deaths occurred after the first course of treatment. That means that by applying the current American Society of Clinical Oncology (ASCO) guidelines for the use of growth factors,74,75 calling for an episode of neutropenic infection prior to the institution of colony-stimulating factor prophylaxis, these deaths might not be prevented (level II-1 evidence). • The risk of neutropenia and neutropenic infections increased with age, in both the Southwest Oncology Group (SWOG)76 and the International Breast Cancer Study Group (IBCSG)77 studies (level II-2 evidence). • Four randomized controlled trials showed that prophylactic hematopoietic growth factors reduced by 50–75% the risk of neutropenic infections in older persons treated with CHOP or CHOP-like chemotherapy (level I evidence).66,71,78,79 • The study of Price et al80 showed that the response to filgrastim (recombinant human granulocyte colony- stimulating factor, G-CSF) was similar in healthy individuals aged 70 and older and in those younger. Economic considerations also support this recommendation. In 1993, Lyman et al.81 showed that the prophylactic use of G-CSF was cost-effective when the predicted risk of neutropenic infection was higher than 40%, which

Table 43.7 Myelodepression in elderly patients treated with CHOP-like combination chemotherapy Authors

No. of Regimen patients

Zinzani et al66

161 VNCOP-B

Age Neutropenia (%) ≥60

44

Neutropenic fever (96) 32

Treatment related-deaths (%) 1.3

Guidelines for the management of the older cancer patient

Sonneveld et al67

Gomez et al70

Tirelli et al68

148 CHOP

≥60

NR

NR

14

CNOP

≥60

NR

NR

13

249 CHOP

≥60

24

8

0

≥70

73

42

20

≥70

50

21

7

≥70

48

21

5

70

9

7

12

≥70

29

13

15

≥70

91

47

8

50

20

8

119 VMP CHOP

Bastion et al69

444 CVP CTVP

Bjorkholm et al71

941

411 CHOP/ CNOP

O’Reilly et al72

63 POCE

≥65

Coiffier et al73

399 CHOP/

≥60

CHOPrituximab

NR

5 12–20

NR, not reported

Figure 43.1 Cost-effectiveness of granulocyte colony-stimulating factor (G-CSF) for the risk of infection

Comprehensive Geriatric Oncology

942

versus cost of hospitalization or duration of hospitalization. G-CSF is cost-effective for all conditions above the curve. For example, institution of G-CSF treatment would be costeffective for a 20% risk of neutropenic infection if the cost of hospitalization were $1800.00/day or the duration of hospitalization more than 15 days. occurred in at least two of the lymphoma studies. An update of this analysis showed that the threshold risk of neutropenic infections beyond which neutropenia prophylaxis was cost-effective decreased with increasing duration and cost of hospitalization for neutropenic infections (see Chapter 42 of this volume82). In the case of older cancer patients, this threshold may well be around 20–25% (Figure 43.1). In the case of acute myeloid leukemia (AML), colony-stimulating factors may improve patient survival83–85 and can definitely reduce the duration of hospitalization for neutropenic infections (level I evidence).86 The use of prophylactic antibiotics may represent an alternative to colony-stimulating factors.87 However, there are no data on the use of prophylactic antibiotics specifically in the elderly. In view of the clear benefits of colony-stimulating factors in preventing potentially lethal complications, a randomized controlled study comparing these two treatment strategies may not appear ethically acceptable. Maintenance of hemoglobin levels at 12g/dl or higher with erythropoietin The main basis of this recommendation was the finding that anemia was an independent risk factor for myelotoxicity in patients treated with anthracyclines, epipodophyllotoxins, and camptothecins (level II-2 evidence).88–93 Since the publication of the guidelines, a number of new data have emerged supporting this recommendation. These data are discussed in Chapter 37 of this volume,94 and may be summarized as follows: • At least four studies indicate that anemia is an independent risk factor for mortality among elderly patients.95–98 Three of these studies were retrospective (evidence level II-2) and one was a cohort study (evidence level II-1). The Women’s Health Study demonst rated that in a cohort of community-dwelling women aged 65 and older, hemoglobin levels below 13.4g/dl were a harbinger of increased mortality.95 • Two retrospective analysis of the management of cancer patients with erythropoietin indicated that the best incremental improvement in fatigue was obtained when hemoglobin levels were increased from 11 to 13g/dl (level II-2 evidence).99,100 • There is a documented association of fatigue and functional dependence in elderly individuals (level II-2 evidence).101 • Chronic anemia may lead to congestive heart failure (level II-2 evidence) and this may be prevented with erythropoietin (level I evidence).102,103

Guidelines for the management of the older cancer patient

943

• A study in patients with end-stage renal disease showed that correction of anemia with erythropoietin may prevent cognitive disorders (level II-2 evidence).104 Acute myeloid leukemia in individuals aged 70 and older should be preferentially treated in a cancer center This is a commonsense recommendation based on the following considerations: • The risk of treatment complications is higher in older individuals (see Chapter 45 of this volume105). • A cancer center may be better equipped to deal with these complications. Potential modifications to treatment guidelines emerging from new evidence Hopefully, in the near future, we may be able to predict the pharmacokinetics of antineoplastic agents based on renal function, body composition, activity of cytochrome P450 enzymes, drug interactions, and pharmacogenomics. When available, this approach should substitute for the current recommendation to adjust the doses to the GFR. The recommendation related to the use of growth factors should include pegfilgrastim (pegylated filgrastim) in patients treated with chemotherapy less often than weekly. The advantages of pegfilgrastim include a single administration and a degree of selfregulation that obviates the need for repeated controls of blood count. Also, in patients with diseases other than AML, the expression ‘colony-stimulating factor’ should be substituted with ‘G-CSF’, because there are no data on the value of granulocytemacrophage colony-stimulating factor (GM-CSF) in lymphoma and solid tumors. The management of anemia may not undergo substantial changes. With regard to erythropoietin, the use of darbepoietin in lieu of epoietin alfa may improve the convenience of treatment, requiring less frequent administrations. Although levels of hemoglobin higher than 12g/dl may be desirable, they are not supported by present evidence, nor is the prophylactic use of erythropoietin in non-anemic patients receiving chemotherapy. The guideline panel will have the opportunity to address the prevention of muscositis from fluorinated pyrimidines, to which older individuals appear particularly prone (see Chapter 39 of this volume106). At least two strategies may be effective for this purpose: • the use of oral capecitabine in lieu of intravenous preparations;107 • the prophylactic use of keratinocyte growth factors, which may become available in the near future.108

Conclusions The evidence reviewed here justifies a special approach to the assessment and the treatment of older cancer patients. This uniform approach is considered a framework able to accommodate new insights related to the assessment and the treatment of older persons with cancer.

Comprehensive Geriatric Oncology

944

References 1. Siddall R. Managers and medicine: eight pieces of evidence. Health Service J 2002; 112:34–36. 2. Harris RP, Helfan M, Woolf SH et al. Current methods of the US preventive service task force: a review of the process. Am J Prev Med 2001; 20(3 Suppl):21–35. 3. Balducci L. The geriatric cancer patient: equal benefit from equal treatment. Cancer Control J Moffitt Cancer Center 2001; 8(2 Suppl): 1–25, 27–8. 4. Balducci L, Yates G. General guidelines for the management of older patients with cancer. In: Oncology, NCCN Proceedings, November 2000:221–7. 5. Balducci L, Extermann M. Assessment of the older patient with cancer. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:223–35. 6. Extermann M, Overcash J, Lyman GH et al. Comorbidity and functional status are independent in older cancer patients. J Clin Oncol 1998; 16:1582–7. 7. Repetto L, Fratino L, Audisio RA et al. Comprehensive Geriatric Assessment adds information to the Eastern Cooperative Group Performance Status in elderly cancer patients. An Italian Group for Geriatric Oncology Study. J Clin Oncol 2002; 20:494–502. 8. Reuben DB, Rubenstein LV, Hirsch SH et al. Value of functional status as predictor of mortality. Am J Med 1992; 93:663–669. 9. Inouye SK, Peduzzi PN, Robison JT et al. Importance of functional measures in predicting mortality among older hospitalized patients. JAMA 1998; 279:1187–93. 10. Siu AL, Moshita L, Blaustein J. Comprehensive Geriatric Assessment in a day hospital. J Am Geriatr Soc 1994; 42:1094–9. 11. Ramos LR, Simoes EJ, Albert MS. Dependence in activities of daily living and cognitive impairment strongly predicted mortality in older urban residents in Brazil. J Am Geriatr Soc 2001; 49:1168–75. 12. Stump TE, Callahan CM, Hendrie HC. Cognitive impairment and mortality in older primary care patients. J Am Geriatr Soc 2001; 49: 934–40. 13. Nakanishi N, Tatara K, Ikeda K et al. Relation between intellectual dysfunction and mortality in community-residing older people. J Am Geriatr Soc 1998; 46:583–9. 14. Eagles JM, Beattie JAG, Restall DB et al. Relationship between cognitive impairment and early death in the elderly. BMJ 1990; 300: 239–40. 15. Bruce ML, Hoff RA, Jacobs SC et al. The effect of cognitive impairment on 9-year mortality in a community sample. J Gerontol 1995; 50B:P289–96. 16. Kivela S-L, Pahkala K. Depressive disorder as predictor of physical disability in old age. J Am Geriatr Soc 2001; 49:290–6. 17. Blazer DG, Hybels CF, Pieper CF. The association of depression and mortality in elderly persons: a case for multiple independent pathways. J Gerontol 2001; 56A:, M505–9. 18. Covinsky KE, Kahana E, Chin MH et al. Depressive symptoms and three year mortality in older hospitalized medical patients. Ann Intern Med 1999; 130:563–9. 19. Bruce ML, Leaf PJ, Rozal GP et al. Psychiatric status and nine year mortality data in the New Haven Epidemiologic Catchment Area Study. Am J Psych 1994; 151:716–21. 20. Lyness JM, Ling DA, Cox C et al. The importance of subsyndromal depression in older primary care patients. Prevalence and associated functional disability. J Am Geriatr Soc 1999; 47:647– 52. 21. Lyness JM, Noel TK, Cox C et al. Screening for depression in elderly primary care patients: a comparison of the Center for Epidemiologic Studies Depression Scale and the Geriatric Depression Scale. Arch Intern Med 1997; 157:449–54. 22. Satariano WA, Ragland DR. The effect of comorbidity on 3-year survival of women with primary breast cancer. Ann Intern Med 1994; 120:N104–10.

Guidelines for the management of the older cancer patient

945

23. Piccirillo JF, Feinstein AR. Clinical symptoms and comorbidity: significance for the prognostic classification of cancer. Cancer 1996; 77:834–42. 24. Yancik R, Ganz PA, Varricchio CG et al. Perspectives on comorbidity and cancer in the older patient: approach to expand the knowledge base. J Clin Oncol 2001; 19:1147–51. 25. Tinetti ME, Williams CS. The effects of falls and fall injuries in functioning in community dwelling older persons. J Gerontol 1998; 53A:Ml 12–19. 26. Rockwood K, Stadnyk K, Macknigt C et al. A brief instrument to classify frailty in elderly people. Lancet 1999; 353:205–6. 27. Bucht G, Gustafson Y, Sandberg O. Epidemiology of delirium. Dement Geriatr Cogn Disord 1999; 10:315–18. 28. Verdery RB. Failure to thrive in old age: follow-up on a workshop. J Gerontol 1997; 52:M333– 6. 29. Pavlik VN, Hyman DJ, Festa NA. Quantifying the problem of abuse and neglect in adults: analysis of a statewide data base. J Am Geriatr Soc 2001; 49:45–8. 30. Lachs MS, Williams C, O’Brien S et al. Risk factors for reported elder abuse and neglect: a nine-year observational cohort study. Gerontologist 1997; 37:469–74. 31. Dyer CB, Pavlick VN, Murphy KP et al. The high prevalence of depression and dementia in elder abuse or neglect. J Am Geriatr Soc 2000; 48:205–8. 32. Beck JR, Pauker SG. Does DEALEing stack the deck? Med Decis Making 1999; 19:385–93. 33. Cohen HJ, Feussner JR, Weinberger M et al. A controlled trial of inpatient and outpatient geriatric assessment. N Engl J Med 2002; 346:905–12. 34. Reuben DB, Franck J, Hirsch S et al. A randomized clinical trial of outpatient geriatric assessment (CGA), coupled with an intervention, to increase adherence to recommendations. J Am Geriatr Soc 1999; 47:269–76. 35. Bula CJ, Berod AC, Stuck AE et al. Effectiveness of preventive in-home geriatric assessment in well functioning, community dwelling older people: secondary analysis of a randomized trial. J Am Geriatr Soc 1999; 47:389–95. 36. Tulloch AJ, Moore V. A randomized controlled trial of geriatric screening and surveillance in general practice. J R Coll Gen Pract 1979; 29:733–42. 37. Landi F, Onder G, Russo A et al. A new model for integrated home care in the elderly: impact on hospital use. J Clin Epidemiol 2001; 54:968–70. 38. Bernabei R, Venturiero V, Tarsitani P et al. The Comprehensive Geriatric Assessment: when, where, how? Crit Rev Hematol Oncol 2000; 33:45–56. 39. Boult C, Boult LB, Morishit L et al. A randomized clinical trial of outpatient geriatric evaluation and management. J Am Geriatr Soc 2001; 49:351–9. 40. Inouye SK, Bogardus ST, Charpentier PA et al. A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med 1999; 340:669–74. 41. Tinetti ME, McAvay G, Claus G et al. A multifactorial intervention to reduce the risk of falling among elderly people living in the community. N Engl J Med 1994; 331:821–7. 42. McCorkle R, Strumpf NE, Nuamah IF et al. A specialized home care intervention improves survival among old post-surgical cancer patients. J Am Geriatr Soc 2000; 48:1707–13. 43. Burns R, Nichols LO, Martindale-Adams J et al. Interdisciplinary geriatric primary care evaluation and management. Two year outcomes. J Am Geriatr Soc 2000; 48:8–13. 44. Stuck AE, Siu AL, Wieland GD et al. Comprehensive Geriatric Assessment: meta-analysis of controlled trials. Lancet 1993; 342: 1032–6. 45. Hamerman D. Toward an understanding of frailty. Ann Intern Med 1999; 130:945–50. 46. Balducci L, Stanta G. Cancer in the frail patient: a coming epidemic. Hematol Oncol Clin North Am 2000; 14:235–50. 47. Fried LP, Tangen CM, Walston J et al. Frailty in older adults: evidence for a phenotype. J Gerontol 2001; 56A:M146–56. 48. Saliba D, Elliott M, Rubenstein LZ et al. The Vulnerable Elders Survey: a tool for identifying vulnerable older people in the community. J Am Geriatr Soc 2001; 49:1691–9.

Comprehensive Geriatric Oncology

946

49. Hamerman D, Berman JV, Albers GW et al. Emerging evidence of inflammation in conditions frequently affecting older adults: reports of a symposium. J Am Geriatr Soc 1999; 47:1016–25. 50. Ershler WB, Keller ETR. Age-associated increased interleukin-6 gene expression, late life disease and frailty. Annu Rev Med 2000; 51: 245–70. 51. Ferrucci L, Harris TB, Guralnik JM et al. Serum 116 level and the development of disability in older persons. J Am Geriatr Soc 1999; 47:639–46. 52. Cohen HJ, Pieper CF, Harris T. Markers of inflammation and coagulation predict decline in function and mortality in community-dwelling elderly. J Am Geriatr Soc 2001; 49(S1):A3. 53. Martin F. Frailty and the somatopause. Growth Hormone IGF Res 1999; 9:3–10. 54. McDermott M, Greenland P, Ferrrucci L et al. Lower extremity performance is associated with daily life physical activity in individuals with and without peripheral arterial disease. J Am Geriatr Soc 2002; 50:247–55. 55. Pavol MJ, Owings TM, Foley KT et al. Influence of lower extremities strength of healthy older adults on the outcome of induced trip. J Am Geriatr Soc 2001; 50:256–62 56. Daltroy LH, Larson MG, Eaton HM et al. Discrepancies between self-reported and observed physical function in the elderly: the influence of response shift and other factors. Soc Sci Med 1999; 48: 1549–61. 57. Merrill SS, Seeman TE, Kasl SV et al. Gender differences in the comparison of self-reported disability performance measures. J Gerontol 1997; 52:19–26. 58. Lachs MS, Williams C, O’Brien S et al. Risk factors for reported elder abuse and neglect: a nine-year observational cohort study. Gerontologist 1997; 37:469–74. 59. Ingram SS, Seo PH, Martell RE et al. Comprehensive assessment of the elderly cancer patient: the feasibility of self-report methodology. J Clin Oncol 2002; 20:770–5. 60. Duthie E. Physiology of aging: relevance to symptoms, perceptions, and treatment tolerance. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:207–22. 61. Gelman RS, Taylor SG. Cyclophosphamide, methotrexate and 5-fluorouracil chemotherapy in women more than 65 years old with advanced breast cancer. The elimination of age trends in toxicity by using doses based on creatinine clearance. J Clin Oncol 1984; 2: 1406–14. 62. Kinzel PE, Dorr RT. Anticancer drug renal toxicity and elimination: dosing guidelines for altered renal function. Cancer Treat Rev 1995; 21:33–64. 63. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16:31–42. 64. Levey AS, Bosch JP, Lewis JB et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999; 130:461–70 65. Gurney H. Dose calculations of anticancer drugs: a review of the current practice and introduction of an alternative. J Clin Oncol 1996; 14:2590–611. 66. Zinzani PG, Storti S, Zaccaria A et al. Elderly aggressive histology non-Hodgkin’s lymphoma: first line VNCOP-B regimen: experience on 350 patients. Blood 1999; 94:33–8. 67. Sonneveld P, de Ridder M, van der Lelie H et al. Comparison of doxorubicin and mitoxantrone in the treatment of elderly patients with advanced diffuse non-Hodgkin’s lymphoma using CHOP vs CNOP chemotherapy. J Clin Oncol 1995; 13:2530–9. 68. Tirelli U, Errante D, Van Glabbeke M et al. CHOP is the standard regimen in patients ≥70 years of age with intermediate and high grade non-Hodgkin’s lymphoma: results of a randomized study of the European Organization for the Research and Treatment of Cancer Lymphoma Cooperative Study. J Clin Oncol 1998; 16:27–34. 69. Bastion Y, Blay J-Y, Divine M et al. Elderly patients with aggressive non-Hodgkin’s lymphoma: disease presentation, response to treatment and survival. A Groupe d’Etude des Lymphomes de l’Adulte study on 453 patients older than 69 years. J Clin Oncol 1997; 15:2945– 53. 70. Gomez H, Mas L, Casanova L et al. Elderly patients with aggressive non-Hodgkin’s lymphoma treated with CHOP chemotherapy plus granulocyte-macrophage colony-stimulating factor:

Guidelines for the management of the older cancer patient

947

identification of two age subgroups with differing hematologic toxicity. J Clin Oncol 1998; 16:2352–8. 71. Bjorkholm M, Osby E, Hagberg H et al. Blood 1999; 94:599a (Abst 2665). 72. O’Reilly SE, Connors JM, Howdle S et al. In search of an optimal regimen for elderly patients with advanced-stage diffuse large-cell lymphoma: results of a phase II study of P/DOCE chemotherapy. J Clin Oncol 1993; 11:2250–7. 73. Coiffier B, Lepage E, Briere J et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B cell lymphoma. N Engl J Med 2002; 346:235–42. 74. Ozer H, Artmitage JO, Bennett CL et al. 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based clinical practice guidelines. J Clin Oncol 2000; 18: 3558–85. 75. Balducci L, Lyman GH. Patients aged ≥ 70 are at high risk for neutropenic infection and should receive hemopoietic growth factors when treated with moderately toxic chemotherapy. J Clin Oncol 2001; 19:1583–5. 76. Kim YJ, Rubenstein EB, Rolston KV et al. Colony stimulating factors (CSFs) may reduce complications and death in solid tumor patients (pts) with fever and neutropenia. Proc Am Soc Clin Oncol 2000; 19:612a (Abst2411). 77. Crivellari D, Bonetti M, Castiglione-Gertsch M et al. Burdens and benefits of adjuvant cyclophosphamide, methotrexate, and fluorouracil and tamoxifen for elderly patients with breast cancer: the International Breast Cancer Study Group Trial VII. J Clin Oncol 2000; 18:1412–22. 78. Zagonel V, Babare R, Merola MC et al. Cost-benefit of granulocyte colony-stimulating factor administration in older patients with non-Hodgkin’s lymphoma treated with combination chemotherapy. Ann Oncol 1994; 5(Suppl 2):127–32. 79. Bertini M, Freilone R, Vitolo U et al. The treatment of elderly patients with aggressive nonHodgkin’s lymphomas: feasibility and efficacy of an intensive multidrug regimen. Leuk Lymphoma 1996; 22:483–93. 80. Price TH, Chatta GS, Dale DC. Effect of recombinant granulocyte colony-stimulating factor on neutrophil kinetics in normal young and elderly humans. Blood 1996; 88:335–40. 81. Lyman GH, Lyman CG, Sanderson RA, Balducci L. Decision analysis of hematopoietic growth factor use in patients receiving cancer chemotherapy. J Natl Cancer Inst 1993; 85:488–93. 82. Lyman GH, Kuderer NM. Diagnosis and treatment of cancer in the elderly: cost-effectiveness considerations. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:510–24. 83. Rowe JM, Andersen JW, Mazza JJ et al. Randomized placebo-controlled phase III study of granulocyte-macrophage colony stimulating factor in adult patients (>55–70 years) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood 1995; 86:457–62. 84. Witz F, Sadoun A, Perrin MC. A placebo-controlled study of recombinant human granulocyte macrophage colony-stimulating factor administered during an induction treatment for ‘de novo’ acute myelogenous leukemia in older patients. Blood 1998; 15:2722–30. 85. Dombret H, Chastang C, Fenaux P et al. A controlled study of recombinant human granulocyte colony-stimulating factor in elderly patients after treatment for acute myelogenous leukemia. N Engl J Med 1995; 332:1678–83. 86. Balducci L, Hardy CL, Lyman GH. Hematopoietic growth factors in the older cancer patient. Curr Opin Hematol 2001; 8:170–87. 87. Kerr KG. The prophylaxis of bacterial infections in neutropenic patients. J Antimicrob Chemother 1999; 44:587–91. 88. Pierelli L, Perillo A, Greggi S et al. Erythropoietin addition to granulocyte-colony stimulating factor abrogates life-threatening neutropenia and increases peripheral blood progenitor-cell mobilization after epirubicin, paclitaxel and cisplatin in combination chemotherapy. J Clin Oncol 1999; 17:1288–96.

Comprehensive Geriatric Oncology

948

89. Ratain MJ, Schilsky RL, Choi KE et al. Adaptive control of etoposide administration: impact of interpatient pharmacodynamic variability. Clin Pharmacol Ther 1989; 45:226–33. 90. Silber JH, Fridman M, Di Paola RS et al. First-cycle blood counts and subsequent neutropenia, dose reduction or delay in early stage breast cancer therapy. J Clin Oncol 1998; 16:2392–400. 91. Extermann M, Chen A, Cantor AB et al. Predictors of toxicity from chemotherapy in older patients. Proc Am Soc Clin Oncol 2000; 19: 617a. 92. Schijvers D, Highley M, DeBruyn E et al. Role of red blood cell in pharmakinetics of chemotherapeutic agents. Anticancer Drugs 1999; 10:147–53. 93. Ratain MJ, Irinotecan dosing. Does the CPT in CPT 11 stand for ‘can’t predict toxicity’? J Cin Oncol 2002; 20:7–8. 94. Balducci L, Hardy CL. Anemia and aging: relevance to the management of cancer. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:442–52. 95. Chaves PH, Volpato S, Fried L. Challenging the world health organization criteria for anemia in the older woman. J Am Geriatr Soc 2001; 49(S3):A10. 96. Kikuchi M, Inagaki T, Shinagawa N. Five-year survival of older people with anemia: variation with hemoglobin concentration. J Am Geriatr Soc 2001; 49:1226–8. 97. Izaks GJ, Westendorp RGJ, Knook DL. The definition of anemia in older persons. JAMA 1999; 281:1714–17. 98. Ana BJ, Suman VJ, Fairbanks VF et al. Incidence of anemia in older people: an epidemiologic study in a well defined population. J Am Geriatr Soc 1997; 45:825–31. 99. Gabrilove JL, Einhorn LH, Livingston RB et al. Once-weekly dosing of epoetin alfa is similar to three-times weekly dosing in increasing hemoglobin and quality of life. Proc Am Soc Clin Oncol 1999; 18:574a. 100. Cleeland CS, Demetri GD, Glaspy J et al. Identifying hemoglobin levels for optimal quality of life. Results of an incremental analysis. Proc Am Soc Clin Oncol 1999; 18:574A (Abst 2215). 101. Liao S, Ferrell BA. Fatigue in an older population. J Am Geriatr Soc 2000; 48:426–30. 102. Metivier F, Marchais SJ, Guerin AP et al. Pathoysiology of anaemia: focus on the heart and blood vessels. Nephrol Dial Transplant 2000; 15:14–18. 103. Wu WC, Rathore SS, Wang Y et al. Blood transfusions in elderly patients with acute myocardial infarction, N Engl J Med 2001; 345: 1230–6. 104. Pickett JL, Theberge DC, Brown WS et al. Normalizing hematocrit in dialysis patients improves brain function. Am J Kidney Dis 1999; 33:1122–30. 105. Biichner T. Treatment of acute myeloid leukemia in older patients. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004: 553–60. 106. Cova D, Balducci L. Cancer chemotherapy in the older patient. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004: 463–88. 107. Carreca I, Balducci L. Oral chemotherapy in the older cancer patient. Am J Cancer (to be published). 108. Spielberger RT, Stiff P, Emmanouilides C et al. Efficacy of recombinant human keratinocyte growth factor (rHuKGF) in reducing mucositis in patients with hematologic malignancies undergoing autologous peripheral blood progenitor cell transplantation after radiation-based conditioning. Results of a phase 2 trial. Proc Am Soc Clin Oncol 2001; 20:7a (Abst 25).

44 Oncological emergencies in the elderly Lodovico Balducci, Claudia Beghe’ Introduction This chapter explores the interaction of aging and oncological emergencies. Aging involves progressively restricted functional reserve of multiple organ systems, and lessened cognition, social, and economic resources.1 These changes lead to reduced tolerance of physical, emotional, and social stress; hence, it is reasonable to expect that: • Oncological emergencies are more common and more severe in the elderly. • The presentation of oncological emergencies changes with age. • New forms of emergencies may develop in older individuals.

A construct of aging and emergencies Aging is highly individualized and multidimensional. Changes in different domains may conspire in the genesis, presentation, and outcome of an emergency in the older cancer patient. In the example shown in Figure 44.1, reduced hematopoietic reserve enhances the risk of neutropenia, which, combined with reduced neutrophil and lymphocytic function and enhanced susceptibility to mucositis from chemotherapy and radiotherapy,2,3 increases the risk of a severe infection by intestinal pathogens. This risk is further compounded by the delay in symptom recognition from blunted perception (see Chapter 18 of this volume4) and absence of a caregiver capable to arrange the timely transportation of the patient to a care center5 (see Chapter 63 of this volume6). At the same time, reduced cardiovascular and cerebrovascular reserve may be synergistic in causing an older patient’s death with severe infection (see Chapter 184). For the same reasons, development of paraplegia from spinal cord compression may be more likely in older individuals. This model has important practical implications: 1. It generates testable hypotheses related to the pathogenesis, management and prevention of emergencies in the older cancer patient. 2. It indicates why delirium is common in the elderly, even in the presence of minor infections,7 owing to a reduction in cerebrovascular reserve.

Comprehensive Geriatric Oncology

950

Figure 44.1 Complex of factors that may complicate the recognition and management of medical emergencies in the aged. 3. It illustrates which elements of aging are modifiable and can be targeted for prevention of emergencies. Whereas the reduction in hematopoietic reserve is not reversible, severe neutropenia may be prevented by the prophylactic use of colony-stimulating factors;2,8,9 likewise, prophylactic antibiotics that do not cover anaerobes may ameliorate the risk of gram- negative infections due to intestinal pathogens.10 The provision of a caregiver is pivotal in the management of the older cancer patient; at the same time, it is essential to recognize and remedy situations that may render the patient reluctant to leave the home, such as the care of a disabled or demented spouse5 (see Chapter 636). The maintenance of hemoglobin levels at 12g/dl or higher may improve cardiovascular and cerebrovascular function11 and lessen the risk of death from severe infection (see Chapter 37 of this volume12). 4. It reveals the benefits of a Comprehensive Geriatric Assessment (CGA) in the prevention of oncological highly individualized, the comprehensive assessment emergencies in the older aged person. As aging is reveals the special needs of individual patients.13,14 Using this example as a guide, we shall explore physiologic, cognitive and sociologic changes of age that may worsen the risk and the outcome of oncological emergencies.

Oncological emergencies in the elderly

951

Physiological changes A number of changes (Table 44.1) make older individuals more susceptible to oncological emergencies. Body composition Decline in lean body weight and in the rate of protein synthesis15 (see Chapter 184) may be responsible for delayed wound repair,16 inadequate cellular and humoral immunity, and delayed recovery of normal tissues destroyed by chemotherapy and radiotherapy (including hematopoietic tissues and mucosas). Reduction in total body water enhances the susceptibility of older individuals to volume depletion from gastrointestinal obstruction, mucositis, and diarrhea17,18 (see Chapter 39 of this volume19). Reduction in total body water may lead to a reduction in the volume of distribution of water-soluble agents, increased concentrations of these compounds in the circulation, and augmented risk of toxicity.18 Cardiovascular changes These include a higher prevalence of arteriosclerosis, coronary artery diseases,20 hypercholesterolemia, and hypercoagulability.21 These may enhance the risk of thromboembolic phenomena both from cancer and from cancer chemotherapy21 and hormonal therapy,21 the risk of anoxia, including myocardial cerebral and renal anoxia, in the presence of anemia, infection, and hypotension, and the risk of cardiac failure from cardiotoxic drugs.18 Gastrointestinal changes These include increased proliferation of crypt cells, which portends increased destruction by cell cycle-active agents22 and depletion of mucosal stem cells, which results in delayed repair of mucosal damage. These changes increase the risk and the duration of chemotherapy- and radiotherapy-induced mucositis. In addition, a number of hepatic functions are affected by aging, including a decline in the activity of phase 1 cytochrome P450-dependent reactions, which may increase the risk of drug interactions, compounded by polypharmacy in older cancer patients23–25 (see Chapter 41 of this volume26). Renal changes These include a decline in glomerular filtration rate (GFR), which is probably the most consistent age-related physiologic alteration, and leads to reduced renal excretion of drugs and their active metabolites (see Chapters 18 and 394,19).

Comprehensive Geriatric Oncology

952

Hematopoietic changes These are of special concern, because the hematopoietic complications of chemotherapy and radiotherapy are almost universal. The incidence and severity of the most common oncological emergencies—infection and bleed-prolonged myelodepression2,5,24,25 (see Chapter 184). Both ing—are increased in the aged owing to deeper and more experimental and clinical evidence indicate that the hematopoietic reserve becomes more restricted with aging: • The concentration of pluripotent hematopoietic progenitors is reduced with aging in rodents.27–29 • The activity of telomerases and the length of telomeres of hematopoietic progenitors are also progressively reduced in rodents with age.30 • The ability of both experimental animals and humans to increase the concentration of hematopoietic progenitors in the face of hematopoietic stress declines with age.28,29,31– 33

• The production of hematopoietic cytokines is decreased and that of hematopoiesisinhibiting cytokines increased in the marrow of both aging animals and aging humans.2,34–36 • The active hematopoietic tissue decreases with age in humans (see Chapter 36 of this volume37).

Table 44.1 Physiological changes due to aging that may influence the occurrence of oncological emergencies Change

Consequences

Body composition

• Decreased volume of distribution of water-soluble drugs→increased serum concentration→increased toxicity

• Decline in protein and water • Decreased protein synthesis • Possible increase in adipose tissue

• Increased susceptibility to malnutrition from cancer and chemotherapy • Increased susceptibility to volume depletion

Circulatory system • Decreased number of myocardic sarcomeres • Arteriosclerosis of peripheral vessels • Venous pooling and decreased venous circulation

• Increased risk of myocardial toxicity from chemotherapy

• Increased risk of tissue anoxia, which may lead to perforation of viscera and to cerebral, myocardial, and renal ischemia

Oncological emergencies in the elderly

953

• Increased risk of thromboembolic phenomena connected with cancer, chemotherapy, and hormonal therapy • Increased risk of fluid retention with hormonal therapy Genitourinary system

• Decreased excretion of drugs and active drug metabolites

• Decreased glomerular filtration rate

• Increased risk of urinary retention

• Prostate hypertrophy • Neurogenic bladder dysfunctions Gastrointestinal system • Gastrointestinal atrophy and dysmotility

• Decreased absorption of drug and food→increased risk of malnutrition

• Increased proliferation of mucosal cells, with depletion of mucosal stem cells

• Increased risk of chemotherapy-related diarrhea and mucositis→dehydration

Hematological system

• Increased risk of neutropenia, infections, and infectious death

• Depletion of hematopoietic stem cell reserve

• Increased risk of thrombocytopenia and bleeding

• Decreased production of • Increased risk, prevalence, and incidence of anemia, hematopoietic cytokines and which may enhance the risk of chemotherapy-induced increased concentration of cytokines myelodepression, of fatigue and functional dependence, that inhibit hematopoiesis and of delirium • Decreased sensitivity of stem cells and hematopoietic progenitors to the stimulatory effects of hematopoietic ytokines Central nervous system • Decreased number of neurons • Increased prevalence of degenerative changes

• Increased susceptibility to cognitive complications of chemotherapy • Increased risk of delirium • Altered perception of pain

Peripheral nervous system

• Altered perception of pain

• Decreased number of neurons

• Increased susceptibility to neurological complications of chemotherapy

• Demyelinization and decreased conduction rate • Increased risk of autonomic dysfunctions (postural hypotension, urinary retention and incontinence,

Comprehensive Geriatric Oncology

954

impotence) Systemic effects (endocrine and immune systems)

• Increased risk of intracellular (fungal, viral, and mycobacterial) infection

• Decline in cellular immunity

• Decreased protein synthesis

• Increased production of inflammatory cytokines

• Decreased hematopoiesis

• Decreased production of growth hormone, insulin-like growth factor I, and gonadotropins

• Fatigue

• The risk of anemia of unknown cause increases with age in humans. In some cases, the anemia is due to absolute or relative erythropoietin deficiency.2,3,38 • The risk of neutropenia and neutropenic infections from cytotoxic chemotherapy increases with age 26,39–49 While the vulnerability of the hematopoietic system to myelophthysis and cytotoxic agents increases with age, it is important to remember that the hematopoietic response to pharmacological doses of hematopoietic growth factors is maintained in the aged.31,32,39,44,47,48 These factors represent effective protection from deadly infections. Neurological changes Central nervous system There is a reduction in the number of neurons of the central nervous system (CNS) and an increased prevalence of degenerative changes, such as neurofibrillary plaques and amyloidosis.50,51 Hence, the prevalence of cognitive disorders, from memory loss to dementia52,53 to delirium,54 increases with age. Disturbances of perception that may increase the threshold for pain and other symptoms55 are also more common. These changes may be pivotal to the genesis of oncological emergencies in older individuals, since they may: • predispose older individuals to the cognitive complications of chemotherapy and radiotherapy;56 • predispose older individuals to delirium in the presence of infection or other minor stresses; • delay the recognition of catastrophic complications, such as spinal cord compression and visceral perforation. Peripheral nervous system Changes in the peripheral nervous system include decreased conduction velocity and fragmentation of the myelin sheath, and may predispose older individuals to neuropathic complications of cytotoxic drugs, including vinca alkaloids, epipodophyllotoxins, cisplatin, and taxanes.57,58 By themselves chronic in nature, peripheral neuropathies may

Oncological emergencies in the elderly

955

alter the perception of pain and delay the recognition of abdominal, cardiac, and spinal emergencies. In addition, peripheral neuropathy may precipitate functional dependence that is devastating and costly. Declines in vision and hearing These are almost universal after age 8559 due to peripheral nerve degeneration, and may lead to some degree of functional dependence, especially in use of the telephone and transportation. Systemic changes Systemic changes due to aging may reduce the tolerance of cancer and its treatment and precipitate an emergency. They include the following: • Endocrine senescence involves reduced production of sexual hormones, growth hormone, and insulin-like growth factor I (IGF-I). These changes may be responsible for a catabolic condition (somatopause; see below) that minimizes the response to stress.60,61 • Immune senescence involves a complex variety of changes tending to suppress cellmediated immunity. These changes predispose the older individual to fungal, viral, and parasitic infections by intracellular microorganisms.62,63 (see Chapter 13 of this volume64). • Increased production of inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor (TNF), may inhibit hematopoiesis and protein synthesis, and in general lead to a catabolic status.65–67 The emerging construct of somatopause encompasses most systemic changes of aging. Somatopause indicates a catabolic status resulting from the simultaneous exhaustion of growth hormone and increased production of inflammatory cytokines.60,61 Precise diagnostic criteria for somatopause are still lacking. Functional changes Functional dependence becomes more common with age, and may be associated with increased incidence and severity of oncological emergencies. A taxonomy of age may be constructed based on the degree of functional dependence with: (Table 44.2).66,68–70 Functional dependence is associated • an increased risk of developing complications of cytotoxic chemotherapy;71 • a lessened ability to seek timely medical treatment in case of an emergency; • more generally, severely restricted functional reserves of multiple organ systems and greater requirements upon caregivers. Dependence in instrumental activities of daily living (IADL) is more common than generally thought: it has been found that approximately 70% of cancer patients aged 70

Comprehensive Geriatric Oncology

956

and older, attending the senior adult oncology program at the H Lee Moffitt Cancer Center and Research Institute in Tampa, were dependent in at least one IADL.13

Table 44.2Taxonomy of aging Stage

Rehabilitation needs

Clinical characteristics

Primary

No rehabilitation needs beside preservation • Independent in ADL and IADL of function • No serious comorbidity • No geriatric syndromes • 2-year mortality rate 8%

Intermediate

Need for functional rehabilitation that may be fully successful

• Dependent in one or more IADL (with exclusion or housekeeping and laundering) • Presence of some incapacitating comorbidity • No geriatric syndromes • 2-year mortality rate 16–30%

Secondary (frailty)

Functional rehabilitation is probably ineffective; the main goal is to delay further functional deterioration

Classical definition: • Dependent in one or more ADL • Presence of one or more geriatric syndrome • Serious comorbid conditions • 2-year mortality rate ~40% Alternative definition: three or more of the following: • Involuntary weight loss ≥10% of original body weight over 1 year • Low energy level • Slow movements • Difficulty in initiating movements • Decreased grip strength

Tertiary (near death)

Further functional deterioration unavoidable

• Immediately life-threatening condition • 2-year mortality rate >95%

ADL, activities of daily living; IADL, instrumental activities of daily living.

Oncological emergencies in the elderly

957

The prevalence of IADL dependence may be even higher in the general population, since patients attending a tertiary care cancer center may well be selected in terms of better function and greater wealth. Two definitions of frailty are provided in Table 44.2—they should be considered complementary. The classical definition72 allows almost-immediate recognition of frailty. The alternative definition is more sensitive, but more time-consuming; it may be applied to individuals who do not appear frail according to the classical definition, but whom the practitioner suspects of frailty.73 Medical changes Two medical aspects of aging may influence oncological emergencies: • There is an increased prevalence of comorbidity14 (see Chapter 19 of this volume74). • A number of disorders emerge that are more typical of age and are referred to as ‘geriatric syndromes’ (Table 47.3)3,68,75 (see Chapter 1974). These syndromes should be qualified: depression when severe, persistent for more than 2 weeks, and resistant to common pharmacological interventions; delirium when it follows mild infections or administration of drugs without known CNS complications; falls when they are frequent (≥3 a month) and without recognizable causes; incontinence when it is complete and irreversible. Failure to thrive is a condition of progressive weight loss despite adequate food intake;76 neglect and abuse involves poor self-care and vulnerability to financial swindling and to emotional and physical abuse.77 This condition is generally associated with dementia, depression, and loneliness. Comorbidity and geriatric syndromes may contribute to render the emergencies more likely and more serious in a number of ways. Comorbidity may be associated with reduced function of a specific organ system and increased susceptibility to complications ofcancer and cancer treatment on that specific

Table 44.3 Geriatric syndromes • Dementia • Depression • Delirium • Falls • Spontaneous fractures • Severe incontinence • Neglect and abuse • Failure to thrive

organ. Anemia may enhance the risk of myelodepression from cytotoxic chemotherapy;78–82 coronary artery disease may enhance susceptibility to cardiotoxic agents, including anthracyclines;83 degenerative brain disease may enhance the risk of

Comprehensive Geriatric Oncology

958

delirium;43,84 pre-existing heart disease, reduced lean body weight, and restricted hematopoietic reserve may contribute to an enhanced risk of surgical mortality, especially from emergency surgery.85 Dysfunction of certain organ systems may enhance the seriousness of treatment complications and transform relatively benign conditions into lethal ones. For example, diarrhea due to fluorinated pyrimidines may result in severe fluid depletion when the kidney loses its ability to retain fluid and the perception of thirst is blunted. Severe volume depletion may become deadly hypovolemic shock in the presence of heart disease and autonomic dysfunction. In the presence of coronary artery disease, volume depletion may lead to myocardial infarction. Pre-existing diseases may delay the recognition of emergencies. This may occur through a number of mechanisms, including masking and summation.86 In masking, symptoms of pre-existing disease may occult a new condition. A classical example is the failure to recognize impending spinal cord compression because of pre-existing back pain from spinal stenosis. Likewise, an inadequate inflammatory response, due to immunosuppressive treatment and chronic diseases, may prevent timely recognition of bowel perforation. In summation, the effects of two coexisting diseases synergistically produce a syndrome that is unrelated to either condition. A classical example summation is delirium that may develop from conditions unrelated to the CNS, such as a combination of of upper respiratory infection and heart failure. Pre-existing diseases and geriatric syndromes may prevent timely access to care. For example, a fall on the way to the telephone by a patient who lives alone may delay for hours or days admission to hospital for neutropenic infection. Social aging A number of demographic and social changes may influence the recognition and management of oncological emergencies in the aged. There is a higher prevalence of widowed women in the older population. This is due to the more prolonged life-expectancy of women. For lack of a companion or adult children living nearby, the majority of these widows live alone. Although they may be able to provide for their daily needs in conditions of homeostasis, they may not be able to react properly to an emergency. Disease may cause deconditioning and functional dependence in persons who previously were fully dependent. This occurs especially after prolonged hospitalization.87– 89

The prevalence of functional dependence increases with age. By age 85, at least 50% of the population is dependent in one or more activities of daily living (ADL).59,68,69 Progressive declines of vision and hearing may cause dependence even in those persons who are cognitively intact;69 as these changes occur slowly, many persons may adapt to them in conditions of homeostasis, but at the same time their readiness to confront an emergency wanes. The person who supervises the care ofan older individual at home (the caregiver) is often inadequate. In many cases, the caregiver is an elderly spouse with health problems

Oncological emergencies in the elderly

959

of his or her own, or an adult child, already committed to his or her profession or family5,89 (see Chapter 636). The economic aspects of aging may definitely predispose to an emergency. Older individuals may not be able to buy oral medications, such as antibiotics used to prevent gram-negative sepsis during prolonged neutropenia, or to pay for transportation to the clinic to receive daily growth factors. In general, financial restrictions may prevent hiring of adequate home help or admission to an assisted living faculty.89 There may be adaptive reactions following admission to an assisted living facility or to a nursing home. These may compromise the administration of antineoplastic treatment.90 Clinical implications of age-related changes Medical, functional, social, and emotional aspects of aging influence the genesis and management of medical emergencies. Clearly, a comprehensive assessment of the older person, described in Chapter 19,74 is one of the keys for ameliorating the outcome of oncological emergencies in older cancer patients. The benefits of the geriatric assessment in other areas of geriatrics include: • improved functional preservation and survival and decreased hospitalization and institutionalization rate of older individuals;91–94 • prevention of a number of conditions that may facilitate the development of emergencies, including in-hospital delirium and falls.95–97 In clinical oncology, the geriatric assessment allows the practitioner a number of interventions that minimize the risk and seriousness of an emergency. It is necessary to individualize patient treatment based on life-expectancy, tolerance of treatment, and expected outcome. The taxonomy of aging proposed by Hamerman et al65 (Table 44.2) may be used as the basis for these decisions, as illustrated in Figure 44.2. Each group of

Comprehensive Geriatric Oncology

960

Figure 44.2 Algorithm for the management of the older patient with chemotherapy. patients has a different life-expectancy98 and different functional reserve and stress tolerance. The least well-defined group in this classification is the intermediate group, which is the most common among older cancer patients. The integration of the Hamerman taxonomy with the concept of vulnerability, proposed by Saliba et al70 (see Table 43.5 in Chapter 43 of this volume99), may further qualify this group of individuals. These investigators defined vulnerability according to a score obtained from a 13-item questionnaire, and established a clear correlation between the score, life-expectancy, and

Oncological emergencies in the elderly

961

risk of functional decline over 2 years. It should be underlined here that frailty is a chronic condition. It should not be confused with the rapid changes in the functional status that are common among older patients faced by serious diseases. For example, we have had the opportunity to manage an 82-year-old woman who had come to the hospital hypotensive and confused, but until a week earlier had been living alone and fully independent. The patient had a large cell lymphoma of the stomach and had become volume-depleted owing to vomiting for 3 days. After appropriate fluid resuscitation, she received CHOP chemotherapy at full dose and experienced a complete recovery. It would have been unfortunate if her treatment had been compromised by a wrong determination of frailty. Special precautions should be taken for patients who are at increased risk of complications, recognized thanks to the CGA. As indicated in Figure 44.2, special precautions include initial reduction of chemotherapy doses, closer observation, provision of adequate caregiver, etc. Conditions that were previously unrecognized and that may interfere with cancer treatment should be brought to light. These include comorbidity, functional dependence, malnutrition, and poor economic resources. In individuals at risk, it is important that malnutrition be prevented. Mild memory loss and depression should be addressed, since even mild depression, if untreated, may be associated with reduced life-expectancy in older individuals.100–104 Furthermore, mild depression may predispose to severe depression in the course of stress. The social situation of a patient should be considered, with the provision of an adequate caregiver, temporary admission to a assisted living facility, and the assurance of regular access to meals and healhcare. Although one tries to avoid the use of chronological age as a landmark of senescence, it may be helpful to acknowledge two chronological milestones: ages 70 and 85. Age 70 may be considered the lower limit of senescence, because the prevalence of age-related changes increases steeply between ages 70 and 75.105 Age 85 represents a warning sign for frailty.59 A number of laboratory and physical performance tests have been proposed for the evaluation of the older person.106–112 Of special interest, simultaneous increase in the concentrations of IL-6 and D-dimer in the circulation appears to be diagnostic of frailty.112 It is not far-fetched to expect that these tests may gain wider clinical application in the future, but it is not clear whether they may ever substitute for, rather than complement, the CGA. The panel for the guidelines on the management of the older patient in the US National Cancer Center Network (NCCN) has recognized the importance of the CGA in the management of the older cancer patient, and has recommended that some form of CGA be performed in all cancer patients aged 70 and older.8 A number of questions linger related to the CGA. These are outlined in Chapter 19,74 and may be summarized thus: • Who should perform the CGA? Ideally, the CGA should be performed on a regular basis by the primary care physician of the older patient and transmitted to other specialists, including medical oncologists. Unfortunately, less than half of individuals over 70 have a primary care physician in the USA,113 and even fewer have a primary care physician willing to invest the time necessary to coordinate patient care. In these

Comprehensive Geriatric Oncology

962

circumstances, it is reasonable to expect that any practitioner involved in the management of older individuals should be able to perform and interpret a CGA. • Is a full assessment necessary for all patients? A number of screening tests may be used to determine which patient need a full assessment8 (see Chapter 1974). Although not foolproof, this screening test may be better than nothing in the context of a busy oncological practice. • Could the determination of vulnerability forsake the need for a full CGA? Certainly, the determination of vulnerability represents an important contribution to the management of the older aged person.70 As vulnerability does not include nutritional or caregiver issues, it is unlikely that vulnerability alone may provide all information necessary to prevent emergencies in older cancer patients. With this construct of aging as background, we shall study in detail oncological emergencies in the aged. Oncological emergencies in the elderly Common emergencies and age Neutropenic infections Aging may be associated with increased risk and severity of neutropenic infections, on the following basis. The risk of chemotherapy-induced neutropenia increases with age24,25,39,49,114,115 (see Chapter 3919). This may appear to be controversial, since six retrospective studies of patients treated in cooperative oncology groups and major cancer centers116–121 failed to detect an increased risk of chemotherapy-induced neutropenia after age 70. As expected in this context, however, the patient population was highly selected, and the oldest old (i.e. those over 85) were not represented. These studies are important, since they show that cytotoxic chemotherapy may be tolerated without special support even by persons of advanced age, but they do not provide reliable information on the whole elderly population. At the same time, a number of other studies have shown quite a different picture. Reviewing the experience of the Southwest Oncology Group (SWOG), Kim et al114 showed that aging was associated with increased risk of neutropenia and neutropenic infections. Similar conclusions had been reached by Crivellari et al115 in reviewing the incidence of myelodepression in patients of different ages treated according to the adjuvant protocols of the International Breast Cancer Study Group (IBCSG). Dees et al25 demonstrated that the risk and severity of myelodepression following adjuvant treatment of breast cancer with cyclophosphamide and doxorubicin increases with the age of the patients. They also noticed that the myelotoxicity was cumulative (i.e. became more severe with the number of treatment cycles) for woman aged 65 and older, but not for younger women. This observation was highly suggestive of reduced hematopoietic reserve in the elderly. Age over 65 was found to be associated with increased risk of neutropenic infection and infectious death in patients with acute myeloid leukemia (AML).122–127 Of course, in the case of AML, the disease itself might have led to

Oncological emergencies in the elderly

963

suppression of hematopoiesis, because AML in older individuals generally follows myelodysplasia, which is characterized by ineffective hematopoiesis. Perhaps the most convincing evidence derives from nine studies of older patients with large cell lymphoma treated with CHOP and CHOP-like chemotherapy regimens (Table 44.4).39–49,128 In these studies, eight of which were prospective, the risk of grade 3 and 4 neutropenia was consistently 50% or higher, and the risk of death from neutropenic infection also varied between 5% and 30%.39–49 In addition, with a now-obsolete regimen (MACOP-B), the risk of infectious death was 3% below age 60 and 11% for older patients.129 Of special interest, Gomez et al130 showed that the risk of neutropenic infections was higher after age 70, especially in persons with poor functional status. A number of pre-existing conditions become more common with age and may contribute to the risk and the lethality of neutropenic infections. These conditions include urinary incontinence and retention (which favor bacterial colonization of the urinary tract) and diverticulosis, constipation, chronic bronchitis, and poor oral care, (which favor overgrowth of pathogens in the colon, the upper airways, and the mouth). The bacteria that colonize these systems may be resistant to multiple antibiotics, especially in elderly patients living in assisted living facilities.131 Infection may present in an unusual way and may be recognized late. This, as well as inadequate access to care, may lead to delayed recognition and delayed management of the infection. Common presentation of infections in the elderly may include delirium (encompassing a wide array of manifestations from somnolence to agitation), absence of fever, and hypothermia.132,133 Delirium may be more prominent and distressing than symptoms related to specific organs, and thus may distract the attention of the observer who is not used to the management of older individuals with infection. Another more subtle manifestation of infection in older individuals is the development of functional dependence in those who were previously completely independent. Common manifestations of dependence include incontinence, unwillingness or inability to eat or to provide to one’s own meal, inability to manage money, loss of interest in personal relationships, and neglect of self-care. Some authors have proposed that

Table 44.4 Incidence of life-threatening neutropenia; neutropenic infections and death in older individuals with large cell non-Hodgkin lymphomas treated with CHOP-like regimens Authors

No. of Regimen Age Neutropenia Neutropenic Treatment- Growth patients (%) fever (%) related factor deaths (%)

Zinzani et al39

161 VNCOPB

≥60

44

32

1.3 —

Sonneveld et al40

148 CHOP

≥60

NR

NR

14 —

CNOP

≥60+

NR

NR

13 —

26 CHOP

≥60

24

8

Gomez et al41

0 GMCSF

Comprehensive Geriatric Oncology

964

≥70

73

42

20 GMCSF

≥70

50

21

7 —

≥70

48

21

5 —

>70

9

7

12 —

CTVP

≥70

29

13

15 —

O’Reilly et al45

63 POCE

≥65

50

20

8 —

Armitage and Potter46

20 CHOP

≥70

NR

NR

30 —

≥60

NR

12–20

5 —

Tirelli et al42

119 VMP CHOP

Bastion et al43

Coiffier et al49

444 CVP

399 CHOP/ CHOPrituximab

NR, not reported. GM-CSF, granulocyte-macrophage colony-stimulating factor.

any increase in body temperature above the usual body temperature (2°F or 1°C) be considered fever in older individuals132,133 and trigger investigation of infection. This approach requires that the temperature of older individuals be taken regularly around the clock—which may not be practical in the absence of a caregiver. No provision can substitute for the alertness of the provider in considering any sudden change in cognition, mood, and functional status as a warning sign of infection in older individuals receiving cytotoxic chemotherapy. Aging may be associated with important changes in the course of infection, including: • increased risk of death;132,133 • increased duration of antibiotic treatment;134–136 • increased risk of disability and functional dependence, with compromised quality of life;136–138 • delay in antineoplastic treatment and worsened outcome of cancer. Although the approach to neutropenic infections in older persons is not different from that in younger persons, two management-related issues deserve special attention in the aged, namely outpatient treatment with oral antibiotics and functional rehabilitation. Outpatient treatment of neutropenic infections was found to be safe and effective in low-risk patients.137–139 ‘Low-risk’ here includes absence of sepsis and of pneumonia, normal serum blood urea nitrogen (BUN), creatinine, and liver enzymes. Patients thus treated receive oral antibiotics, generally a quinolone and amoxicillin/clavulanic acid (or clindomycin for patients allergic to penicillin) The advantages of this approach include avoidance of the cost and the risks of hospitalization. In older individuals, these include delirium, functional deterioration, and nosocomial infections. Despite the lack of specific studies addressing outpatient

Oncological emergencies in the elderly

965

treatment of neutropenic infections in the elderly, it is reasonable to follow the same procedures used in younger patients, as long as the following conditions are met: • the patient lives less than a hour’s drive from an emergency room or treatment facility; • a caregiver is available on short notice 24 hours a day to evaluate the patient and to provide immediate help and transportation; • a visiting nurse is available to evaluate clinical changes in the patient’s condition. Special measures necessary to maintain the function of the older patient in the hospital include: • beds that can be lowered enough so that patients can go in and out on their own; • help and encouragement with feeding, grooming, and use of the bathroom; • daily walk, airway control, and aggressive management of depression;137 • minimization of physical and pharmacological restraints, which should be used only to prevent the patient from hurting him/herself; phenothiazines are preferred instead of benzodiazepines; if benzodiazepines are used, then those with the shortest half-life should be chosen, such as lorazepam.7,54,96 Prevention is undoubtedly the mainstay in the management of neutropenic infections in the elderly. Patients should be selected based on individual benefits and risks. These can be estimated according to the algorithm in Figure 44.2. Hematopoietic growth factors should be used as prophylaxis in all patients aged 70 and older receiving chemotherapy of dose intensity comparable to that of CHOP. This recommendation was unanimously supported by the NCCN panel for the guidelines for management of older cancer patients.8 The chairman of the American Society of Clinical Oncology (ASCO) guideline panel for the use of growth factors concurred with this recommendation,9 which is based on three considerations: safety and effectiveness of growth factors, lack of valid alternatives, and cost. The high risk of neutropenia, neutropenic infections and mortality in older patients is well documented (Table 44.4). Furthermore, two-thirds of the infectious deaths in older individuals occur during the first course of treatment;41 hence, by applying the current ASCO guidelines (which require an episode of neutropenic fever prior to instituting treatment with growth factors), these deaths could not be prevented. At the same time, at least four randomized and controlled studies have documented the activity of pharmacological doses of growth factors in older patients (Table 44.5). Whereas the benefits of growth factors have been clearly demonstrated, alternative form of infection prevention appear unadvisable or inadequate. Dose reduction may compromise the antineoplastic effects of treatment, according to five randomized controlled studies and a retrospective analysis (at least in patients with lymphoma).40,42,43,128,140,141 The value of prophylactic antibiotics has not been well established in older individuals, and at most they may be complementary to growth factors.138 From a pharmaco-economic viewpoint, the use of growth factors should not increase the cost of treatment, and may indeed lead to some cost savings.2,27,142,143 The incidence of neutropenic infections in the elderly is higher than the threshold of 40% above which the use of growth factors is cost-effective. Hospitalization is more costly in older than in younger individuals because it is more prolonged and may be associated with long-term functional complications.

Comprehensive Geriatric Oncology

966

Hemoglobin levels should be maintained at 12 g/dl or higher with erythropoietin. This recommendation is also unanimously supported by the NCCN panel for the management of cancer in the older person8 and is based on the facts that anemia is a risk factor for death in the course of serious infections,3,11–12 that anemia is an independent risk factor for myelodepression in older individuals receiving cytotoxic chemotherapy, according to five studies,78–82 and that anemia is associated with fatigue that may precipitate functional dependence and other iatrogenic complications.144–149

Table 44.5 Randomized controlled studies demonstrating the benefits of hematopoietic growth factors in older patients with large cell lymphoma receiving combination chemotherapy Study Zinzani et al39

No. of patients

Incidence of grade 3 and 4 neutropenia (96)

Incidence of neutropenic infections (%)

350

VNCOP-B +G-CSF

23

5

No GCSF

56

21

4.8

4.8

27.7

15.6

+G-CSF

22

2

No GCSF

44

9

Zagonel et al48 CHOP +G-CSF No GCSF Bertini et al44

90

VEPBC

G-CSF, granulocyte colony-stimulating factor.

The geriatric assessment may lead to recognition of coexisting problems that could contribute to the seriousness of infections. Such problems require management, including the following measures: • Provision of an adequate caregiver is recommended for all older patients, and is essential for vulnerable patients.70 The ideal caregiver should be fully independent, own personal transportation, and be able to help the patient on short notice.

Oncological emergencies in the elderly

967

• There is a need for optimal management of pre-existing conditions that may favor the development of infections, including diabetes, malnutrition, poor personal hygiene, constipation, restricted mobility, and depression. It should be emphasized that malnutrition is particularly likely during some forms of treatment, including combined chemoradiation to the chest. For these patients and for those with swallowing disorders, prophylactic gastrostomy or jejunostomy may be indicated. Volume depletion Volume depletion may lead to hypovolemic shock more rapidly in older than in younger individuals due to a limited reserve of body water and a blunted response of capacitance vessels to sympathetic stimulation. Mucositis, leading to dysphagia and diarrhea, is highlighted among the causes of volume depletion in older individuals. Several studies have shown that age is an independent risk factor for mucositis, especially that induced by fluorinated pyrimidines17,18,150–152 (see Chapter 3919). In the initial study by the Gastrointestinal Tumor Study Group (GITSG) of 5-fluorouracil (5-FU) and leucovorin, 10 patients aged 65 and older, but only 1 of those younger, have died as a direct consequence of volume depletion from mucositis, indicating that mucositis may quickly become an emergency in older individuals.18 Likewise, the mortality from the Salz regimen including 5-FU, leucovorin, and irinotecan was increased among older individuals.152 Not unlike neutropenic infections, the presentation of volume depletion may be delayed for a number of reasons, including poor appreciation of the initial symptoms of mucositis, inadequate fluid replacement due to swallowing disorders, and inadequate access to transportation. The mainstay of the management of fluid depletion includes timely fluid resuscitation. Early management may prevent both death and chronic complications, including functional dependence and delay of further chemotherapy. Both the patient and the caregiver should be alerted about mucositis, diarrhea, and their implications, and should be instructed to report immediately both diarrhea and any condition that may prevent fluid intake. Prevention of mucositis is not as effective as prevention of neutropenia, but some provisions may be helpful: • Sucralfate is effective in relieving the discomfort of mucositis, and maintaining fluid intake.150 • Keratinocyte growth factors have proved effective in ameliorating mucositis and should become available in the near future in the USA.154 Other growth factors, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and oral IL-11 (oprelvekin) are being explored for this purpose; so far, their activity has not been conclusively demonstrated.151,152 • A reduction of 25% in the initial dose of fluorinated pyrimidines may be prudent, especially in patients with some functional dependence and comorbidity: • Whenever feasible, the substitution of capecitabine for systemic fluorinated pyrimidines may be advisable.155 Thanks to the oral formulation of this drug, the exposure of normal tissues to 5-FU is minimized.

Comprehensive Geriatric Oncology

968

Visceral perforation The risk of spontaneous visceral perforation increases with age, owing to a number of factors, including ischemia, muscular atrophy, and higher prevalence of colonic diverticuli and constipation.156 Also, the presentation of visceral perforation may be less dramatic and acute than in the young, owing to less intense inflammation, blunted perception of pain, and summation with other conditions, such as diverticulosis and mesenteric ischemia, that may be associated chronically with abdominal swelling. The administration of chemotherapy or radiation therapy may both increase the risk and delay the recognition of visceral perforation. Early diagnosis may allow life-saving treatment for this mostly fatal complication. A high degree of suspicion is the key to early diagnosis. Patients at risk include those with intraluminal or intraperitoneal cancer, those treated with corticosteroids for a prolonged time, and those subjected to prolonged neutropenia. Rapid changes in mental status, a drop in blood pressure, or a sudden drop in neutrophil count may herald visceral perforation in these individuals, even in the presence of a benign physical examination of the abdomen, and should prompt proper investigation, including upright radiography of chest and abdomen, looking for free air. Emergencies typical of aging Delirium Any practitioner dealing with older individuals should be familiar with the causes and the management of delirium, one of the most vexing problems for the patient, the family and the caregiver. According to DSM-IV, the diagnosis of delirium involves an acute alteration of consciousness, with waxing and waning of orientation, disturbance of cognition, development over a short period of time (hours or days), accompanied by neurovegetative signs, including fever, tachypnea, and tachycardia.7 Delirium is always associated with an underlying organic disorder (Table 44.6). The pathogenesis of delirium is complex and may involve many different conditions. Recent studies have shown that delirium is more likely in the presence of high concentrations of cytokines in the circulation.157 The assessment of delirium involves the differential diagnosis between delirium and the so-called catastrophic reactions that represent acute exacerbations of advanced dementia and are associated with delusions and hallucinations.7,157 This differentiation requires considerable experience, and is based on the capacity of attention: the patient with delirium experiences a continuous variation in focus, while the patient with a catastrophic reaction is generally well focused on his or her delusions or inappropriate endeavor. Delirium reveals a serious underlying disease. In addition, it is a geriatric syndrome indicating the frailty of the patient. The differential diagnosis of delirium in the older cancer patients should be related to the specific context in which delirium occurs. Common clinical pictures include:

Oncological emergencies in the elderly

969

Table 44.6 Differential diagnosis of delirium Drugs E electrolytes L Infection Restraints Immobilization Urinary catheter Malnutrition

• Delirium occurring approximately 10 days to 2 weeks from the administration of chemotherapy should be considered a manifestation of infection unless proven otherwise, and its management includes blood urine and sputum cultures, chest radiograph, complete blood count, and broad-spectrum antibiotic coverage. • Delirium in a patient with intraabdominal cancer should suggest the possibility of visceral perforation. • Delirium in a patient in whom new medications have been instituted, especially pain medications or corticosteroids, suggests a drug-related cause.158,159 In the case of drugrelated delirium, one should consider drug withdrawal. Older individuals may forget to take their pain medications or may deliberately omit to take them because they are troubled by nausea and constipation. • Delirium in the presence of prolonged nausea and vomiting, or reduced food intake, suggests a metabolic cause, such as hypercalcemia, hyponatremia, or uremia. Some medications, including corticosteroids and diuretics, may mask diabetes. • In the presence of cancer, there is always the possibility that delirium is a manifestation of CNS involvement, especially for those neoplasms with high likelihood to metastasize to the CNS or to produce neoplastic meningitis. These include large cell lymphoma, melanoma, and small cell cancer of the lung. • Finally, in older individuals with multiple comorbidities, delirium may also be a manifestation of a coexisting condition, especially cardiovascular diseases, and may be totally independent from cancer. Upon presentation of delirium, the following steps should be taken: necessary: • Recent medical history should be reviewed, including the dates of chemotherapy, the most recent complete blood counts, recent changes of medication (especially opioid analgesics and glucocorticoids), changes in bowel habit, reduced food intake, and recent episodes of nausea and vomiting. • Physical examination should assess the patient for fever, postural hypotension, signs of volume depletion, (e.g. decreased skin turgor and lack of jugular vein distention with the patient lying supine), new cardiac abnormalities suggesting coronary artery diseases (e.g. an S4 gallop or a pansystolic murmur of mitral regurgitation), signs of

Comprehensive Geriatric Oncology

970

pulmonary infection (including rales), pleural effusion, bronchial breathing signs of acute abdomen (including rebound tenderness and disappearance of bowel sounds), and presence of focal neurological signs suggesting a recent cerebrovascular accident. • Immediate laboratory tests should include complete blood counts, serum glucose, BUN, serum creatinine, electrolytes (including magnesium and calcium), hepatic and cardiac enzymes, serum troponin levels, blood cultures and sensitivity, and urine culture, and radiograph of the thorax and an electrocardiogram should be taken. • Additional tests, including magnetic resonance imaging (MRI) of the brain, lumbar puncture, possibly a ventilation/perfusion scan of the chest, and abdominal computed tomography (CT) scans, should be performed if dictated by the clinical situation and if no diagnosis has emerged from the initial evaluation. Management includes rapid control of the causes of delirium, management of agitation, and prevention. Once the diagnosis of delirium has been established, emergency admission to hospital is mandatory, because the patient needs to be prevented from harming him/herself or other individuals and needs to receive intravenous fluids and medication. Furthermore, emergency interventions available only in hospital may be required. Whereas the diagnostic workup may be initiated in the outpatient department, outpatient management of delirium should be discouraged. While the cause of delirium is sought, it is prudent to establish venous access with intravenous fluid running, and to start broad-spectrum antibiotics in patients at risk for neutropenic infections. The management of agitation should be directed exclusively at preventing personal harm: it has been stated several times that it is ethically unacceptable to use physical or pharmacological restraints because the patient disturbs other patients or because the hospital is short-staffed. One-to-one supervision should be instituted as necessary. If medications is to be used to resolve agitation, the haloperidol or droperidol is preferred.27 Prevention of delirium includes prevention and early detection of its causes, such as infection, volume depletion, hyperglycemia, and anemia, as well as a multidisciplinary effort to manage conditions that may lead to delirium, such as depression, loneliness, family tensions, poor food intake, and polypharmacy. A multidisciplinary intervention has proved to be effective in preventing delirium in hospitalized older patients, and appears to be the most promising approach to the prevention of delirium in the older patient with cancer. Conclusions Oncological emergencies are common in older individuals. Age is generally associated with increased risk and severity of neutropenic infections, volume depletion, and visceral perforation. In the older patient, delirium as an emergency presentation is more common than in younger individuals. Prevention is the most effective management of emergencies in older individuals, and includes prophylactic use of hematopoietic growth factors in patients treated with moderately toxic chemotherapy, maintenance of hemoglobin at or above 12g/dl, lower initial dose of fluorinated pyrimidines, aggressive fluid replacement in the presence of

Oncological emergencies in the elderly

971

diarrhea and mucositis, prevention of malnutrition, and good mouth, skin, and bowel hygiene. In general, a multidisciplinary assessment of the older cancer patient seems the key to emergency prevention, since it allows: • recognition of patients at high risk for complications of chemotherapy; • evaluation of the adequacy of the caregiver; • proper management of coexisting conditions that may enhance the risk of treatment complications; • rehabilitation of functional disability; • prevention of malnutrition and polypharmacy. Ideally, older individuals should have a primary care provider to coordinate their care and direct the patient in the case of an emergency. In the absence of such a provider, it behooves the oncologist to assume this role. References 1. Balducci L, Repetto L. A case for geriatric oncology. Lancet Oncol 2002; 3:287–97. 2. Balducci L, Hardy CL, Lyman GH. Hematopoietic growth factors in the older cancer patient. Curr Opin Hematol 2001; 8:170–87. 3. Balducci LM, Extermann M. A practical approach to the older patient with cancer. Curr Probl Cancer 2001; 25:6–76. 4. Duthie EH Jr. Physiology of aging: relevance to symptoms, perceptions, and treatment tolerance. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:207–22. 5. Weitzner MA, Haley WE, Chen H. The family caregiver of the older cancer patient. Hematol Oncol Clin North Am 2000; 14: 269–82. 6. Haley WE, Burton AM, LaMonde LA, Schonwetter RS. Family caregiving issues in geriatric oncology. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:843–52. 7. Chan DC, Brennan NJ. Delirium: making the diagnosis, improving the prognosis. Geriatrics 1999; 54:28–42. 8. Balducci L, Yates J. Guidelines for the management of older cancer patients. Oncology (Huntingt) 2000; 14:221–7. 9. Balducci L, Lyman GH, Ozer H. Patients aged ≥70 are at high risk for neutropenic infection and should receive hemopoietic growth factors when treated with moderately toxic chemotherapy. J Clin Oncol 2001; 19:1583–5. 10. Bow EJ, Rayner E, Louie TJ. Comparison of norfloxacin and cotrimoxazole for infection prophylaxis in acute leukemia. Am J Med 1988; 84:847–54. 11. Balducci L, Ershler WB. Anemia in the older person Arch Intern Med in press. 12. Balducci L, Hardy CL. Anemia of aging: relevance to the management of cancer. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:442–52. 13. Extermann M, Overcash J, Lyman GH et al. Comorbidity and functional status are independent in older cancer patients. J Clin Oncol 1998; 16:1582–7. 14. Extermann M. Measurement and impact of comorbidity in older cancer patients. Crit Rev Oncol Hematol 2000; 35:181–200.

Comprehensive Geriatric Oncology

972

15. Melton LJ, Khosla S, Crowson CS et al. Epidemiology of sarcopenia. J Am Geriatr Soc 2000; 48:625–30. 16. Baumgartner RN, Heymsfield SB, Roche SF. Human body composition and the epidemiology of chronic diseases. Obes Res 1995; 3: 73–95. 17. Stein BN, Petrelli NJ, Douglass HO et al. Age and sex are independent predictors of 5fluorouracil toxicity. Cancer 1995; 75:11–17. 18. Jacobson SD, Cha S, Sargent DJ et al. Tolerability, dose intensity and benefit of 5FU based chemotherapy for advanced colorectal cancer (CRC) in the elderly. A North Central Cancer Treatment Group Study. Proc Am Soc Clin Oncol 2001; 20:384a (Abst 1534). 19. Cova D, Balducci L. Cancer chemotherapy in the older patient. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:463–88. 20. Weisfeldt ML (ed). The Aging Heart: Its Function and Response to Stress. New York: Raven Press, 1980. 21. Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for prevention of breast cancer: report from the National Adjuvant Breast and Bowel Project. J Natl Cancer Inst 1998; 90:1371–88. 22. Atillasoy E, Holt PR. Gastrointestinal proliferation and aging. J Gerontol 1993; 48: B43–9. 23. Vestal RE. Aging and pharmacology. Cancer 1997; 80:1302–10. 24. Balducci L, Corcoran MB. Antineoplastic chemotherapy of the older cancer patient. Hematol Oncol Clin North Am 2000; 14: 193–212. 25. Dees EC, O’Reilly S, Goodman SN et al. A prospective pharmacologic evaluation of agerelated toxicity of adjuvant chemotherapy in women with breast cancer. Cancer Invest 2000; 18:521–9. 26. Corcoran ME. Polypharmacy in the senior adult patient. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:502–9. 27. Balducci L, Hardy CL, Lyman GH. Hemopoietic reserve in older cancer patients: clinical and economic considerations. Cancer Control 2000; 7:539–47. 28. Marley SB, Lewis JL, Davidson RJ et al. Evidence for a continuous decline in hemopoietic cell function from birth: application to evaluating bone marrow failure in children. Br J Haematol 1999; 106:162–6. 29. Lipschitz DA. Age-related decline in hemopoietic reserve capacity. Semin Oncol 1995; 22(Suppl 1): 3–6. 30. Van Zant G. Stem cells and genetics in the study of development, aging and longevity. In: Results and Problems in Cell Differentiation, Vol 29. Berlin: Springer-Verlag, 2000:203–35. 31. Price TH, Chatta GS, Dale DC. Effect of recombinant granulocyte colony-stimulating factor on neutrophil kinetics in normal young and elderly humans. Blood 1996:88:335–40. 32. Chatta DS, Dale DC. Aging and haemopoiesis. Implications for treatment with haemopoietic growth factors. Drugs Aging 1996; 9: 37–47. 33. Chatta GS, Price TH, Allen RC et al. Effects of ‘in vivo’ recombinant methionyl human granulocyte colony-stimulating factor on the neutrophil response and peripheral blood colonyforming cells in healthy young and elderly adult volunteers. Blood 1994; 84: 2923–9. 34. Baraldi-Junkins CA, Beck AC, Rothstein G. Hematopoiesis and cytokines. Relevance to cancer and aging. Hematol Oncol Clin North Am 2000; 14:45–61. 35. Bagnara GP, Bonsi L, Strippoli P et al. Hemopoiesis in healthy old people and centenarian; well maintained responsiveness of CD34+ cells to hemopoietic growth factors and remodeling of cytokine network. J Gerontol 2000; 55: B61–70. 36. Kumagai T, Morimoto K, Saitoh H et al. Age-related changes in myelopoietic response to lipopolysaccaride in senescence-accelerated mice. Mech Ageing Dev 2000; 112:153–7. 37. Moscinsky LC. Hematopoiesis and aging. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:427– 41.

Oncological emergencies in the elderly

973

38. Balducci L, Hardy CL. Anemia of aging: a model of erythropoiesis in cancer patients. Cancer Control 1998; 5(Suppl 1): 17–21. 39. Zinzani PG, Storti S, Zaccaria A et al. Elderly aggressive histology non-Hodgkin’s lymphoma: first line VNCOP-B regimen: experience on 350 patients. Blood 1999; 94:33–8. 40. Sonneveld P, de Ridder M, van der Lelie H et al. Comparison of doxorubicin and mitoxantrone in the treatment of elderly patients with advanced diffuse non-Hodgkin’s lymphoma using CHOP vs. CNOP chemotherapy. J Clin Oncol 1995; 13:2530–9. 41. Gomez H, Mas L, Casanova L et al. Elderly patients with aggressive non-Hodgkin’s lymphoma treated with CHOP chemotherapy plus granulocyte-macrophage colony-stimulating factor: identification of two age subgroups with differing hematologic toxicity. J Clin Oncol 1998; 16:2352–8. 42. Tirelli U, Errante D, Van Glabbeke M et al. CHOP is the standard regimen in patients ≥70 years of age with intermediate and high grade non-Hodgkin’s lymphoma: results of a randomized study of the European Organization for the Research and Treatment of Cancer Lymphoma Cooperative Study. J Clin Oncol 1998; 16:27–34. 43. Bastion Y, Blay J-Y, Divine M et al. Elderly patients with aggressive non-Hodgkin’s lymphoma: disease presentation, response to treatment and survival. A Groupe d’Etude des Lymphomes de l’Adulte Study on 453 patients older than 69 years. J Clin Oncol 1997; 15:2945–53. 44. Bertini M, Freilone R, Vitolo U et al. The treatment of elderly patients with aggressive nonHodgkin’s lymphomas: feasibility and efficacy of an intensive multidrug regimen. Leuk Lymphoma 1996; 22:483–93. 45. O’Reilly SE, Connors JM, Howdle S et al. In search of an optimal regimen for elderly patients with advanced-stage diffuse large-cell lymphoma: results of a phase II study of P/DOCE chemotherapy. J Clin Oncol 1993; 11:2250–7. 46. Armitage JO, Potter JF. Aggressive chemotherapy for diffuse histiocytic lymphoma in the elderly. J Am Geriatr Soc 1984; 32:269–73. 47. Bjorkholm M, Osby E, Hagberg H et al. Randomized trial of R-methu granulocyte colony stimulating factors as adjunct to CHOP or CNOP treatment of elderly patients with aggressive non-Hodgkin’s lymphoma. Blood 1999; 94(Suppl): 599a (Abst 2665). 48. Zagonel V, Babare R, Merola MC et al. Cost-benefit of granulocyte colony-stimulating factor administration in older patients with non-Hodgkin’s lymphoma treated with combination chemotherapy. Ann Oncol 1994; 5(Suppl 2): 127–32. 49. Coiffier B, Lepage E, Briere J et al. CHOP chemotherapy plus rituximab compared with CHOP alone for elderly patients with diffuse B-cell lymphoma. N Engl J Med 2002; 346:280–2. 50. De-Toledo Morrell L, Goncharova I, Dickerson B et al. from healthy aging to early Alzheimer’s disease: in vivo detection of entorhinal cortex atrophy. Ann NY Acad Sci 2000; 911:240–53. 51. Weller RO, Massey A, Kuo YM et al. Cerebral amyloid angiopathy: accumulation of A (5 in intercerebral fluid drainage pathway in Alzheimer’s disease. Ann NY Acad Sci 2000; 903:110– 17. 52. Kinosian BP, Stallard E, Lee JH et al. Predicting 10-year care requirement for older people with suspected Alzheimer disease. J Am Geriatr Soc 2000; 48:631–8. 53. Wolfson C, Wolfson DB, Asgharian M et al. A reevaluation of the duration of survival after the onset of dementia. N Engl J Med 2001; 344:1111–16. 54. Inouye SK, Schlesinger MJ, Lydon TJ. Delirium: a symptom of how hospital care is failing older persons and a window to improve quality of care. Am J Med 1999; 106: s65–573. 55. Kugler CFA. Interrelations of age, sensory functions and human brain signaling process. J Gerontol 1999; 54A: B231–8. 56. Schagen SB, Van Dam FSAM, Muller MJ et al. Cognitive deficit after postoperative adjuvant chemotherapy for breast carcinoma. Cancer 1999; 85:640–50.

Comprehensive Geriatric Oncology

974

57. Longo DL, Young RC, Wesley M et al. Twenty years of MOPP therapy for Hodgkin’s disease. J Clin Oncol 1986; 8:1157–9. 58. Apfel SC. Managing the neurotoxicity of paclitaxel and docetaxel with neurotrophic factors. Cancer Invest 2000; 18:564–73. 59. Hogan DB, Ebly EM, Fung TS. Disease, disability, and age in cognitively intact seniors: results from the Canadian Study of Health and Aging. J Gerontol 1999; 54A: M77–82. 60. Rosen CJ. Growth hormone and aging. Endocrine 2000; 12: 197–201. 61. Martin F. Frailty and the somatopause. Growth Hormone IGF Res 1999; 9:3–10. 62. Franceschi C, Bonafe M, Valnesiu S et al. Inflamm-aging: an evolutionary perspective on immunosenescense. Ann NY Acad Sci 2000; 908:244–54. 63. Ershler WB. The influence of an aging immune system on cancer incidence and progression. J Gerontol 1993; 48: B3–7. 64. Burns E, Goodwin JS. Immunological changes of aging. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:158–70. 65. Hamermann D, Berman JW, Albers GW et al. Emerging evidence for inflammation in conditions frequently affecting older adults: report of a symposium. J Am Geriatr Soc 1999; 47:995–9. 66. Hamermann D. Toward an understanding of frailty. Ann Intern Med 1999; 130:945–50. 67. Yeh SS, Schuster MW. Geriatric cachexia: the role of cytokines. Am J Clin Nutr 1999; 70:183– 97. 68. Balducci L, Beghe’ C. The application of geriatric principles to the management of the older cancer patient. Crit Rev Hematol Oncol 2000; 35:147–55. 69. Cassel CK. Money, medicine and Methuselah. Mt Sinai J Med 1998; 65:237–45. 70. Saliba D, Elliott M, Rubenstein LZ et al. The Vulnerable Elders Survey: a tool for identifying vulnerable older people in the community. J Am Geriatr Soc 2001; 49:1691–9. 71. Monfardini S, Ferrucci L, Fratino L et al. Validation of a multidimensional evaluation scale for use in elderly cancer patients. Cancer 1996; 77:395–401. 72. Balducci L, Stanta G. Cancer in the frail patient: a coming epidemic. Hematol Oncol Clin North Am 2000; 14:235–50. 73. Fried LP, Tangen CM, Walston J et al. Frailty in older adults: evidence for a phenotype. J Gerontol 2001; 56A: M146–56. 74. Balducci L, Extermann M. Assessment of the older patient with cancer. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:223–35. 75. Kao AC, Nanda A, Williams CS et al. Validation of dizziness as a possible geriatric syndrome. J Am Geriatr Soc 2001; 49:72–5. 76. Thompson MP, Morris LK. Unexplained weight loss in ambulatory elderly. J Am Geriatr Soc 1991; 39:497–500. 77. Pavlik VN, Hyman DJ, Festa NA. Quantifying the problem of abuse and neglect in adults: analysis of a statewide data base. J Am Geriatr Soc 2001; 49:45–8. 78. Pierelli L, Perillo A, Greggi S et al. Erythropoietin addition to granulocyte-colony stimulating factor abrogates life-threatening neutropenia and increases peripheral blood progenitor-cell mobilization after epirubicin, paclitaxel and cisplatin in combination chemotherapy. J Clin Oncol 1999; 17:1288–96. 79. Ratain MJ, Schilsky RL, Choi KE et al. Adaptive control of etoposide administration: impact of interpatient pharmacodynamic variability. Clin Pharmacol Ther 1989; 45:226–33. 80. Silber JH, Fridman M, Di Paola RS et al. First-cycle blood counts and subsequent neutropenia, dose reduction or delay in early stage breast cancer therapy. J Clin Oncol 1998; 16:2392–400. 81. Extermann M, Chen A, Cantor AB et al. Predictors of toxicity from chemotherapy in older patients. Proc Am Soc Clin Oncol 2000; 19: 617a.

Oncological emergencies in the elderly

975

82. Schijvers D, Highley M, DeBruyn E et al. Role of red blood cell in pharmakinetics of chemotherapeutic agents. Anticancer Drugs 1999; 10:147–53. 83. Von Hoff DD, Layard MW, Basa P et al. Risk factors for doxorubicin induced congestive heart failure. Ann Intern Med 1979; 91: 710–17 84. Brezden CB, Phillips KA, Abdollel M et al. Cognitive function in breast cancer patients receiving adjuvant chemotherapy. J Clin Oncol 2000; 18:2695–700. 85. Kemeny MM, Busch-Devereaux E, Merriam LT et al. Cancer surgery in the elderly. Hematol Oncol Clin North Am 2000; 14: 169–92. 86. Balducci L. Quality of life in the older cancer patient. Drugs Aging, 1994. 87. Leape LL, Brennan TA, Laird NM et al. The nature of adverse events in hospitalized patients: results of the Harvard Medical Practice Study II. N Engl J Med 1991; 324:377–84. 88. Wu AW, Yasui Y, Alzola C et al. Predicting functional status outcomes in hospitalized patients 80 years and older. J Am Geriatr Soc 2000; 48(Suppl 5): S6–15. 89. Lewis ME. An economic profile of American older women. J Am Med Women Assoc 1997; 52:107–12. 90. Haight BK, Michel Y, Hendrix S. The extended effects of life review in nursing home residents. Int J Aging Hum Dev 2000; 50:151–68. 91. Bernabei R, Landi F, Gambassi G et al. Randomised trial of impact of model of integrated care and case management for older people living in the community. BMJ 1998; 316:1348–51. 92. Alessi CA, Stuck AE, Aronow HU et al. The process of care in preventive ‘in home’ comprehensive geriatric assessment. J Am Geriatr Soc 1997; 45:1044–50. 93. Reuben DB, Effros RB, Hirsch SH et al. An in-home nurse-administered geriatric assessment for hypoalbuminemic older persons: development and preliminary experience. J Am Geriatr Soc 1999; 47:1244–8. 94. Reuben DB, Rubenstein LV, Hirsch SH et al. Value of functional status as predictor of mortality. Am J Med 1992; 93:663–9. 95. Inoyue SK, Peduzzi PN, Robison JT et al. Importance of functional measures in predicting mortality among older hospitalized patients. JAMA 1998; 279:1187–1193. 96. Inouye SK, Bogardus ST, Charpentier PA et al. A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med 1999; 340:669–74. 97. Tinetti ME, McAvay G, Claus G et al. A multifactorial intervention to reduce the risk of falling among elderly people living in the community. N Engl J Med 1994; 331:821–7. 98. Rockwood K, Stadnyk K, Macknigt C et al. A brief instrument to classify frailty in elderly people. Lancet 1999; 353:205–6. 99. Balducci L. Guidelines for the management of the older cancer patient. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:525–33. 100. Blazer DG, Hybels CF, Pieper CF. The association of depression and mortality in elderly persons: a case for multiple independent pathways. J Gerontol 2001; 56A: M505–9. 101. Covinsky KE, Kahana E, Chin MH et al. Depressive symptoms and three year mortality in older hospitalized medical patients. Ann Intern Med 1999; 130:563–9. 102. Bruce ML, Leaf PJ, Rozal GP et al. Psychiatric status and nine year mortality data in the New Haven Epidemiologic Catchment Area Study. Am J Psych 1994; 151:716–19. 103. Lyness JM, Ling DA, Cox C et al. The importance of subsyndromal depression in older primary care patients. Prevalence and associated functional disability. J Am Geriatr Soc 1999; 47: 647–52. 104. Lyness JM, Noel TK, Cox C et al. Screening for depression in elderly primary care patients: a comparison of the Center for Epidemiologic Studies Depression Scale and the Geriatric Depression Scale. Arch Intern Med 1997; 157:449–54. 105. Sehl ME, Yates E. Kinetics of human aging. I: Rates of senescence between ages 30 and 70 in healthy people. J Gerontol 2001; 56A: B198–08.

Comprehensive Geriatric Oncology

976

106. Ostchega Y, Harris TB, Hirsch R et al. Reliability and prevalence of physical performance examination assessing mobility and balance in older persons in the US: data from the Third National Health and Nutrition Examination Survey. J Am Geriatr Soc 2000; 48:1136–41. 107. Ferrucci L, Penninx BWJH, Leveille SG et al. Characteristics of nondisabled older persons who perform poorly in objective tests of lower extremities function. J Am Geriatr Soc 2000; 48:1102–10. 108. Hack V, Breitkreutz R, Kinscherf R et al. The redox status as a correlate of senescence and wasting and as a target for therapeutic intervention. Blood 1998; 54:59–67. 109. Hager K, Platt D. Fibrin degeneration product concentration (D-dimer) in the source of aging. Gerontology 1995; 41:159–65. 110. Reuben DB, Ferrucci L, Wallace R et al. The prognostic value of serum albumin in healthy older person with low and high serum interleukin 6 (11–6) levels. J Am Geriatr Soc 2000; 48:1404–7. 111. Cohen HJ. In search of the underlying mechanisms of frailty. J Gerontol 2001; 55A: 706–8. 112. Cohen HJ, Piper CS, Harris T. Markers of inflammation and coagulation predict decline in function and mortality in community dwelling elderly. J Am Geriatr Soc 2001; S1: A3. 113. Clarfield AM, Bergman H, Kane R. Fragmentation of care for frail older people—an international problem. Experience from three countries: Israel, Canada, and the United States. J Am Geriatr Soc 2001; 49:1714–21. 114. Kim YJ, Rubenstein EB, Rolston KV et al. Colony stimulating factors (CSFs) may reduce complications and death in solid tumor patients with fever and neutropenia. Proc Am Soc Clin Oncol 2000; 19:612a (Abst 2411). 115. Crivellari D, Bonetti M, Castiglione-Gertsch M et al. Burdens and benefits of adjuvant cyclophosphamide, methotrexate and fluorouracil and tamoxifen for elderly patients with breast cancer: the International Breast Cancer Study Group Trial VII. J Clin Oncol 2000; 18:1412–22. 116. Christman K, Muss HB, Case D et al. Chemotherapy of metastatic breast cancer in the elderly. JAMA 1992; 268:57–62. 117. Ibrahim N, Frye DK, Buzdar AU et al. Doxorubicin based combination chemotherapy in elderly patients with metastatic breast cancer. Tolerance and outcome. Arch Intern Med 1996; 156: 882–8. 118. Begg CB, Carbone P. Clinical trials and drug toxicity in the elderly. The experience of the Eastern Cooperative Oncology Group. Cancer 1983; 52:1986–92. 119. Giovannozzi-Bannon S, Rademaker A, Lai G et al. treatment tolerance of ederly cancer patients entered onto phase II clinical trials. An Illinois Cancer Center study. J Clin Oncol 1994; 12: 2447–52. 120. Gelman RS, Taylor SG. Cyclophosphamide, methotrexate and 5-fluorouracil chemotherapy in women more than 65 years old with advanced breast cancer. The elimination of age trends in toxicity by using doses based on creatinine clearance. J Clin Oncol 1984; 2: 1406–14. 121. Ibrahim NK, Buzdar AU, Asmar L et al. Doxorubicin based adjuvant chemotherapy in elderly breast cancer patients: the MD Anderson experience with long term follow-up. Ann Oncol 2000; 11:1–5. 122. Rowe JM, Andersen JW, Mazza JJ et al. Randomized placebocontrolled phase III study of colony stimulating factor in adult patients (>55–70 years) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood 1995; 86:457–62. 123. Heil D, Hoelzer D, Sanz MA et al. A randomized double blind placebo controlled phase III study of filgrastim in remission induction and consolidation therapy for patients with ‘de novo’ acute myeloid leukemia. The International Acute Leukemia Study Group. Blood 1997; 90:4710–18. 124. Tilly H, Castaigne S, Bordessoule D et al. Low-dose cytarabine versus intensive chemotherapy in the treatment of acute non-lymphocytic leukemia in the elderly. J Clin Oncol 1990; 8:272–9.

Oncological emergencies in the elderly

977

125. Cheson BD, Jasper DM, Simon R et al. A critical appraisal of low-dose cytosine arabinoside in patients with acute non-lymphocytic leukemia and myelodysplastic syndromes. J Clin Oncol 1986; 4: 1857–64. 126. Meyer RJ, Davis RB, Schiffer CH et al. Intensive postremission chemotherapy in adult with acute myeloid leukemia. N Engl J Med 1994; 31:896–903. 127. Bloomfield CD, Lawrence D, Byrd JC et al. Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies with cytogenetics subtype. Cancer Res 1998; 58:4173–9. 128. Kouroukis CT, Browman GP, Esmail R et al. Chemotherapy for older patients with newly diagnosed advanced stage aggressive histology non-Hodgkin lymphoma: a systematic review. Ann Intern Med 2002; 136:136–43. 129. Fisher RI, Gaynor ER, Dahlberg S et al. A phase III comparison of CHOP vs. mBACOD vs. ProMACE-CytaBOM vs. MACOP-B in patients with intermediate or high grade non-Hodgkin’s lymphoma: results of SWOG-8516. Ann Oncol 1994; 5(Suppl 2): 91–5. 130. Gomez H, Hidalgo M, Casanova L et al. Risk factors for treatment-related death in elderly patients with aggressive non-Hodgkin’s lymphoma: result of a multivariate analysis. J Clin Oncol 1998; 16: 2065–9. 131. Strausbaugh LJ, Joseph CL. The burden of infection in long-term care. Infect Control Hosp Epidemiol 2000; 21:674–9. 132. Yoshikawa TT. Perspectives: Aging and infectious diseases: past, present and future. J Infect Dis 1997; 176:1053–7. 133. Norman DC. Fever and aging. Infect Dis Clin Pract 1998; 7:387–90. 134. Yoshikawa TT. Epidemiology and unique aspects of aging and infectious diseases, Clin Infect Dis 2000; 30:931–3. 135. Deulofeu F, Cervello B, Capell S et al. Mortality of patients with bacteremia: the importance of functional status. J Am Geriatr Soc 1998; 46:14–18. 136. von Sternberg T, Kepburn K, Cibuzar P et al. Post-hospitalization subacute care: an example of managed care model. J Am Geriatr Soc 1997; 45:384–5. 137. Rolston KVI, Talcott JA. Ambulatory antimicrobial therapy for hematologic malignancies. Oncology 2000; 14(6 Suppl): 17–22. 138. Freifeld AG, Pizzo PA. The outpatient management of febrile neutropenia in cancer patients. Oncology 1996; 10:599–612. 139. Rolston KV. New trends in patient management: risk-based therapy for febrile patients with neutropenia. Clin Infect Dis 1999; 29:2561–8. 140. Dixon DO, Neilan B, Jones SE et al. Effect of age on therapuetic outcome in advanced diffuse histiocytic lymphoma: the Southwest Oncology Group experience. J Clin Oncol 1986; 4:295– 305. 141. Meyer RM, Browman GP, Samosh ML et al. Randomized phase II comparison of standard CHOP with weekly CHOP in elderly patients with non-Hodgkin’s lymphoma. J Clin Oncol 1995; 13: 2386–93. 142. Ozer H, Armitage JO, Bennett CL et al. 2000 updated recommendations for the use of hematopoietic colony-stimulating factors. Evidence-based clinical practice guidelines. J Clin Oncol 2000; 18: 3558–85. 143. Lyman GH, Kuderer N, Green J et al. The economics of febrile neutropenia: the implications for the use of colony stimulating factors. Eur J Cancer 1998; 34:1857–64. 144. Curt GA, Breitbart W, Cella D et al. Impact of cancer-related fatigue on the lives of patients: new findings from the fatigue coalition. Oncologist 2000; 5:353–60. 145. Cleeland CS, Demetri GD, Glaspy J et al. Identifying hemoglobin levels for optimal quality of life. Results of an incremental analysis. Proc Am Soc Clin Oncol 1997; 16: Abst 2215. 146. Gabrilove JL, Einhorn LH, Livingston RB et al. Once weekly dosing of epoietin alfa is similar to three-times weekly dosing in increasing hemoglobin and quality of life. Proc Am Soc Clin Oncol 1999; 18:574A.

Comprehensive Geriatric Oncology

978

147. Glaspy J, Bukowski R, Steinberg C et al. Impact of therapy with epoietin alfa on clinical outcomes in patients with non-myeloid malignancies during cancer chemotherapy in community oncology practices. J Clin Oncol 1997; 5:1218–34. 148. Demetri GD, Kris M, Wade J et al. Quality of life benefits in chemotherapy patients treated with epoietin alfa is independent from disease response and tumor type. Result of a prospective community oncology study. The Procrit Study Group. J Clin Oncol 1998; 16:3412–20. 149. Marcantonio ER, Flacker JM, Michaels M et al. Delirium is independently associated with poor functional recovery after hip fracture. J Am Geriatr Soc 2000; 48:618–24. 150. Carl W, Havens J. The cancer patient with severe mucositis. Curr Rev Pain 2000; 4:192–202. 151. Gordon B, Spadinger A, Hodges E et al. Effect of granulocyte—macrophage colonystimulating factor on oral mucositis after hematopoietic stem cell transplantation. J Clin Oncol 1994; 12:1917–22. 152. Symonds RP. Treatment induced mucositis: an old problem with new remedies. Br J Cancer 1998; 77:1689–95. 153. Rothenberg ML, Meropol N, Poplin EA et al. Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel. J Clin Oncol 2001; 18:3801–7. 154. Spielberger RT, Stiff P, Emmanouilides C et al. Efficacy of recombinant human keratinocyte growth factor (rHuKGF) in reducing mucositis in patients with hematologic malignancies undergoing autologous peripheral blood progenitor cell transplantation after radiation-based conditioning. Results of a phase 2 trial. Proc Am Soc Clin Oncol 2001; 20:7a (Abst 25). 155. Balducci L, Carreca I. Oral chemotherapy of cancer in the elderly. drugs and aging. To be published. 156. Maurer CA, Renzulli P, Mazzucchelli L et al. Use of accurate diagnostic criteria may increase the incidence of stercoral perforation ofthe colon. Dis Colon Rectum 2000; 43:991–8. 157. Flacker JM, Lipsitz LA. Neural mechanisms of delirium: current hypotheses and evolving concepts. J Gerontol 1999; 54: B239–46. 158. Mulder GJ. Glucuronidation and its role in regulation of biological activities of drugs. Annu Rev Pharmacol Toxicol 1990; 32:25–43. 159. Abbott FV, Palmour RM. Morphine 6-glucuronide. Analgesic effects and receptor binding profile in rats. Life Sci 1988; 43: 1685–91.

PART 7 Management of specific tumors in older persons

45 Treatment of acute myeloid leukemia in older patients Thomas Büchner Introduction The challenge Dealing with acute myeloid leukemia (AML) in older patients is a twofold challenge. First, these patients do not show the increasing cure rates seen in younger patients. While their diseases are more resistant to common chemotherapy, their treatment is generally less intensive. Second, patients aged 60 and older represent only one-third of the patients in the large multicenter studies, but may actually account for the majority of AML patients. When compared with AML in younger patients, the disease more often emerges secondary to myelodysplasia1 or treatment of a previous cancer,2 and even without such a history, karyotypic changes associated with secondary AML3–5 occur more frequently in older patients.6–10 The observed abnormalities of chromosomes 5 and 7 and complex abnormalities are known to predict an unfavorable outcome.5–11 Unlike younger patients, in elderly patients with AML, clonality markers of the leukemic cells are also positive in all hematopoietic cells.12 It has been suggested that neutropenia after chemotherapy lasts longer in older patients,13 and a defective pool of hematopoietic stem cells could prolong myelosuppression.14 The age-related differences in the disease biology explain in part why patients aged 60 and older do not achieve the same remission rates15–25 and remission duration18,19,21,23–25 as achieved in younger patients. It should also be noted, however, that inadequate antileukemic treatment might have contributed to the inferior results, since chemotherapy intensity has commonly been reduced in older patients. According to the relevant population-based evaluations, the incidence of AML increases by more than 10-fold between the ages of 20 and 65.26 On the other hand, in a 1992 study by the German AML Cooperative Group (AMLCG), patients of 60 years and older typically contributed 35% of the entire adult patients included, but 63% of the patients excluded from the study according to various protocol criteria. Assuring similar proportions in the unknown number of patients not referred to the study centers and not registered, patients over age 60 may well represent 50% or more of AML patients. From an analysis of published trials and our own data, we address here the following questions: • What kinds of treatment intensification may improve outcome in older patients?

Treatment of acute myeloid leukemia in older patients

981

• Does age-related hematotoxicity have to be taken into account? • What can growth factors contribute? • What are the future directions in terms of supportive treatment and antileukemic options? Age and trends in chemotherapy The trends in modern chemotherapy for AML in patients of all ages are best exemplified by multicenter randomized trials and their results published since 1981.15,17–24,27,28 In these trials, a total of 6757 patients were treated. The average complete remission (CR) rate is 62% and the probability to remain in CR after 4–5 years is 21%. These representative results can serve as a standard for the relative ranking of specific results. Comparing publications from the 1980s with those from the 1990s, there is no difference in CR rate (62% versus 63%), but the 5-year continuous complete remission (CCR) rate has increased from 16% to 25%. The age-related study results are listed in Table 45.1 in the order of increasing age in the groups of patients treated.14–25,27–41 The standard CR rate (see above) of 62% is frequently exceeded in younger but not in older patients, with one exception.29 The same is true for the 21% standard 5-year CCR rate, which is exceeded in older patients in only three trials.17,34,39 In the same trials, markedly inferior CR rates and 5-year CCR rates were found in older when compared with younger groups of patients.

Table 45.1 Age-related complete remissions (CR) and 4- to 5-year continuous complete remissions (CCR) in multicenter randomized trials (in the order of patients’ age) Ref Age range (years)

No. of patients

CR rate (%)

4–5-Yr CCR rate (%)

30

0–55

1857

82

42a

15–55

448

68

31 32

24 b

15

0–60

247

36–59

22c,d

16

1–60

427

57–72e

—f

17

16–60

255

68

8–24g

18

0–60

740

73

18

33

10–60

257

66

17d

19

14–60

564

65

17

19

14–60

564

65

17

Comprehensive Geriatric Oncology

982

34

17–60

135

60

34

35

15–60

449

71

16–27d

21

16–60

742

71

24–44h

36

15–60

301

73

23–41i

37

<65

665

54

19j

24

16–60

725

68

32

25

16–60

450

74

36

33

60–65

30

47

—k

34

60–65

39

46

30

35

60–65

73

52

—k

38

55–70

117

61

—f

39

55–75

132

62

23l

40

56+

1314

50–62m

18–26

n

—k

15

60+

105

16–45

16

60–84

226

31–47o

—f

17

60–78

79

39

0–28p

18

60–83

305

48

9

19

60+

104

41

17

20

60–83

100

41

—h

21

60–86

346

47

15

14

60+

388

53

—f

23

60+

340

42–54q

22

r

—f

29

65+

172

47–70

22

1–79

923

63

26d

41

60–88

489

38–47s

8t

a

Autologous bone marrow transplantation better than no further treatment (p=0.04). Cytarabine infusion better than bolus (p<0.05) and ‘7+3’ better than ‘5+2’ (p<0.01). c Cytarabine in maintenance s.c better than i.v. (p<0.01). d Not age-specific. e Daunorubicin 60mg/m2 better than 30mg/m2 or doxorubicin 30mg/m2 (p< 0.05). f Not given. g Maintenance better than no maintenance (p<0.05). h Relapse-free survival positively correlated with postremission cytarabine dosage (p=0.002). i,j High-dose better than standard-dose cytarabine (ip=0.007; jp=0.049). k No age-specific data. l GM-CSF during and after chemotherapy better than no GM-CSF in 2-year relapse-free survival (p=0.003). b

Treatment of acute myeloid leukemia in older patients

983

m

Thioguanine better than etoposide (p=0.002). ‘7+3’ better than ‘5+2’. 0 Daunorubicin 30mg/m2 better than 45mg/m2 or doxorubicin 30mg/m2 (p<0.05). p Maintenance better than no maintenance (p=0.002). 1 Daunorubicin 60mg/m2 better than 30mg/m2 (p=0.026). r G-CSF better than no G-CSF (p=0.002). s Mitoxantrone better than daunorubicin (p=0.069). t Low-dose cytarabine for maintenance better than no maintenance (p=0.006). n

The impact of special treatment modalities in younger and older patients is also shown in Table 45.1, as far as is documented by significant differences in randomized comparisons, which show important effects of high-dose cytarabine (cytosine arabinoside, Ara-C), of daunorubicin dosage, and of prolonged maintenance treatment. Thus, high-dose cytarabine either in induction36,37 or in postremission2 treatment significantly improved the 5-year CCR rate in younger patients, while older patients treated in only one trial21 did not benefit from postremission high-dose cytarabine. In contrast, daunorubicin and its dosage showed a significant impact on the CR rate of patients over age 60.23 Table 45.2 summarizes the results from studies using different doses of daunorubicin. As demonstrated by the German AMLCG, daunorubicin 60mg/m2 induced significantly more remissions than the traditional dose of 30mg/m2 (54% versus 43%; p=0.038). Importantly, in the 60mg/m2 arm, more remissions were induced by only one course (38%) when compared with the 30mg/m2 arm (20%; p=0.002).23 As shown in Table 45.1, prolonged maintenance significantly improved the 5-year CCR rate in two trials,17,41 both of them treating older patients. The AMLCG showed that prolonged maintenance resulted in a 5-year survival rate of 25% for the responders (Figure 45.1). Thus, the gain in remissions induced by the higher daunorubicin dosage translated into a gain in long-term survival. Figure 45.2 illustrates the relapse-free survival of older patients receiving prolonged maintenance or no maintenance or highdose cytarabine/mitoxantrone in sequential trials of the AMLCG. While the maintenance treatment produced a consistent 5-year relapse-free survival rate of around 20%, inferior results were found with no maintenance or with high-dose cytarabine/mitoxantrone instead of maintenance. While Table 45.1 provides a synopsis of different treatment modalities, differences between the trials must be interpreted with caution. Since children were included in some trials15,16,18,30,31,33 and various proportions of patients were excluded at the time of randomization in remission in some,15,17,19,21,32,33,35 fair interstudy comparisons are certainly compromised by unknown selection factors. Attenuated treatment in older patients As alternative approaches, treatment attenuation strategies for older patients have been investigated in four major studies (Table 45.3).43–45 The attenuated or oral regimens showed some advantages in survival and CR rate in two of the studies43,45 and in relapsefree survival in one,45 with no improvement on common results.

Comprehensive Geriatric Oncology

984

Table 45.2 Outcome by daunorubicin dosage in older patients Ref Daunorubicin dose (mg/m2)

Age range (years)

18

50×1

60–83

16

30×3

19

No. of patients

5-year overall survival rate (%)

Complete remission rate (%)

5-year relapse-free survival rate (%)

305

9

48

9

60+

72

—

47

—

30×3

60+

104

10

41

17

42

30×3

65–85

31

13

58

17

20

30×3

60–83

100

3

41

<10

21

30×3

60–86

346

9

47

15

23

30×3

60–83

103

10

42

17

41

30×3

60–88

489

6

38

8

16

45×3

60+

68

—

31

—

14

45×3

60–80+

388

—

53

—

29

45×4

64–83

172

—

47–70

—

23

60×3

60–83

240

16

54

22

Figure 45.1Survival in patients 60 years of age and older who attained complete remission after induction

Treatment of acute myeloid leukemia in older patients

985

therapy with the TAD regimen (thioguanine, cytarabine, and daunorubicin) containing daunorubicin either 60mg/m2 or 30mg/m2×3. The remission rate was 54% versus 43% (p=0.038). The higher number of patients in the 60mg/m2 arm is explained by the closure of the 30mg/m2 arm when a significantly superior response rate to the higher dose became obvious

Figure 45.2 Relapse-free survival in patients aged 60 and older who received or did not receive prolonged maintenance treatment in sequential trials of the German AMLCG. Table 45.3 Full-dose versus attenuated or low-dose chemotherapy in older patients with AML Ref Treatment

Age No. of range patients

Median overall survival

Complete remission rate (%)

Median relapse-free survival (months)

Comprehensive Geriatric Oncology

986

43

Fulla vs attenuatedb dose DAT

70+

40

29 vs 159 days (p<0.02)

25 vs 30 (P=NS)

42

Immediate intensive induction chemotherapyc vs wait and seed

65–85

60

21 vs 11 weeks (p<0.05)

58 vs 0

44

65–83 Intensive chemotherapye vs low-dose cytarabine’

87

12.8 vs 8.8 months (p=NS) (p=0.001)

52 vs 32

13.8 vs 8.3 (p=NS)

45

TADg vs oral ETIh

51

3.7 vs 9.9 months (p=0.042)

23 vs 60 (p=0.007)

2.7 vs 7.2 (p=NS)

65–87

a

Daunorubicin 60mg/m2/d×3; cytarabine 200mg/m2/d×5; thioguanine 200mg/m2/d×5. Daunorubicin 50mg/m2/d×1; cytarabine 100mg/m2/d×5; thioguanine 200mg/m2/d×5. c Daunorubicin 30mg/m2/d×3; vincristine 1mg/m2/d×1; cytarabine 200mg/m2/d×7. d Cytoreduction by hydroxyurea 3g/d×2; cytarabine 200mg/m2/d×4. e Rubidazone 100mg/m2/d×4; cytarabine 200mg/m2/d×7. f Cytarabine 20mg/m2/d×21. g Thioguanine 200mg/m2/d×5; cytarabine 200mg/m2/d×5; daunorubicin 60mg/m2×1. h Etoposide 160mg/m2/d orally×5; thioguanine 200mg/m2/d orally×5; idarubicin 15mg/m2/d orally×3. b

Age-related disease biology and treatment intensity Prognostic features could be compared between younger and older patients by the AMLCG within the same trial involving 1065 patients.23,24 There was a striking difference in the occurrence of favorable karyotypes, with 22% in younger and 2% in older patients (p=0.001), and the unfavorable complex karyotypic abnormalities, with 6% versus 20% (p=0.001). These data explain the 35% disadvantage for the older patients. As additional cellular features predicting poor prognosis, the Southwest Oncology Group (SWOG) detected a CD34+ phenotype in 65%, multidrug-resistance gene (MDR1) expression in 71%, and functional drug efflux in 58% of their older AML patients.46,47 While those cell biologic features explain the general experience of a greatly unfavorable and chemoresistant disease, the few older patients with favorable karyotypes apparently share a good prognosis with similar

Treatment of acute myeloid leukemia in older patients

987

Figure 45.3 Recovery time to 500 neutrophils/µl and 50000 platelets/µl after the start (b) and end (a) of chemotherapy, comparing patients younger and older than 60. The patients were treated within the same trial. The data shown are restricted to patients receiving two identical courses of TAD with daunorubicin 60mg/m2. The splitting of the right-hand curves (b) is explained by the longer delay of the second induction course in the older patients. Table 45.4 Use of growth factors in induction treatment for older patients with AML: synopsis of clinical studies Ref Special risk

Growth factor Product Daily dose

Start

Controls Chemo therapy dose

No. of Growth patients factor benefit

No difference

49

Early/ GMmultiple CSF relapse (yeast) or age 65+

Historic 250µg/m2 Day 4 after chemotherapy

Relapses: 112 highdose Age 65+: standard

Neutropenia (p=0.002) Mortality (p=0.009)

38

Age

250µg/m2 Day 4 after

Standard

Neutropenia Disease-free

GM-W

Placebo

124

Disease-free survival Leukemic regrowth

Worse with growth factor

Comprehensive Geriatric Oncology

988

55–70

(Yeast)

chemotherapy

14

Age 60+

GM5µg/kg CSF (E. coli)

Day 1 after Placebo chemotherapy

Standard

388

Neutropenia Mortality (p=0.002) Remissions Leukemic regrowth Survival Hospitalization

39

Age 55–75

GM5µg/kg CSF (E. coli)

With start of Placebo chemotherapy

Standard

240

Neutropenia (p=0.001) Diseasefree survival (p=0.003)

50

Age 60+

GM5µg/kg CSF (E. coli)

Day 1 before Random chemotherapy

Standard

318

Neutropenia Remissions (p=0.002) Infections Survival Disease-free survival

29

Age 65+

GMCSF

Day 2 after Placebo chemotherapy

Standard

172

Neutropenia (p<0.001) Remissions (p<0.002)

5µg/kg

(p=0.001) Grade 4/5 infections (p=0.002) Survival (p=0.048)

survival

Mortality Remissions Leukemic regrowth Survival Hospitalization Fever Chills Hypotension Fluid retention

Mortality at 8 weeks Infections Leaukemic regrowth Survival

younger patients.48 In contrast to the general prognosis, there was no difference between younger and older patients in terms of the recovery time of neutrophils and platelets after identical chemotherapy (Figure 45.3). Suggestions of defective hematopoiesis in older patients13,14 could thus not be confirmed. As Figure 45.3 also shows, the neutrophil and platelet recovery time calculated from the start of induction treatment does not show a major delay for older compared with younger patients. In the same trial of the AMLCG, patients under age 60 were randomized to receive double induction either at standard dosage or with the inclusion of high-dose cytarabine. While there was no difference in outcome in the patients overall, those with poor risk according to karyotype, lactate dehydrogenase (LDH), and slow response had a significantly superior response and survival in the high-risk arm that was not seen in the good-risk patients.24 This first evidence that a poor prognosis can be improved by more intensive treatment appears to be confirmed by the dose effects of daunorubicin and the effect of prolonged maintenance in the older patients—again a poor prognosis group.

Treatment of acute myeloid leukemia in older patients

989

The role of growth factors in older patients The effect of granulocyte-macrophage colony-stimulating factor (GM-CSF)14,38,39,49,50 or granulocyte colony-stimulating factor (G-CSF)29 given after,14,29,38,49 during and after,39 or before, during, and after50 chemotherapy for older patients with AML has now been explored in six studies (Table 45.4). There were benefits in neutrophil recovery in all studies, in mortality and survival in two studies,38,49 in remissions in one,29 and in relapsefree survival in one.39 Except for some toxicity of GM-CSF in one study,50 no adverse effects were observed. Treatment recommendations Present evaluation strongly suggests that patients aged 60 and older receive their best chance of achieving a remission and surviving disease-free by the administration of fulldose induction treatment containing daunorubicin 60mg/m2/d×3 and prolonged maintenance chemotherapy. This strategy is being pursued in the studies of the German AMLCG using the regimens described in Figure 45.4. Needless to say, up-to-date supportive care such as adequate platelet support, early empiric prophylactic antimicrobial treatment, and protective programs are indispensable prerequisites for delivering an intensive antileukemic therapy to older patients. The additional individual use of G-CSF or GM-CSF as an adjunct to supportive care also appears to be justified and reasonable. New directions Beyond the above recommendations, it remains open whether further intensification of chemotherapy such as the use of high-dose cytarabine in induction treatment as investigated in a current trial of the AMLCG will further

Comprehensive Geriatric Oncology

990

Figure 45.4 Therapeutic regimens used by the German AML Cooperative Group. TAD and HAM are used for induction treatment, with HAM starting on day 21 of treatment. After attaining remission, patients receive an additional TAD for consolidation. Subsequent maintenance treatment is given for 3 years, and consists of AD or AT or AC rotating every month. The only age adaptation is the use of cytarabine at 1g/m2 in HAM (instead of 3g/m2) for patients aged over 60. improve the outcome in older AML patients. New approaches to supportive care such as granulocyte transfusion51 or mucous membrane protection by interleukinII52 may facilitate delivery of intensive treatment. Novel antileukemic approaches such as antibody-targeted cytotoxic treatment53 or multidrug-resistance modifiers54 may help in overcoming chemoresistance in higher-age AML. Finally, allogeneic hematopoietic stem cell-transplantation using non-myeloablative conditioning is a promising treatment modality that may be offered even to older patients with AML.55

Treatment of acute myeloid leukemia in older patients

991

References 1. Hamblin TJ. The treatment of acute myeloid leukemia preceded by the myelodysplastic syndrome. Leuk Res 1992; 16:4101–8. 2. Hoyle CF, de Bastos M, Wheatley K et al. AML associated with previous cytotoxic therapy. MDS or myelo-proliferative disorders: results from the MRC’s 9th AML trial. Br J Haematol 1989; 72:45–53. 3. Second International Workshop on Chromosomes in Leukemia: general report. Cancer Genet Cytogenet 1980; 2:93–6. 4. Rowley J. Annotation: chromosome changes in acute leukaemia. Br J Haematol 1980; 44:339– 46. 5. Yunis JJ, Lobell M, Arnesen MA et al. Refined chromosome study helps define prognostic subgroups in most patients with primary myelodysplastic syndrome and acute myelogenous leukaemia. Br J Haematol 1988; 68:189–94. 6. Fourth International Workshop on Chromosomes in Leukemia. Clinical significance of chromosomal abnormalities in acute non-lymphoblastic leukemia. Cancer Genet Cytogenet 1984; 11:332–50. 7. Keating MJ, Smith TL, Kantarjian H et al. Cytogenetic pattern in acute myelogenous leukemia: a major reproducible determinant of outcome. Leukemia 1988; 2:403–12. 8. Schiffer CA, Lee EJ, Tomiyasu T et al. Prognostic impact of cytogenetic abnormalities in patients with de novo acute nonlymphocytic leukemia. Blood 1989; 73:263–70. 9. Swansbury GJ, Lawler SD, Alimena G et al. Long-term survival in acute myelogenous leukemia: a second follow-up of the Fourth International Workshop on Chromosomes in Leukemia. Cancer Genet Cytogenet 1994; 73:1–7. 10. Dastugue N, Paven C, Lafage-Pochitaloff M et al. Prognostic significance of karyotype in de novo adult acute myeloid leukemia. Leukemia 1995; 9:1491–8. 11. Yunis JJ, Brunninng RD, Howe RB et al. High-resolution chromosomes as an independent prognostic indicator in adult acute nonlymphocytic leukemia. N Engl J Med 1984; 311:812–18. 12. Fialkow PJ, Singer JW, Raskind WH et al. Clonal development, stemcell differentiation, and clinical remissions in acute nonlymphocytic leukemia. N Engl J Med 1987; 317:468–73. 13. Hamblin TJ. Meeting report: 1st International Conference on Reversal of Multidrug Resistance in Cancer. Leuk Res 1995; 19:509–14. 14. Stone RM, Berg TB, George SL et al. Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. N Engl J Med 1995; 332:1671–7. 15. Rai KR, Hollannd JF, Glidewell OJ et al. Treatment of acute myeloid leukemia: a study by Cancer and Leukemia Group B. Blood 1981; 58: 1203–12. 16. Yates J, Glidewell O, Wiernik P et al. Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: a CALGB study. Blood 1982; 60:454–62. 17. Biichner T, Urbanitz D, Hiddemann W et al. Intensified induction and consolidation with or without maintenance chemotherapy for acute myeloid leukemia (AML): two multicenter studies of the German AML Cooperative Group. J Clin Oncol 1985; 3:1583–9. 18. Rees JKH, Gray RG, Swirsky D, Hayhoe FGJ. Principal results of the Medical Research Council’s 8th Acute Myeloid Leukaemia Trial. Lancet 1986; 332:1236–41. 19. Preisler H, Davis RB, Kirshner J et al. Comparison of three remission induction regimens and two postinduction strategies for the treatment of acute nonlymphocytic leukemia: a Cancer and Leukemia Group B study. Blood 1987; 69:1441–9. 20. Dillman RO, Davis RB, Green MR et al. A comparative study of two different doses of cytarabine for acute myeloid leukemia: a phase III trial of Cancer and Leukemia Group B. Blood 1991; 78:2520–6.

Comprehensive Geriatric Oncology

992

21. Mayer RJ, Davis RB, Schiffer CA et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 1994; 6:896–942. 22. Rees JKH, Gray RG, Weathley K. Dose intensification in acute myeloid leukaemia: greater effectiveness at lower cost. Principal report of the Medical Research Council’s AML9 study. Br J Haematol 1996; 94:89–98. 23. B#auchner T, Hiddemann W, Wormann B et al. Daunorubicin 60 instead of 30mg/sqm improves response and survival in elderly patients with AML. Blood 1997; 90(Suppl 1): 583a. 24. Büchner T, Hiddemann W, Wormann B et al. Double induction strategy for acute myeloid leukemia: the effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine. A randomized trial by the German AML Cooperative Group. Blood 1999; 93:4116–24. 25. Büchner T, Hiddemann W, Wormann B et al. One single course of sequential high-dose AraC/mitoxantrone (S-HAM) has the same long-term effect as three years of maintenance in AML patients after TAD-HAM double induction. Randomized trial by the German AMLCG. Blood 1999; 94(Suppl 1): 383a 26. McNally, RIQ, Rowland D, Roman E et al. Age and sex distributions of hematological malignancies in the U.K. Hematol Oncol 1997; 15: 173–89. 27. Vogler WR, Winton EF, Gordon DS et al. A randomized comparison of postremission therapy in acute myelogenous leukemia. A Southeastern Cancer Study Group trial. Blood 1984; 63:1039–45. 28. Vogler WR, Velez-Garcia E, Weiner RS et al. A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group study. J Clin Oncol 1992; 10:1103–11. 29. Dombret H, Chastang C, Fenaux P et al. A controlled study of recombinant human granulocyte colony-stimulating factor in elderly patients after treatment for acute myelogenous leukemia. N Engl J Med 1995; 332:1678–83. 30. Hann IM, Stevens RF, Goldstone AH et al. Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia. Results of the Medical Research Council’s 10th AML Trial (MRC AML10). Blood 1997; 89: 2311–18. 31. Burnett AK, Goldstone AH, Stevens RM et al. Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy of acute myeloid leukaemia in first remission: results of MRC AML10 trial. Lancet 1998; 351:700–8. 32. Mandelli F, Vegna ML, Awisati G et al. A randomized study of the efficacy of postconsolidation therapy in adult acute nonlymphocytic leukemia: a report of the Italian Cooperative Group GIMEMA. Ann Hematol 1992; 64:166–72. 33. Hayat M, Jehn U, Willemze R et al. A randomized comparison of maintenance treatment with androgens, immunotherapy, and chemotherapy in adult acute myelogenous leukemia. Cancer 1986; 58:617–23. 34. Hansen OP, Pedersen-Bjergaard J, Ellegaard J et al. Aclarubicin plus cytosine arabinoside versus daunorubicin plus cytosine arabinoside in previously untreated patients with acute myeloid leukemia: a Danish national phase III trial. Leukemia 1991; 5:510–16. 35. Cassileth PA, Lynch E, Hines JD et al. Varying intensity of postremission therapy in acute myeloid leukemia. Blood 1992; 79:1924–30. 36. Bishop JF, Matthews JP, Young GA et al. A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood 1996; 87:1710–17. 37. Weick JK, Kopecky KJ, Appelbaum FR et al. A randomized investigation of high-dose versus standard dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood 1996; 88: 2841–51. 38. Rowe JM, Andersen JW, Mazza JJ et al. A randomized placebocontrolled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (>55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood 1995; 86:457–62.

Treatment of acute myeloid leukemia in older patients

993

39. Witz F, Sadoun A, Perrin MC et al. A placebo-controlled study of recombinant human granulocyte-macrophage colony-stimulating factor administered during and after induction treatment for de novo acute myelogenous leukemia in elderly patients. Blood 1998; 91:2722–30. 40. Goldstone AH, Burnett AK. Wheatly K et al. Superior CR rates with DAT induction compared to ADE or MAC in older patients with AML, but three additional courses of consolidation chemotherapy and maintenance with interferon do not improve survival: results of the MRC AMLll trial. Proc Am Soc Clin Oncol 1999; 18:6a. 41. Lowenberg B, Suciu S, Archimbaud E et al. Mitoxantrone versus daunorubicin in inductionconsolidation chemotherapy—the value of low-dose cytarabine for maintenance of remission, and an assessment of prognostic factors in acute myeloid leukemia in the elderly: final report of the Leukemia Cooperative Group of the European Organization for the Research and Treatment of Cancer and the Dutch-Belgian Hemato-Oncology Cooperative HOVON Group randomized phase III study AML-9. J Clin Oncol 1998; 16:872–81. 42. Lowenberg B, Zittoun R, Kerkhofs H et al. On the value of intensive remission-induction chemotherapy in the elderly patients of 65+ years with acute myeloid leukemia: a randomized phase III study of the European Organization for Research and Treatment of Cancer Leukemia Group. J Clin Oncol 1989; 7:1268–74. 43. Kahn SB, Begg CB, Mazza JJ et al. Full dose versus attenuated dose daunorubicin, cytosine arabinoside and 6-thioguanine in the treatment of acute nonlymphocytic leukemia in the elderly. J Clin Oncol 1984; 2:865–70. 44. Tilly H, Castaigne S, Bordessoule D et al. Low-dose cytarabine versus intensive chemotherapy in the treatment of acute nonlymphocytic leukemia in the elderly. J Clin Oncol 1990; 8:272–9. 45. Ruutu R, Almqvist A, Hallmann H et al. Oral induction and consolidation of acute myeloid leukemia with etoposide, 6-thioguanine, and idarubicin (ETI) in elderly patients. a randomized comparison with 5-day TAD. Leukemia 1994; 8:11–15. 46. Leith CP, Chen I, Kopecky KJ. Correlation of multidrug resistance (MDRl) protein expression with functional dye/drug efflux in acute myeloid leukemia by multiparameter flow cytometry: identification of discordant MDR−/Efflux+ and MDR1+/Efflux− cases. Blood 1995; 86:2329–42. 47. Leith CP, Kopecky KJ, Godwin J et al. Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetic distinguishes biologic subgroups with remarkable distinct response to standard chemotherapy. A Southwest Oncology Group study. Blood 1997; 89:3323–9. 48. Hiddemann W, Kern W, Schoch E et al. Management of acute myeloid leukemia in elderly patients. J Clin Oncol 1999; 17:3569–76. 49. Biichner T, Hiddemann W, Koenigsmann M et al. Recombinant human granulocytemacrophage colony-stimulating factor after chemotherapy in patients with acute myeloid leukemia at higher age or after relapse. Blood 1991; 78:1190–7. 50. Löwenberg B, Suciu S, Archimbaud E et al. Use of recombinant granulocyte-macrophage colony-stimulating factor during and after remission induction chemotherapy in patients aged 61 years and older with acute myeloid leukemia (AML): final report of AML-11, a phase III randomized study of the Leukemia Cooperative Group of European Organisation for the Research and Treatment of Cancer (EORTC-LCG) and the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON). Blood 1997; 90:2952–61. 51. Peters C, Minkov M, Matthes-Martin S et al. Leucocyte transfiisions from rhG-CSF or prednisolone stimulated donors for treatment of severe infections in immunocompromised neutropenic patients. Br J Haematol 1999; 106:689–96. 52. Keith CR, Albert L, Sonis ST et al. IL-11, a pleiotropic cytokine: exciting new effects of IL-11 on gastrointestinal mucosal biology. Stem Cells 1994; 12:79–90. 53. Sievers EL, Appelbaum FR, Spielberger RT et al. Selective ablation of acute myeloid leukemia using antibody-targeted chemotherapy: a phase I study of an anti CD33 calicheamicin immunoconjugate. Blood 1999; 93:3678–84.

Comprehensive Geriatric Oncology

994

54. List AF, Kopecky KJ, Willrnan CL et al. Benefit of cycloporine (CsA) modulation of anthracycline restistance in high-risk AML: a South-west Oncology Group (SWOG) study. Blood 1998; 92(Suppl 1): 312a. 55. Xun CQ, McSweeney PA, Boeckh M et al. Successful nonmyeloablative allogeneic hematopoietic stem cell transplantation in an acute leukemia patient with chemotherapy-induced marrow aplasia and progressive pulmonary aspergillosis. Blood 1999; 94:3273–6.

46 Chronic leukemias in the elderly Alexander SD Spiers Introduction Definitions The chronic leukemias are defined as a group of hematologic neoplasms with a clinical course that is measured in years rather than in the weeks that used to characterize the clinical course of the acute leukemias. The distinction was made in the era before any effective therapy was available for the acute leukemias and rapid death was the usual outcome. As a result, the chronic leukemias were considered to be ‘favorable’ diseases because of their longer prognosis. In young patients, advances in the treatment of the acute leukemias have been dramatic, frequently resulting in cure, and as a result the chronic leukemias are no longer considered so ‘favorable’. In older patients, progress in treating the acute leukemias has been much more modest, and as a rule the prognosis of the chronic leukemias remains the better of the two. The broad categories of the chronic leukemias that are encountered in the older person are listed in Table 46.1. The older person is not so readily defined, because the concept of age is to many people, including physicians, highly subjective. A wry definition of ‘elderly’ is ‘anyone significantly older than the observer’, and psychologically there is much truth in this. From the viewpoint of the

Table 46.1 Chronic leukemias that are encountered in the older person Chronic lymphoid leukemias •

B-cell chronic lymphocytic leukemia (B-CLL)

•

B-cell prolymphocytic leukemia (B-PLL)

•

B-cell hairy cell leukemia (B-HCL)

•

B-cell lymphomas with blood involvement

•

T-cell variants of the above disorders (uncommon)

Chronic myeloid leukemias •

Chronic granulocytic leukemia (CGL)

•

Atypical myeloproliferative syndrome

•

Chronic myelomonocytic leukemia (CMML)

Comprehensive Geriatric Oncology

•

996

Rarer subvarieties of chronic myeloid neoplasia

hematologist who treats leukemia by conventional means, the age of 70 years may be taken as the beginning of the older person’s estate. A physician who treats by hematopoietic stem cell transplantation might draw the boundary at 60, or even 55, years. Significance of older age in managing chronic leukemias Older age has a significant impact on the management of most hematologic malignancies.1 Its most obvious effect in the clinical situation is its strong association with the presence of multiple medical problems. Although disease should never be considered as an inevitable consequence of older age, the fact remains that as years accumulate, so do metabolic, degenerative, and neoplastic disorders, all of which may have a profound influence on the care of the patient when a chronic leukemia must be managed. The most important medical conditions that affect the hematologist’s approach to the older person with a chronic leukemia are listed in Table 46.2. Of almost equal importance is a physiologic change that inevitably accompanies aging: a reduced functional reserve capacity that affects all organ systems. As a result of this natural and universal phenomenon, the healthy 80-year-old who looks 20 years younger is, in fact, much more frail than a genuine 60-year-old, and when subjected to stress may develop failure of one, and then multiple, organs in a fashion that would not occur in a younger person. Because of this major, although clinically occult, impairment in the elderly, certain types of therapy are fraught with risk (e.g. intensive chemotherapy) or may even be precluded (e.g. allogeneic stem cell transplantation). In the older person with significant other disease, the prognosis of a chronic leukemia may exceed the life-expectancy of the patient, and thus be of small importance. A younger person with a chronic leukemia will die from the disease unless it is cured, for example by bone marrow transplantation. By contrast, in an elderly patient with severe coronary artery disease, the discovery of a low-stage chronic lymphocytic leukemia has virtually no

Table 46.2 Concurrent medical problems that affect the management of chronic leukemia in the older person Problem

Consequences

Intellectual impairment

Problems with adherence to treatment

Chronic lung disease

Mortality from intercurrent infection; problems with some cytotoxic drugs

Hypertension

Cerebral hemorrhage when thrombocytopenic

Angina

Poor tolerance of anemia

Cardiac failure

Poor tolerance of transfusion and of some drugs

Atherosclerosis

Poor tolerance of anemia and leukocytosis

Chronic leukemias in the elderly

997

Arthritis

Medications promote gastrointestinal hemorrhage

Diabetes mellitus

Exacerbations with corticosteroid therapy

Liver disease

Altered drug metabolism

Diverticulosis

Infection, perforation, sepsis

Renal impairment

Poor tolerance of hyperuricemia; problems with antibiotic therapy

Uterine prolapse

Urinary tract infections

Prostatomegaly

Urinary tract infections

Incontinence

Decubitus ulcers

Other primary cancers

Multiple problems, depending on site

This list is not exhaustive. Consideration must also be given to the psychological, social, environmental, and often pressing economic problems that have a profound impact on the practice of geriatric oncology

impact on life-expectancy, and there is no necessity to even treat the disease, let alone cure it. The reduced life-expectancy that is an inevitable accompaniment of aging should not, however, be exaggerated. For example, a healthy woman of 75 has a life-expectancy of 12 years; the diagnosis at age 75 of stage II chronic lymphocytic leukemia, with a prognosis of approximately 6 years, therefore is not an unimportant event. Chronic lymphoid leukemias in the older person Introduction The following sections will consider the diagnosis, clinical features, and management of a group of disorders that are characterized by the neoplastic proliferation of relatively mature-appearing (i.e. not blastic) lymphocytes, with involvement of the peripheral blood and the bone marrow. There are numerous subvarieties of chronic lymphoid leukemia and also several related disorders, but the T-cell varieties are all so uncommon as to be of lesser importance clinically. Of the B-cell leukemias, chronic lymphocytic leukemia (B-CLL or simply CLL) is by far the most frequent and the most important, and will be the principal subject of discussion here. For many years a relatively neglected disease, CLL has more recently been the focus of much important research that has increased our understanding of its biology and significantly improved its management, to the benefit of many older patients. Terminology and classification of CLL The terminology outlined in Table 46.3 is widely accepted, although some variations are encountered. For example, some authors have reclassified many cases of T-cell chronic lymphocytic leukemia (T-CLL) as a subacute, not a chronic, process,2 while others flatly deny the existence of T-CLL as a disease entity. The nomenclature of the chronic

Comprehensive Geriatric Oncology

998

lymphoid leukemias was until recently based mainly on morphologic considerations; descriptions of cells as ‘mature’ or ‘differentiated’ were based on their appearance. The ability to characterize cells by surface markers, antigenic determinants that are located on the cell membrane, led to major conceptual changes, the first and most fundamental of which was the recognition of T and B cells. With the advent of automated flow cytometry and the ability to study the surface markers of thousands of cells in every patient, subtle differences that are undetectable by morphologic methods alone are continually emerging. For example, the cells of B-CLL, despite their mature appearance, turn out to be more

Table 46.3 Chronic lymphoid leukemias and related disorders • B-cell chronic lymphocytic leukemia (B-CLL) • B-cell prolymphocytic leukemia (B-PLL) • B-cell hairy cell leukemia (B-HCL) • B-cell non-Hodgkin lymphomas with blood involvement: – Small cleaved cell – Lymphoplasmacytic • T-cell variants of the above disorders (uncommon) • Unique T-cell disorders: – Sézary syndrome – Adult T-cell leukemia/lymphoma (ATLL) – Large granular lymphocytic (LGL) leukemia

primitive than previously suspected. With the widespread application of flow cytometry, more accurate diagnoses of lymphoid neoplasms are now being made, and ongoing revisions of current terminology can be anticipated. It remains to be seen to what extent these fine distinctions will be clinically important in selecting the most appropriate management for each patient. B-cell chronic lymphocytic leukemia (B-CLL or simply CLL) Definition CLL is a neoplastic disease of unknown etiology characterized by an absolute lymphocytosis in the bone marrow and peripheral blood. Cell proliferation is usually slow, but there is a remorselessly progressive accumulation of monoclonal, long-lived, mature-appearing B lymphocytes that are immunoincompetent and indeed produce immunosuppression. Whereas many other clinical features are regularly encountered in CLL—for example lymphadenopathy, splenomegaly, hepatomegaly, hematopoietic

Chronic leukemias in the elderly

999

failure, hypogammaglobulinemia, and autoimmune phenomena—none is constant or essential to the diagnosis. Epidemiology CLL is the leukemia par excellence of the older person. It is rarely seen in patients aged less than 40, and its incidence increases steadily with advancing age—apparently without limit, since it continues to rise in the ninth and tenth decades of life. The incidence of CLL increases 350-fold when ages 25–29 are compared with ages 80–84.3 A high incidence of CLL (approximately one-third of all new cases of leukemia) combines with a lengthy survival to produce a high prevalence of the condition; CLL comprises approximately half of all cases of leukemia in Western populations. It is safe to say that almost every geriatric practice or long-term care facility will have one or more patient with CLL, and physicians in every medical specialty will regularly encounter patients with this important disease. There is a male predominance that appears to have decreased with time; early in the 20th century, the male-to-female ratios for CLL in Western countries ranged from 2.5 to 3.0, whereas in more recent studies they are between 1.6 and 1.9. There are rare families that show clustering of cases of CLL, sometimes in association with cases of lymphoma or of immunologic diseases. Geographic and ethnic variation in incidence is greater for CLL than for any other type of leukemia.4 The highest incidences of CLL are observed in Whites in North America and in Europe. Lower rates are reported from South America and the Caribbean, and exceptionally low rates are found in India, Japan, China, and other areas of Asia, where B-CLL is a truly rare disease. This finding persists when adjustment is made for the lower average age of the population in some Asian countries. The reason for these fascinating variations that are peculiar to CLL is unknown. The geriatric oncologist who practices in North America or Europe is in an area where the incidence of CLL is already very high, and continues to increase as the average age of the population increases. Symptoms More than any other leukemia, CLL is apt to be diagnosed when it is still asymptomatic. A common scenario is the senior citizen who requires a surgical procedure for one of the conditions that are frequent in older age, for example inguinal hernia, uterine prolapse, or prostatomegaly. A routine preoperative blood count shows a marked absolute lymphocytosis, a follow-up bone marrow examination shows infiltration with matureappearing lymphocytes, and flow cytometry shows the circulating lymphocytes to be positive for surface membrane immunoglobulin (slg) and the CD5 and CD21 antigens— findings typical for B-CLL. At one time, establishing the diagnosis of CLL would have led to the immediate cancellation of surgery, which might have been appropriate if acute leukemia had been diagnosed, but would be quite unnecessary for most patients with asymptomatic CLL. It is now widely recognized that the diagnosis of uncomplicated CLL does not preclude the provision of necessary surgery or other treatment, and indeed may not alter the patient’s lifestyle or longevity in any way. Even open-heart surgery can be

Comprehensive Geriatric Oncology

1000

successfully performed in elderly patients with CLL, although special attention must be paid to the high risk of serious infections.5 Because routine physical examinations and blood tests in the absence of symptoms are becoming a regular feature of modern healthcare, increasing numbers of patients are being diagnosed with early CLL. Furthermore, flow cytometry has conferred the ability to diagnose CLL at a particularly early stage, when an absolute lymphocytosis has not become established, but a monoclonal lymphocytosis is unequivocally demonstrable. As a result of these advances, the survival of patients with CLL is likely to increase significantly, but it should be remembered that much of this ‘improvement’ will be factitious and due to the statistical phenomenon of lead time bias, i.e. longer survival that is due solely to earlier diagnosis. Some patients with CLL present with symptoms that are frequently associated with malignancy and with immunodeficiency disorders: malaise, weakness, night sweats, fever without apparent infection, and weight loss. Such constitutional symptoms are less frequent in CLL than they are in Hodgkin lymphoma. Other patients with CLL may present with symptoms of anemia: loss of energy, fatigue, dyspnea, anorexia, weight loss, and pallor. In the older person with cardiac disease or peripheral vascular disease, the symptoms of anemia may be angina, cardiac failure, or intermittent claudication. In an elderly patient with CLL, the anemia may be exacerbated—or be entirely due to—intercurrent unrelated problems, for example gastrointestinal bleeding or a deficiency of vitamin B12 or folate. Such problems should be excluded before anemia is attributed to the leukemia itself; otherwise the disease may be erroneously upstaged. A less frequent presentation of CLL is with symptoms attributable to thrombocytopenia: bruising, purpura, or hemorrhage. Presentation with infection is more common; patients with CLL are prone to infection by reason of hypogammaglobulinemia, decreased T-cell function, neutropenia, or combinations of these defects. Respiratory tract infection, particularly bronchitis and bronchopneumonia, may be the precipitating problem that leads to the diagnosis of CLL. Some patients present with the symptoms of one of the autoimmune disorders that are frequent in patients with CLL: immune thrombocytopenic purpura, autoimmune hemolytic anemia, or connective tissue disease. Some patients with CLL initially present with symptoms that are due to organomegaly. Lymphadenopathy in the neck, axilla, or groin may become quite severe before it is symptomatic. In CLL, splenomegaly is less frequent and usually much less marked than it is in chronic granulocytic leukemia, and symptomatic enlargement of the spleen is rarely a cause of initial presentation. Similarly, splenic infarction is rare in CLL. Although leukocytosis greater than 200×109/l is not rare in untreated CLL, it is almost never symptomatic. Hyperviscosity of the blood and leukostatic lesions in the lungs and brain, which are frequent in acute myeloid leukemia with a high blast cell count, have been reported in CLL6 but are very rare, even when the leukocyte count exceeds 1000×109/l. This is because the lymphocyte of CLL, unlike the myeloblast, is small, readily deformable, and relatively non-adherent, and does not invade blood vessel walls. Thus, emergency treatment for hyperleukocytosis is rarely required in CLL, and the height of the leukocyte count per se is seldom an indication for treatment. Most patients, and not a few physicians, are difficult to convince that this is so.

Chronic leukemias in the elderly

1001

Physical signs The patient with CLL not only may be asymptomatic but also may have no physical signs that are referable to the disease. When abnormal findings are present, pallor and lymphadenopathy are the most frequent. Lymphadenopathy may be found in a single area or in multiple lymph node fields. The nodes are typically soft, mobile, non-tender, and not matted together, and generally they are small, in the 1–2 cm range. Massive lymphadenopathy, with a bull neck or a severely distorted axilla, occurs, but is uncommon. Lymphedema is rarely associated with the lymphadenopathy of CLL. Clinically, the enlarged lymph nodes of CLL are quite different from the hard, adherent nodes that characterize involvement by carcinoma. Splenomegaly is frequently absent, and when present is rarely massive; splenic enlargement that extends below the umbilicus or across the midline is more suggestive of chronic granulocytic leukemia, prolymphocytic leukemia, or hairy cell leukemia. Hepatomegaly, if present at diagnosis, is usually mild. Bruises and purpura are not frequent features of newly diagnosed CLL, but both conditions may be observed in the older person in the absence of any hematologic disease, as a consequence of decreased elasticity of the skin. Cutaneous infiltrates may occur in B-CLL, but are more frequent in the rare T-cell variant of the disease. Lesions of herpes zoster are not uncommon in CLL, and are sometimes a presenting feature. Presentation with meningeal involvement7 or with neurologic problems suggestive of progressive multifocal leukoencephalopathy8 is rare, but important to bear in mind, particularly in the older patient in whom central nervous system disorders of diverse etiology are relatively frequent. Laboratory findings CLL is characterized by an absolute and sustained lymphocytosis in the peripheral blood, with predominantly mature-appearing lymphocytes, although some atypical forms can be detected in most cases and in a few instances 50% or more of the cells possess atypical morphologic features. There is an accompanying lymphocytosis in the bone marrow, but evidence of bone marrow failure—anemia, neutropenia, or thrombocytopenia—is frequently absent. A Working Group sponsored by the US National Cancer Institute (NCI) has further specified typical cases of B-CLL that can be considered for protocol studies.9 Marker studies should show sIg+, CD19+, CD20+, or CD24+. The cells must be CD5+ but negative for other pan-T markers, express either κ or λ light chains, and slg must be present at low density. The minimum threshold for blood lymphocytes is 5×109/l, and the blood lymphocytosis must be sustained over a period of at least 4 weeks upon repeated examinations. The lymphocytes must appear mature, and no more than 55% may be atypical prolymphocytes or lymphoblasts. Patients with 11–55% prolymphocytes—socalled prolymphocytic leukemia (PLL)—should be considered for special studies, because the prognostic significance of their high incidence of cellular atypia is not well defined. The bone marrow aspirate must contain 30% or greater of lymphoid cells. The bone marrow biopsy may show diffuse or nodular lymphocytic infiltration and the marrow must be normocellular or hypercellular.

Comprehensive Geriatric Oncology

1002

The above specification is not universally accepted. Some hematologists will diagnose CLL when the lymphocytosis is less than 5×109/l if a B-cell monoclone with the appropriate surface markers is demonstrable. While such cases may indeed have CLL at an early stage, their inclusion in clinical studies may affect survival data by the mechanism of lead time bias referred to earlier. Cytogenetic findings in CLL This topic has been reviewed in depth,10 and only a few salient features will be considered here. Most types of chromosomal analysis require dividing cells that are in metaphase. Whereas this is no great problem in the acute leukemias or in chronic granulocytic leukemia, it is a major obstacle in CLL, since the tumor cells have a very low mitotic index and must be activated in vitro with mitogens that are effective for B cells (e.g. Escherichia coli lipopolysaccharide or Epstein-Barr virus). Cells from some patients with CLL do not respond to mitogens and evaluable metaphases cannot be obtained; in general, it is not known if such unresponsive cells harbor any chromosomal anomalies. In some cases, fluorescent stains for specific chromosomes can be applied to interphase cells and may demonstrate numerical abnormalities (e.g. trisomies). Cytogenetic techniques in CLL cells have shown two major chromosomal abnormalities with a probable pathogenetic role: trisomy 12 and deletions of the long arm of chromosome 13 (13q14). No relevant gene on chromosome 12, and no pathogenetic mechanism by which the occurrence of trisomy 12 may lead to the development of CLL, have been documented. Terminal deletions of the long arms of chromosomes 6 and 11 might also be significant in CLL. Additional material on the long arm of chromosome 14 (14q+) to form a marker chromosome is a common additional abnormality that does not appear to be of prognostic significance. Trisomy 12 has been associated with poor survival, whereas 13q deletions or a normal karyotype indicate a good prognosis. Complex abnormal karyotypes in the CLL cells are more commonly found at diagnosis than developing during the course of the disease, and are adverse prognostic signs. A large Danish study of 480 unselected newly diagnosed patients produced new cytogenetic data in CLL and correlated them with immunophenotypic studies.11 Of note, 25% (122 of 358) of patients were considered to have an atypical immunophenotype. In patients with a typical CLL immunophenotype, chromosomal abnormalities were found in 22%, but they occurred in 48% of those with an atypical phenotype. Isolated trisomy 12 had no apparent prognostic effect, whereas anomalies of chromosome 17 and multiple cytogenetic abnormalities both correlated with shorter survival. In a multivariate survival analysis, chromosome 17 abnormalities were the only cytogenetic findings with independent prognostic value irrespective of immunophenotype. A study by a German group12 showed improved detection of genomic aberrations when interphase CLL cells were studied by the technique of fluorescence in situ hybridization (FISH). Chromosomal aberrations were found in 268 of 325 patients (82%), and patients could be divided into five cytogenetic categories: 17p–, 11q–, trisomy 12q, normal karyotype, and 13q–. The median survival times for patients in these groups were 32, 79, 114, 111, and 133 months, respectively. Patients with 17p– or 11q– had a significantly higher incidence of higher-stage CLL, while those with 13q- had the highest incidence of low-stage disease, so the correlation between cytogenetic and

Chronic leukemias in the elderly

1003

clinical findings was strong. Of special importance in this study is that because dividing cells were not required, all patients could be evaluated. Despite their undoubted interest and prognostic significance, it has not been unequivocally shown that cytogenetic studies in CLL provide information significantly beyond that which is obtainable from clinically staging the disease (see below). If cytogenetic and immunophenotypic studies can be proved to identify the few poorprognosis patients contained within a group with low-stage CLL, it will be possible to select these patients for earlier interventions that would not be indicated by the clinical stage alone. Natural history and prognosis of CLL General While it is true that CLL may run a very long and extremely indolent course, there has been a strong tendency to overemphasize the supposedly benign nature of the disease and to use this as a pretext for undertreatment. While some patients with CLL may live for more than 20 years, will never require treatment for leukemia, and will die from unrelated causes, most patients do far less well than this. The fact that most patients with CLL are elderly and many suffer from multiple medical problems means that in some instances the leukemia will not be the limiting factor in their survival and will not require treatment. However, many elderly people with CLL will die from the disease, and effective treatment for CLL can be expected to improve both the quality and the duration of life. This is especially so now that overall life-expectancy in the elderly has improved significantly. If an elderly patient’s life-expectancy without CLL significantly exceeds their estimated survival with a diagnosis of CLL, then the leukemia cannot be regarded as inconsequential. Progression of CLL Although the rate at which progression occurs is very variable, in almost every case of CLL there is ongoing replication of leukemia cells and the progressive accumulation of long-lived, immunoincompetent CLL cells. This increasing leukemic cell mass can induce hematopoietic failure, with consequent anemia, thrombocytopenia, neutropenia, and their complications. There is also progressive immunologic failure, with deficient humoral and cellular immunity, and immune dysregulation, with the onset of autoimmune diseases. In very advanced CLL, the leukemic cell mass causes problems directly: hypersplenism, compression of vital structures, hypermetabolism, and cachexia. Unless death occurs from an unrelated intercurrent disease, untreated CLL progresses inexorably to a fatal termination, whether this be in 12 months or 20 years. Transformations of CLL During its usually lengthy course, CLL may undergo a distinct transformation to a more adverse process; this is much less frequent than the disease evolution that is seen in

Comprehensive Geriatric Oncology

1004

almost every case of CGL. Transformations of CLL and some neoplastic complications of the disease are listed in Table 46.4. Acceleration of disease and acquisition of multidrug resistance Acceleration of the disease to a more aggressive phase is relatively common and its time of onset is unpredictable. The blood lymphocytosis increases rapidly, and the lymph nodes, liver, and spleen enlarge progressively. The patient

Table 46.4 Transformations and complications in CLL • Acceleration without morphologic change • Acquisitlon of multidrug resistance • Prolymphocytoid acceleration • Richter syndrome: non-Hodgkin lymphoma • Richter syndrome: Hodgkin lymphoma • Multiple myeloma • Acute lymphoblastic leukemia • Acute myeloid leukemia • Additional primary cancers

may develop constitutional symptoms, and hematopoietic failure and immunodeficiency appear for the first time, or worsen if already present. Although matters may be improved with a change of treatment, resistance to previously effective drug therapy usually appears, and the patient dies from progressive and refractory CLL. In some patients, acceleration of CLL is accompanied by increasing numbers of prolymphocytoid cells in the peripheral blood, and this is termed prolymphocytoid acceleration.13 Although the cells resemble prolymphocytes, their surface immunoglobulin density is low, like that of CLL cells, rather than high, as in de novo PLL. The immunoglobulin type is the same as that of the original CLL cells, from which the prolymphocytoid cells are apparently evolved. Once prolymphocytoid acceleration has occurred, responsiveness to therapy declines and progressive clinical deterioration is the rule. New clinical findings may appear at this stage, for example increasing splenomegaly, soft tissue masses,14 and malignant ascites and pleural effusion.15 Richter syndrome The evolution of a large cell non-Hodgkin lymphoma (NHL) in a patient with CLL was first described in 1928, and bears the eponym Richter syndrome.16 The literature relating to this development of CLL has been reviewed by Han and Rai.17 The clinical features of Richter syndrome include fever, weight loss, increasing lymphadenopathy, splenomegaly, hepatomegaly, lymphocytopenia, and resistance to both chemotherapy and radiation

Chronic leukemias in the elderly

1005

therapy. Rapid clinical deterioration is the rule; many cases of Richter syndrome have been diagnosed only at autopsy. This transformation occurs in less than 10% of patients with CLL; it appears to be more frequent in patients with multiple chromosome abnormalities in the CLL cells and a monoclonal gammopathy in the peripheral blood. In the older patient, Richter syndrome is difficult to treat, because aggressive therapies are apt to be poorly tolerated. Although Richter syndrome usually involves an NHL, cases of Hodgkin lymphoma have been reported. A very rare myelomatous transformation of CLL has been reported, with the heavy and light immunoglobulin chains of the myeloma cells identical to those of the original CLL cells.18 After this transformation, survival is reported as short. Transformation to acute leukemia Whereas transformation to a picture resembling acute myeloid leukemia (AML) occurs in over 75% of patients with chronic granulocytic leukemia (CGL), transformation to acute lymphoblastic leukemia (ALL) is seen in less than 1% of patients with CLL.19 In most cases, the lymphoblasts are of L2 morphology. AML appears to occur with increased frequency in patients with CLL, even after adjusting for their older age. It is not thought that the AML is a direct development from the CLL cells. The reason for the association is unclear; whereas treatment of the CLL with ionizing irradiation or the leukemogenic alkylating agent chlorambucil may account for some cases of AML, the two diseases have been observed concurrently in patients with CLL who have never received any treatment. Additional primary cancers Reports on the occurrence of additional primary cancers in patients with CLL are conflicting,17 although Whipham20 first reported the association in 1878. Gunz and Angus21 reported that, except for an increased number of skin cancers, the incidence of other malignant diseases in CLL was not significantly higher than in the rest of the population. A later study at Roswell Park Memorial Institute22 indicated an increased incidence of second cancers in patients with CLL; after skin cancers, lung cancer was the most frequent (14 of 191 patients). The confounding effects of age and smoking make firm interpretation of the data difficult, but it seems reasonable to recommend that the physician caring for a patient with CLL should always be attentive to symptoms that might indicate a lung cancer. Immunologic complications of CLL The immunologic complications of CLL are outlined in Table 46.5. The immunosuppression that is characteristic of this disease is of great clinical importance. Patients with CLL are prone to infections with tuberculosis, yeasts, and other vegetative microorganisms because of defective cellular immunity, and are also liable to respiratory and other mucosal infections because of defective antibody production. In the older patient with CLL, opportunistic infections are productive of much morbidity and mortality,

Comprehensive Geriatric Oncology

1006

Table 46.5 Immunologic complications of CLL Immunosuppression •

Hypogammaglobulinemia

•

Decreased cellular immunity

Immune dysregulation •

Immune hemolytic anemia

•

Immune thrombocytopenic purpura

•

Immune neutropenia

•

Pure red cell aplasia

•

Connective tissue diseases

even when there is no neutropenia. The immunosuppression of CLL is very rarely improved by treatment of the leukemia, and indeed may be made worse by it, particularly if severe neutropenia is induced by cytotoxic agents or the inflammatory response is suppressed by corticosteroids, thus impairing two additional body defenses. Immune dysregulation in CLL may be the result of attempts by the immune system to control the neoplastic production of B cells, with resultant exhaustion of the system of regulatory T cells. Immune cytopenias are frequent in CLL, and should always be sought when the blood count deteriorates, since they generally respond well to treatment with glucocorticoid drugs. Pure red cell aplasia is characterized by severe and progressive anemia with reticulocytopenia, a negative Coombs test, and severe hypoplasia or complete absence of red cell precursors in the bone marrow. This condition usually responds very well to immunosuppressive therapy; it is therefore important to distinguish it from the anemia that results when erythropoiesis is compromised by progression of the CLL itself. Prognosis of CLL The survival from diagnosis of patients with B-CLL varies from a few months to over 20 years. For many years, the survival of individual patients appeared to be unpredictable, and this made treatment decisions difficult: to treat a patient who is destined to live for years without significant progression of the disease is clearly inappropriate, while to withhold therapy until deterioration is obvious is probably leaving things too late. In the absence of reliable indicators of prognosis, recommendations regarding the timing of treatment for CLL were based largely on personal opinions. There existed both ‘interventionist’ and ‘watch and wait’ schools of thought, and the overall results of these approaches were not very different—except that the interventionists treated many patients who would have done as well (or better) had they been left alone. Many studies identified factors that were thought to possess some prognostic significance; these are summarized in Table 46.6.10,11,17,23–36 Carefiil study of these factors indicates that some are without prognostic value (e.g. age or sex), while others (e.g. β2-microglobulin and total body potassium) do not provide

Chronic leukemias in the elderly

1007

any information beyond that provided by the clinical stage. Certain other observations (e.g. lymphocyte doubling time, cytogenetics, and [3H]thymidine uptake) may provide information that is of independent prognostic value after correction for the stage of disease, but this remains to be proved by a multivariate analysis of a large patient database. The most significant advance in assigning prognoses to patients with CLL was the development of a useful staging system.

Table 46.6 Studies of proposed prognostic factors in CLL Proposed factor

Result of study

Refs

Older age

Multivariate analysis shows no effect

23

Sex

Multivariate analysis shows no effect

23

Performance status (PS)

Poor PS associated with poor survival

24

Neutropenia at diagnosis

Does not correlate with prognosis

23

Gammaglobulin

Low IgA indicates poor prognosis

25

Anemia at diagnosis

Strong indicator of poor prognosis

26

Coombs test positive

No prognostic effect

27 9

Lymphocyte count

Poor prognosis when >50×10 /l

17

Lymphocyte doubling

Short doubling time is adverse

28, 29

Lymphocyte atypia

Disputed; atypia possibly adverse

17

Marrow histology

Diffuse CLL infiltrate adverse

17, 30

High serum lactate dehydrogenase (LDH)

Not if corrected for stage

17

Cell phenotype

slg phenotype not prognostic

17, 31

β2-Microglobulin (β2M)

high serum β2M in advanced CLL

32, 33

[ H]thymidine uptake

High uptake means early progression

34

Deoxythymidine kinase

Elevated serum level: progressive CLL

35

Total body potassium

Increases with advancing stage of CLL

36

Cytogenetics

Poor prognosis if complex changes

10, 11

3

Clinical staging of CLL Endeavors to identify groups of patients with CLL and different prognoses were made in the 1960s by Galton28 Boggs et al,37 and Dameshek.38 Rai and his colleagues devised a five-stage system in 1968 and tested it retrospectively on a series of their own patients and on two published series; they then tested the system prospectively on another group of patients who were at that time

Comprehensive Geriatric Oncology

1008

Table 46.7 The Rai system for clinical staging of CLL39 Stage Extent of disease 0

Lymphocytosis in blood and bone marrow

I

Lymphocytosis plus lymphadenopathy (local or generalized, small nodes or bulky)

II

Lymphocytosis plus enlarged spleen and/or liver (nodes may or may not be enlarged)

III

Lymphocytosis plus anemia (hemoglobin <11 g/dl; enlarged nodes, spleen, or liver may or may not be present)

IV

Lymphocytosis plus thrombocytopenia (< 100×109/l; anemia and enlarged nodes, spleen, and liver may or may not be present)

Note: Unlike many other staging systems, a higher stage does not necessarily include all the features of the preceding stage (see above)

undergoing therapy or observation. In all of these analyses, the Rai staging system proved to be simple and easy to use and accurately predicted the survival time of patients with CLL. The system was published in 1975,39 and is set out in Table 46.7. The survival times that were reported in the original series39 are shown in Table 46.8; more recent series have shown broadly similar results, although in some the survivals in stages III and IV are somewhat longer. From inspection of Table 46.8, it is at once apparent that stage 0 or I CLL is a relatively benign disease and stage III or IV CLL is a life-threatening condition with a prognosis that is only a little better than that of acute leukemia in an adult. Perhaps most importantly, it is seen that stage II CLL—the largest category—has a median survival of under 6 years and should not be considered in any sense a ‘benign’ disease. This is particularly so in patients whose age and overall health would confer a prognosis of 12, 18, or more years if they did not suffer from CLL.

Table 46.8 Median survival according to Rai stage39 Clinical stage

Median survival (months)

0

>150

I

101

II

71

III

19

IV

19

All patients

71

Other staging systems have been formulated by Binet et al23 and by the International Workshop on CLL;40 they differ from the Rai system in detail but not in principle, and

Chronic leukemias in the elderly

1009

they produce similar clinical results. In North America, the Rai system is the most widely used. Management of the older patient with CLL General principles In the past, the approach to management of CLL varied considerably between different centers and also between individual physicians, and there was no standard policy. Recent advances in clinical staging and thus in assessing each patient’s prognosis have made it possible to formulate an approach that is more generally accepted. Younger patients (aged 40–60) with CLL pose a special problem because (i) they will almost certainly die of the disease and (ii) they will suffer a major loss of life-expectancy because they have developed CLL. In these patients, trials of innovative and aggressive therapies, in the setting of a formal clinical study, should always be considered. The geriatric oncologist can and should be more conservative for the following reasons. Many patients are asymptomatic at the time of diagnosis, in many the disease will pursue an indolent course for long periods, and the available treatment for elderly patients is palliative rather than curative. Currently, there is no demonstrated advantage to the early, as opposed to the later, use of antileukemic drugs in CLL. In very elderly or infirm patients, the diagnosis of CLL may not affect life-expectancy, and treatment for CLL could not be expected to produce benefit, although it could still do harm by virtue of its side-effects. In asymptomatic patients, who usually will have stage 0, I, or II CLL, it is good practice to observe without treatment, whereas in stage III or IV

Table 46.9 Follow-up of an untreated patient with CLL Symptoms: Night sweats, fever, weight loss, malaise, infections, declining performance status Signs: Development of, or change in, enlarged lymph nodes, liver, or spleen Laboratory: hemoglobin, platelet count, neutrophil count, lymphocyte doubling time, serum immunoglobulin level, Coombs test, bone marrow biopsy. Note: The above represents the desirable minimum; other investigations are done as indicated

disease, treatment is generally begun at once. Patients who are observed without treatment may be seen every 6–12 weeks; the features that are followed are indicated in Table 46.9. An extremely important factor in the care of the elderly patient with CLL is the provision of a high standard of general medical care for any coexisting diseases; the geriatric oncologist is thoroughly familiar with this special aspect of his or her field. Put simply, patients with CLL who receive excellent general care, and frequently no antileukemic therapy, will have a longer duration and a better quality of life than those who do not.

Comprehensive Geriatric Oncology

1010

Indications for active treatment The indications for the institution of active therapy in CLL have been widely discussed.17,41–45 They are summarized in Table 46.10. Most oncologists would concur with these recommendations, although the threshold for considering that splenomegaly is massive or that lymphadenopathy is bulky must be subject to individual variation. Some oncologists would add other indications, for example a short lymphocyte doubling time, usually taken as under 6 months. This indicates progressive disease and the likelihood that the patient’s disease will shortly progress to a higher Rai stage. Treatment as soon as rapid doubling of the lymphocyte count is documented may prevent this occurrence, but no formal study has been reported that tests this hypothesis. Han and Rai17 have recommended active treatment for progressive hyperlymphocytosis, basing their recommendation on three reports of hyperleukocytosis-associated hyperviscosity syndrome in patients with CLL. They suggest instituting therapy when the total leukocyte count is between 100 and 150×109/l. This threshold was set empirically, and it seems unlikely that the recommendation will be widely accepted unless a clinical study is done that supports it, since problems with hyperviscosity are rare and treatment for CLL is far from innocuous, particularly in the older patient.

Table 46.10 Indications for active treatment in CLL 1. Significant disease-related symptoms 2. Anemia or thrombocytopenia due to progressive leukemia (stage III or IV CLL) 3. Autoimmune hemolysis or thrombocytopenia; pure red cell aplasia 4. Progressive massive splenomegaly, with or without hypersplenism 5. Progressive bulky lymphadenopathy, with or without pressure effects or cosmetic problems 6. Increasing frequency of bacterial infections

Available treatments for CLL Over the past half-century, many agents and very numerous schedules of administration have been employed in the management of CLL: these have been extensively reviewed.17,41–46 Some regimens are now of mainly historical interest, and only the treatments that are most important in current clinical practice will be considered here. Aggressive therapies that are not appropriate for the older patient (e.g. allogeneic stem cell transplantation) will not be discussed at length. Radiation therapy Since the advent of cytotoxic chemotherapy, radiation therapy has played only a restricted role in the management of CLL. It is no longer employed for the systemic treatment of the disease, but it is of value in the control of local problems.47 When a patient with CLL has a dominant lymph node mass that is symptomatic, local irradiation

Chronic leukemias in the elderly

1011

is the palliative treatment of choice. Response rates to modest doses of radiation (e.g. 15 Gy) approach 100%, and local and systemic toxic effects are generally minimal. Usually the dose of radiation administered is much smaller than the doses that are administered when a lymphoma is treated with curative intent, and therefore the same area can be irradiated again at a later date should the lymph node mass recur. If a patient is receiving chemotherapy but there is a large mass (lymph node, tonsil, or spleen) that is not responding satisfactorily, then the addition of local irradiation improves the response without significant toxicity. Irradiation of the spleen in CLL usually reduces splenomegaly, and sometimes there is an improvement in lymphocytosis, anemia, and thrombocytopenia. However, in many patients, the hemoglobin level and platelet count decline significantly, and splenic irradiation must be administered with caution, particularly in patients who have received much chemotherapy. Allopurinol The xanthine oxidase inhibitor allopurinol prevents the conversion of xanthine to the less soluble uric acid. When lymphoid malignancies are treated with effective chemotherapy or radiation, massive lysis of tumor tissue sometimes takes place in a very short period, resulting in the production of large amounts of urate. This may lead to renal calculi, or more seriously to urate nephropathy with renal tubular obstruction and renal failure, which is sometimes fatal. When treatment for CLL is begun, good hydration of the patient must be ensured, and consideration should be given to concurrent therapy with allopurinol, 300 mg daily for 21 days, to prevent hyperuricemia and the resultant hyperuricosuria. This is particularly important in the elderly, who are more likely to have reduced renal function. It is also advisable in the presence of bulky disease, or a uric acid level that is elevated before therapy, or if there is a history of renal disease or gout. Treatment with allopurinol is generally well tolerated, but occasional patients develop drug-sensitivity rashes, which can be very severe. Adrenal corticosteroids The adrenal corticosteroids, usually in the form of prednisone, prednisolone, or dexamethasone, are used extensively in the treatment of CLL. They are modestly immunosuppressive and are also potent lympholytic agents, occasionally producing a response so brisk that hyperuricemia results (see above). Unfortunately, steroids produce a galaxy of adverse effects, listed in Table 46.11. Many of these unwanted effects (e.g. diabetes mellitus, osteoporosis, and hypertension) are particularly serious in older people, who are prone to these conditions even in the absence of corticosteroid therapy. Single-agent treatment with a corticosteroid is indicated when CLL is complicated by autoimmune hemolytic anemia or immune thrombocytopenic purpura or when the disease has become unresponsive to other agents. In a previously untreated patient with severe hematopoietic failure, it is common practice to begin therapy with a corticosteroid alone, because these agents can bring about improvement without inducing further myelosuppression. Corticosteroids are frequently administered in combination with an alkylating agent in the management of CLL, although it is questionable if the addition of a steroid actually improves the results when

Comprehensive Geriatric Oncology

1012

the alkylating agent is administered intensively. Long-term therapy with corticosteroids should be avoided, because the adverse effects (Table 46.11) are much more frequent and more severe when treatment is given for an extended period. Intermittent pulses of a corticosteroid, (e.g. 5–7 days per month), even in substantial doses, are better tolerated.

Table 46.11 The side-effects of adrenal corticosteroids General

Particularly important in the elderly

• Psychosis

• Hypertension

• Acne

• Sodium and water retention

• Excessive appetite

• Dependent edema

• Cutaneous striae

• Cardiac failure

• Hirsutism

• Osteoporosis

• Liability to infection

• Reactivation of tuberculosis

• Obesity

• Hyperglycemia, diabetes

• Masking of infection

• Peptic ulceration • Hypokalemia • Hyperuricemia

High-dose corticosteroid therapy (e.g. methylprednisolone 1g/m2/day by the intravenous route for 5 days at monthly intervals) is well tolerated, and has produced partial remissions with a median duration of 8 months (range 6–78 months) in approximately 50% of heavily pretreated patients with refractory CLL.48 This is a useful stratagem in carefully selected patients. Androgens and estrogens Androgens and other anabolic steroids have occasionally been used in CLL when there is bone marrow failure that has not responded to prednisone with or without an alkylating agent. Improvements in anemia and thrombocytopenia have been reported,49–51 but these agents should be used with caution because most of them are hepatotoxic and they may exacerbate pre-existing prostatic hypertrophy. It is probable that erythropoietin will prove to be more effective than anabolic steroids for improving bone marrow failure in CLL; clinical studies are currently addressing this question. It is of considerable interest that some patients with CLL and carcinoma of the prostate, treated for the latter condition with diethylstilbestrol, showed rapid reductions in their peripheral blood lymphocytosis.52,53 Unfortunately, the severe cardiovascular side-effects of estrogens are a relative contraindication to their use in an elderly patient with CLL.

Chronic leukemias in the elderly

1013

Alkylating agents Many alkylating agents, including mechlorethamine, triethylenemelamine, busulfan, chlorambucil, and cyclophosphamide, have been used in the treatment of CLL, but only chlorambucil and cyclophosphamide have remained in regular, widespread use.46 Chlorambucil This agent is reliably absorbed from the gastrointestinal tract, has some selective cytotoxicity for lymphoid cells, and is relatively free of side-effects such as nausea, vomiting, alopecia, and cystitis.28,41,54,55 However, it should not be forgotten that chlorambucil is mutagenic, leukemogenic, and a potent stem cell poison that can permanently impair the function of the bone marrow. Long-term myelosuppression is particularly likely to occur when low doses of chlorambucil are administered every day for many weeks or months; this is probably also the best way to induce resistance of CLL to the drug and perhaps is the mode of administration that is most likely to induce AML. Fortunately, in recent years, most physicians have adopted a high-dose intermittent schedule for the administration of chlorambucil.56–58 This schedule is at least as effective as low-dose daily chlorambucil, patient compliance is excellent, and the hematologic toxicity is less: dose reductions are required less frequently than with a daily dosing regimen. This suggests that the dose of chlorambucil on an intermittent regimen could be escalated and a higher response rate might be obtained. My practice is to administer chlorambucil at night, at a dose of 20mg, for 4–7 consecutive nights, at an interval of 28 days, usually beginning with a four-dose course. If tolerance is good as reflected in serial blood counts, the total dose can be increased, usually by increasing the number of nightly administra- tions per course. Nausea and vomiting are very rare, and progressive hematologic toxicity is avoided because the substantial interval enables the full effects of each course to be seen before another course is prescribed. A practical point worth noting is that chlorambucil should not be taken with orange juice or other vitamin C-containing vehicle, since ascorbic acid is a reducing agent and can inactivate the alkylating agent. Two randomized trials conducted in France have addressed the value of treatment in indolent (Binet stage A) CLL.59 In the first study, 609 patients were randomly assigned to receive no treatment or daily chlorambucil, and in the second trial, 926 patients received either no treatment or combined chlorambucil and prednisone in pulses for 5 days every month. Although 76% of patients in the first trial and 69% in the second had a response to therapy, there was no prolongation of survival compared with the patients who were initially observed and received treatment only if disease progression occurred. In the untreated group in the first trial, 49% of patients did not have progression to more advanced disease and did not need treatment after follow-up of more than 11 years; however 27% of patients with stage A CLL died of causes related to the disease. This important study confirms the relatively good survival of low-stage CLL when untreated, and shows convincingly that early treatment does not improve prognosis. It appears that the addition of prednisone to treatment with chlorambucil confers no advantage. The failure of early treatment with chlorambucil to improve the overall prognosis suggests

Comprehensive Geriatric Oncology

1014

that, even when good hematologic responses are obtained, the treatment is ineffective in a biologic sense. While it is well known that the alkylating agents busulfan and cyclophosphamide possess pulmonary toxicity, it is less widely recognized that chlorambucil, also an alkylating agent, can induce severe and sometimes fatal pulmonary fibrosis.60 The key factor may be that for all of these agents, by virtue of chronic low-dose administration or large intermittent doses, very high total doses are frequently achieved. Elderly patients with reduced lung function are particularly vulnerable to respiratory compromise and thus are at special risk when chlorambucil is administered for long periods to high lifetime doses. Withdrawal of the drug is followed by improvement in some cases. The administration of steroids in high doses is commonly practised, but there is no compelling evidence of the efficacy of this treatment. Like other alkylating agents, chlorambucil is mutagenic, and probably leukemogenic and carcinogenic as well. There are numerous instances of chronic bone marrow failure, AML, or myelodysplasia (MDS) occurring in patients with CLL after prolonged exposure to chlorambucil; this may be cited as an additional reason not to begin treatment with this agent unnecessarily early. On the other hand, most patients with CLL are of an age when neoplastic diseases, including AML and MDS, are relatively frequent, and it is unreasonable to blame chlorambucil—or other treatment—for all these instances. This is underlined in the review by Lai et al,61 in which five men with untreated CLL developed AML (3 patients) or presented with concurrent AML (1 patient) or concurrent MDS (1 patient); numerous other cases were cited from the literature. Thus, in patients who have received it, the leukemogenic role of chlorambucil is easily overestimated. Cyclophosphamide This agent is also widely used in the treatment of CLL. Unlike chlorambucil, cyclophosphamide is available in an intravenous as well as an oral form. It has the disadvantages that it causes alopecia and also hemorrhagic cystitis. This letter complication, well recognized with high-dose parenteral cyclophosphamide, can also occur with chronic low doses given by mouth.62 The principal indications for the use of cyclophosphamide in CLL are when chlorambucil is not well tolerated (which is rare) or when a multi ple-agent chemotherapeutic regimen is administered. Multiple-agent regimens Several multidrug regimens have been employed in the treatment of CLL. The most frequently used are CVP (cyclophosphamide, vincristine, and prednisone),63 ChOP (cyclophosphamide, doxorubicin (low-dose), vincristine, and prednisone),63 M-2 (vincristine, carmustine, cyclophosphamide, melphalan, and prednisone),64 and POACH (prednisone, vincristine, cytarabine, cyclophosphamide, and doxorubicin).65 All of these regimens were originally devised for the treatment of NHL or myeloma, and they all contain vincristine—a drug that has not shown any single-agent activity in CLL. Since vincristine causes both constipation and peripheral neuropathy, both of which are frequent problems in older people even in the absence of drug therapy, it should be omitted from these regimens as a toxic agent of unproven value in CLL. The value of

Chronic leukemias in the elderly

1015

multiple-drug regimens in CLL is controversial. A large French study63 showed that CVP was more toxic, but no more effective, than single-agent chlorambucil. The same group found that in advanced CLL, the survival of patients who were treated with ChOP was markedly superior to CVP (and possibly to chlorambucil, although this was not directly tested). The anthracycline antibiotics have not been particularly active as single agents in CLL, and this apparent superior survival with ChOP has not always been confirmed by other workers.46 In a study of the POACH regimen at the MD Anderson Cancer Center,65 19 of 34 (56%) previously untreated patients responded, with a 21% complete remission rate, while 8 of 31 (26%) previously treated patients responded, with a complete remission rate of 7%. Mortality was very much higher in the previously treated patients. As this was a single-arm study, it is not possible to assess the merits of the POACH regimen relative to other therapies. It is certainly active in CLL, but does not appear to be very effective for previously treated patients. Splenectomy Although splenectomy has been widely studied in CLL,66–70 there have been no formal trials to compare it with systemic chemotherapy or with splenic irradiation. The usual indications for splenectomy are autoimmune hemolysis or autoimmune thrombocytopenia that have responded inadequately to corticosteroids or immunosuppressive drugs, and hypersplenism in the absence of autoimmune disease. Splenectomy has occasionally been performed for the relief of massive, symptomatic splenomegaly. In the older patient, a careful evaluation must be made to determine their suitability for general anesthesia and surgery. As with other elective splenectomies, pneumococcal vaccine may be administered before surgery, but the patient with CLL may fail to mount a satisfactory antibody response, and long-term penicillin prophylaxis after splenectomy may be a more effective preventive measure. Evaluation of response to therapy Definitions of a complete response to therapy in CLL have been proposed in two sets of guidelines.9,71 Both require normalization of the peripheral blood and the bone marrow, together with disappearance of symptoms and physical signs of the disease. One group71 recommends determining by further tests if the complete remission is a ‘clonal’ one, by demonstrating normalization of the T:B cell ratio in the blood and normalization of the κ:λ light-chain ratio among B cells, and a decrease of CD5+ B cells to less than 25%. Completeness of remission can be tested even further by demonstrating resolution of markers of the neoplastic clone—idiotype, immunoglobulin gene rearrangement, and chromosomal abnormalities. From the viewpoint of the clinician, the most relevant criteria of response are relief of symptoms, correction of physical and hematologic abnormalities, resolution of any transfusion needs, and freedom from infections. Most important, the patient’s performance status should improve and be brought as close to normal as the patient’s age and the presence of other illnesses permit. In the case of a partial response, the stage of disease should improve—for example from stage III to stage 0. It seems probable that a patient who is stage 0 by virtue of treatment may not have the excellent prognosis of an untreated stage 0 patient: this is a subject for further study.

Comprehensive Geriatric Oncology

1016

Modern purine antagonists: fludarabine, cladribine, and pentostatin Fludarabine Fludarabine monophosphate is the most recent drug to find a major role in the treatment of CLL, and is the most effective single agent ever to be tested in that disease. It is a purine analogue with a substituted fluorine atom that confers resistance to deamination and consequent inactivation by the cellular enzyme adenosine deaminase.72 Following injection, it is dephosphorylated in plasma to form arabinosyl-2-fluoroadenine.73,74 It is actively taken up by cells and phosphorylated to its 5′-triphosphate, F-ara-ATP, which is the active form of the drug. F-ara-ATP inhibits DNA synthesis by competing with deoxyATP for incorporation into DNA, and also by inhibiting ribonucleotide reductase. F-araATP is also incorporated into RNA, and is an inhibitor of DNA repair. The major toxicity of fludarabine is myelosuppression; it is well tolerated subjectively, with little nausea or vomiting and almost no alopecia.75 In early studies, significant neurotoxicity was encountered, but this occurred at doses approximately fourfold greater than are now employed.76 Fludarabine was evaluated in CLL by Grever et al.77 Of 22 previously treated patients, 19 showed some response, with 1 complete remission and 3 excellent partial remissions. A study by Keating et al78 in 68 previously treated patients with CLL demonstrated complete remission in 15% and a partial response in 44%. These are astonishingly good results, particularly for previously treated patients, when it is recalled that in previously untreated patients who receive chlorambucil and corticosteroids, complete remissions are seen in perhaps 5–10% of patients at best. The major toxic effects associated with fludarabine therapy were myelosuppression and episodes of fever and infection. Ten patients died during the study, seven of them during the first three courses of treatment, and it was clear that this potent agent must be handled with caution. When a drug performs well in patients with a previously treated neoplastic disease, results are usually even better when the drug is administered to previously untreated patients. Keating et al79 administered fludarabine, 30mg/m2/day by the intravenous route for 5 days every 4 weeks, to 33 previously untreated patients with advanced or progressive CLL. The complete remission rate using the NCI’s guidelines, which permit the presence of residual lymphoid nodules in the bone marrow, was a remarkable 75%. Of the 33 patients, 6 (18%) failed to respond and 3 died of infection during the first three cycles of treatment. It is very important to note that all three of these patients were aged over 75 years and all had Rai stage III–IV disease. In a 3-year follow-up of this study,80 there were 35 previously untreated patients, with a complete remission rate of 74% and partial remissions in 6% of patients for an overall response rate of 80%. The median duration of response was 33 months. These results are far superior to any that have been reported in previously untreated patients for alkylating agents, with or without corticosteroids or additional cytotoxic drugs. In another study by the same group, previously treated patients with CLL received fludarabine combined with prednisone.81 The results of treatment were not better than those obtained with fludarabine alone, but as all the patients had received prednisone previously, this study did not completely rule out any synergistic effect of the drug combination if it were used in untreated patients, although later studies appeared to do so.

Chronic leukemias in the elderly

1017

Keating et al82 have also reported on the long-term follow-up of patients with CLL who received fludarabine-based regimens as initial therapy. Three different fludarabine studies were included; patients began treatment between 1986 and 1983, and the results were reported in 1998, with 5–12 years of follow-up in a total of 174 patients with progressive or advanced CLL. The overall response rate was 78% and the median survival was 63 months. No differences in response rate or survival were noted in the 71 patients who received fludarabine as a single agent compared with the 103 patients who received prednisone in addition. The median time to progression of responders was 31 months and the overall median survival was 74 months. Age over 70 and disease that was Rai stage III or IV were associated with shorter survival. Over 50% of patients who relapsed after fludarabine therapy responded to salvage treatment, usually with a fludarabine-based regimen. During treatment, there was severe suppression of both CD4+ and CD8+ T lymphocytes in the blood and recovery towards normal levels was slow, but despite this the incidence of infections was low for patients in remission. Richter syndrome occurred in 9 patients, 8 of whom died. These results indicate that fludarabine is a potent regimen for initial induction therapy in previously untreated CLL and that the safety profile of the treatment compares well with that of other therapies. Four randomized studies83–86 have shown fludarabine to have a higher response rate than chlorambucil, CAP (cyclophosphamide, doxorubicin, and prednisone), or French ChOP (see above). Treatment with fludarabine yields higher response rates than chlorambucil and a longer duration of remission and progression-free survival, but no overall survival advantage has as yet been demonstrated. When fludarabine was compared with chlorambucil and with CAP, there were no increases in toxicity or early death when fludarabine was given as initial therapy. Combinations of fludarabine with other agents It is important to determine if combination with other agents can increase the effectiveness of fludarabine. The combination of cyclophosphamide and fludarabine induced complete responses in three of six patients with CLL, despite unsatisfactory responses to fludarabine alone;87 this combination merits further evaluation. A randomized controlled trial of fludarabine versus chlorambucil versus fludarabine with chlorambucil in previously untreated patients with CLL showed that single-agent fludarabine was superior to single-agent chlorambucil, while the combination of the two drugs was not superior to fludarabine alone and was more toxic, leading to the closure of that arm of the study.86 In Germany, a combination of fludarabine with epirubicin was studied in 44 patients; of the 38 patients who were evaluable for response, 25 were previously untreated.88 For the whole group, the overall response rate was 82%, with 32% complete remissions; for the untreated patients, the corresponding figures were 92% and 40%. These results do not definitely indicate superiority of the regimen to single-agent fludarabine, but might justify a randomized trial of the two treatments. In a small nonrandomized study in previously untreated patients with CLL, induction therapy with fludarabine was followed by consolidation with high-dose cyclophosphamide.89 Before consolidation, 16% of patients achieved a complete or a nodular complete response in the bone marrow; following consolidation, this fraction increased threefold to 48%. These

Comprehensive Geriatric Oncology

1018

interesting results require confirmation, particularly since all the patients were aged less than 69. There is much scope for further therapeutic studies in CLL. With the advent of fludarabine, should the value of earlier treatment be re-evaluated? Is there a place for maintenance therapy with fludarabine? Is there an optimal combination—and sequencing—for administering fludarabine and an alkylating agent as combined therapy? The NCI has sponsored revised guidelines for the diagnosis and treatment of CLL,90 and further revisions are to be expected. Cladribine The purine analogue cladribine (2-chlorodeoxyadenosine) has demonstrable activity in CLL, including refractory cases, but does not appear to be as effective as fludarabine.46 A European group reported their experience with patients aged 70 years and older with CLL that was untreated (33 patients) or relapsed (10 patients).91 They received a median of three 5-day courses of cladribine, and 13 (30%) had a complete response, Only one previously treated patient responded, but with the small numbers there was no significant difference between the groups. No patient had received fludarabine as previous treatment. Thrombocytopenia and infection were frequent, and six patients (14%) died. This study shows that cladribine is active in CLL, but does not suggest that it is as effective or as safe as fludarabine. Pentostatin The antitumor antibiotic pentostatin (2′-deoxyco-formycin) is an antagonist of adenosine deaminase and an intensely lymphocytotoxic purine antagonist. Pentostatin has demonstrable activity in CLL, including refractory cases,92 but does not appear to be as active as fludarabine.46 A British group evaluated pentostatin in 29 patients with relapsed or refractory B-CLL.93 The patients’ ages ranged from 44 to 74, with a median of 60; thus they were younger than the average patient with CLL. Seventeen had received purine analogues (16 fludarabine, and 1 cladribine). Pentostatin was administered as a daily bolus injection at a substantial dose: 2mg/m2/day for 5 days. Of 24 patients who were evaluable for efficacy, 2 had a complete response (neither had previously received a purine analogue) and 5 had a partial response (3 had received a purine analogue). Pentostatin in this schedule demonstrated salvage activity in previously treated patients with CLL and was not always cross-resistant with other purine analogues. Complications of fludarabine therapy Apart from the corticosteroids, all of the potent chemotherapeutic agents that are administered for CLL are myelosuppressive, and fludarabine is no exception. Thrombocytopenia and hemorrhage, and neutropenia and infection, are regular hazards, particularly when marrow function is significantly compromised before treatment is begun. These complications are more serious, and more frequently fatal, in the older patient with multiple medical problems.

Chronic leukemias in the elderly

1019

Fludarabine also has a more unusual adverse effect: autoimmune hemolytic anemia (AIHA).94–97 This can arise de novo or as a recurrence or exacerbation of a previously diagnosed condition. It appears that patients with known AIHA may be more prone to this complication of treatment with fludarabine than other patients with CLL. The condition usually responds to corticosteroid therapy. A suggested mechanism for AIHA in this setting is the severe suppression of T cells that is induced by fludarabine; the inhibition of autoregulatory suppressor cells that maintain tolerance may trigger autoimmune hemolysis.96–98 Since fludarabine antagonises adenosine deaminase, there is accumulation of deoxyadenosine in erythrocytes during treatment with fludarabine; this damages the cells and may make them more susceptible to autoimmune destruction, thus accentuating a pre-existing process. A further possibility that also applies to other therapies (e.g. chlorambucil) is that the myelotoxic activity of chemotherapeutic agents can simply unmask AIHA (rather than causing it) by suppressing the compensatory augmentation of erythropoiesis that may conceal the hemolytic process. It follows that before beginning fludarabine, or other cytotoxic therapy, in a patient with CLL, it is advisable to order a Coombs test, reticulocyte count, and serum folate level, to exclude the presence of AIHA. The tumor lysis syndrome (TLS) of hyperuricemia, hyperkalemia, hypocalcemia, and frequently renal failure has been anecdotally reported in patients with CLL after fludarabine therapy,” but a study of 6137 patients with CLL who received fludarabine on an NCI group C protocol100 disclosed only 20 (0.33%) with clinical and laboratory features of TLS; 4 died of renal failure and 4 of infection or congestive heart failure. Thus, TLS is a rare complication of fludarabine therapy but is frequently fatal. Advanced CLL, organomegaly, and a high pretreatment white blood cell count appeared to be risk factors for TLS. There are isolated reports of AML or MDS arising in patients with CLL after treatment with fludarabine,101,102 but such instances are rare, and since untreated CLL has been associated with AML and also with MDS,103 the fludarabine treatment may not be to blame. The current place of fludarabine in the therapy of CLL If a patient cannot be entered into a formal therapeutic study, and an accepted indication for active treatment exists, should fludarabine be used as first-line therapy in previously untreated CLL? Although there is no universal agreement, I believe that on current evidence the answer is ‘yes’. This opinion is based on the high response rate (80–90%) and the extremely high incidence of complete remission (up to 75%), together with evidence of a remission duration that approaches 3 years and a median survival exceeding 7 years. These results so far exceed those that are obtained with chlorambucil, with or without prednisone, or the more toxic anthracycline-containing regimens, that it may be a disservice to the patient not to administer fludarabine. My policy is to administer 25mg/m2/day as a 30-minute intravenous infusion, daily for 3 days on the first occasion, and to repeat the treatment every 4 weeks, increasing its duration to 4 or 5 days if it is well tolerated. This cautious approach is appropriate for the elderly patient, particularly if the pretreatment blood count is poor, if comorbid conditions are present, or if there is already a history of opportunistic infections.

Comprehensive Geriatric Oncology

1020

Concern has been expressed about the responsiveness of CLL to salvage therapy after relapse in patients who receive fludarabine as initial therapy, but it has now been shown82 that most patients achieve a second remission, particularly if they achieved a complete remission with their first exposure to the drug. Drug resistance in CLL Like many other neoplastic diseases that respond well to initial chemotherapy, CLL frequently demonstrates the phenomenon of the development of secondary resistance to previously effective drugs, evidenced by a failure of clinical and hematologic response. Although the patient whose disease has become refractory to alkylating agents and corticosteroids may in the short term do well with fludarabine as salvage therapy, the onset of drug resistance is always an ominous event that indicates a deteriorating prognosis. Further, CLL shows primary resistance to many drugs that are valuable in the chemotherapy of other diseases (e.g. methotrexate, vincristine, etoposide, and doxorubicin). The mechanisms of drug resistance in CLL have been reviewed by Silber and Potmesil.104 Resistance to methotrexate and several other antimetabolites that are specifically active in S phase of the cell cycle appears to be attributable to the very low proliferative fraction in populations of CLL cells. Resistance to fludarabine—also an antimetabolite, but for uncertain reasons active in CLL despite the low mitotic index—is mediated by loss of enzymes that activate the drug. Resistance to chlorambucil and other alkylating agents appears to be due to enhanced mechanisms for repair of DNA and for the intracellular neutralization of alkylating molecules, while refractoriness to adrenal corticosteroids is associated with loss of the cellular receptors for these agents. Resistance to etoposide and doxorubicin may be due to the low expression of topoisomerase II, a major target of these drugs, in CLL cells105 and/or to overexpression of the multidrug-resistance gene MDR1.106 Activation of MDR1 leads to synthesis of the glycoprotein gp170 (also known as P-glycoprotein, P-gp), which acts as an efflux pump, removing the drugs from the intracellular environment (see also the discussion of multiple drug resistance in CGL later in this chapter). Studies of compounds (e.g. cyclosporine analogues and PSC-833) that may reverse multiple drug resistance are in progress, but these agents have not yet had a significant impact on hematologic practice. Numerous other measures to circumvent drug resistance in CLL have been proposed,104 but have not yet found a place in clinical practice. There are several techniques for evaluating the activity of MDR1 in vitro, including the measurement of drug efflux and the assay of gp170 with monoclonal antibodies.107 The expression of gp170 is more frequent with advancing stage but not with prior alkylating agent therapy. The functional expression of gp170 increases with higher stage and previous treatment with agents of biologic origin (e.g. vincristine and doxorubicin). Sensitivity of CLL cells to fludarabine can be measured in vitro by the differential staining cytotoxicity (DiSC) assay,108 Resistance to fludarabine was found in cells from 12 of 100 (12%) of untreated patients and 45 of 143 (31%) of patients who had received prior therapy, excluding fludarabine. Resistance was found in cells from 17 of 32 (53%) of patients who had been treated with fludarabine. The clinical correlation of these tests was excellent: fludarabine was effective in 69% of patients whose cells were sensitive by DiSC assay, and in only 7% of those whose cells tested resistant. Of note, 81% of

Chronic leukemias in the elderly

1021

fludarabinetest-resistant patients were test-sensitive to other agents. The DiSC assay makes it possible to withhold fludarabine from patients who have a low likelihood of responding to it, thus saving the expense and toxic effects of an ineffective therapy and giving the patient the opportunity to receive an alternative and more effective therapy. Management of autoimmune complications of CLL Anemia in CLL always requires careful evaluation. It may be due to bone marrow compromise induced by the disease, in which case the patient has stage III disease and an anticipated median survival of less than 2 years. The anemia may also be due to coexisting unrelated conditions, for example deficiencies of iron, vitamin B12, or folate, gastrointestinal bleeding, or chronic diseases such as rheumatoid arthritis. All of these conditions are more frequent in the older patient. Finally, anemia may be due to AIHA; this is associated with the leukemia but does not make the patient’s disease stage III. In such cases, the direct antiglobulin (Coombs) test is usually positive and there is a reticulocytosis. It is not uncommon for active hemolysis to be complicated by folate deficiency because of the increased folate consumption, in which case macrocytosis may be observed and reticulocytosis may be suppressed. Immune thrombocytopenic purpura (ITP) also occurs in CLL and is less serious than the thrombocytopenia of bone marrow failure; it does not make the patient’s disease stage IV. The demonstration of antiplatelet antibodies is not a well-standardized test, and at many centers the diagnosis of ITP depends upon the finding of thrombocytopenia with adequate or increased megakaryocytes in the bone marrow (but this may not be the case if there is heavy marrow infiltration with CLL), and a response to corti-costeroid therapy. AIHA and ITP may occur together (Evans syndrome). AIHA and ITP are usually treated with prednisone (100mg/day) or dexamethasone (16mg/day); these high doses can be tapered as soon as a response is seen. In the older patient it is wise to administer an H2 blocking drug (e.g. ranitidine) concurrently with the corti-costeroid, and many would add anticandidal prophylaxis with fluconazole. In the patient with AIHA, folate supplementation is recommended while there is active hemolysis. If the response to steroid therapy is inadequate, or only occurs at an unacceptably high dose that cannot be continued long term, high-dose intravenous immunoglobulin should be added: 400mg/kg/day for 5 days and then maintenance with the same daily dose administered once every 21 days. In occasional patients, splenectomy is necessary for the control of AIHA or ITP, and this operation carries increased risks in the older patient. Overall, the prognosis of patients with AIHA or ITP who respond to prednisone therapy is better than that of patients with anemia or thrombocytopenia that are due to stage III and stage IV CLL respectively. Many patients may also require chemotherapy for active CLL in addition to treatment for AIHA or ITP. It should be remembered that the administration of chlorambucil or other myelotoxic drugs may exacerbate the anemia of AIHA because any compensatory increase in erythropoiesis may be suppressed. The rare autoimmune condition of pure red cell aplasia (PRCA) is occasionally seen in CLL, and may be treated with corti-costeroid, with or without the addition of cyclosporine.

Comprehensive Geriatric Oncology

1022

Supportive care in CLL Anemia in a patient with CLL, if due to the leukemia itself and not to hematinic factor deficiencies, blood loss, or chronic disease, is best treated by controlling the CLL and improving the function of the bone marrow. The transfusion of packed red blood cells is valuable during initial therapy and also for patients whose erythrocyte production is not restored by treating the leukemia. Treatment with erythropoietin improves hemoglobin levels in some patients with CLL, but it is not certain that this treatment is cost-effective when compared with transfusion, and in some patients it fails outright. Platelet transfusion in CLL is indicated only for hemorrhage, as it is in any chronic thrombocytopenic state. For many years, immunoglobulin replacement therapy has been employed empirically in patients with CLL for the prevention of infection, but it was only relatively recently that a randomized, placebo-controlled study demonstrated conclusively that this therapy provides highly effective prophylaxis.109 The recommended dose is 400mg/kg, administered intravenously once every 21 days. This treatment is very expensive, and should only be administered to a patient with CLL if there is hypogammaglobulinemia and a history of repeated infections. As patients with CLL frequently suffer from neutropenia, an excess of suppressor T cells over T helper cells, and deficient natural killer cells, immunoglobulin replacement is unlikely to fully restore immunocompetence. Infections in patients with CLL should be investigated aggressively and treated vigorously, and the physician must be alert to the possibility of infection with tuberculosis, or with unusual organisms, particularly yeasts and fungi.110 Innovative treatment strategies for CLL The introduction of fludarabine is the most significant advance in the management of CLL in four decades, but although fludarabine induces a high proportion of complete remissions in previously untreated patients with CLL, it has not been proved to have the potential for curing the disease. When patients with CLL become refractory to fludarabine, there is no alternative therapy of comparable effectiveness, so there is a pressing need for further advances in treatment. Several innovative treatment strategies are under investigation.111,112 Monoclonal antibodies Treatment with monoclonal antibodies (MoAbs) has been extensively studied in patients with CLL. Passive immunotherapy with unconjugated MoAbs turned out to be relatively safe, but the clinical responses were minor in degree and usually transient, so this did not appear to be an effective treatment. A logical extension of MoAb therapy was to give the antibodies a warhead by conju- gating them with immunotoxins before their administration. Studies have been carried out with single-chain immunotoxins—usually the A chain of ricin—and with two-chain immunotoxins consisting of ricin A and B chains but with the non-specific galactose-binding sites of ricin blocked. These compounds have shown major activity against CLL cells in vitro, but clinical experience

Chronic leukemias in the elderly

1023

thus far is limited and responses have been relatively minor. Clinical studies are in progress with a fusion protein that has been produced by recombinant DNA technology, in which the receptor-binding domain of diphtheria toxin is replaced by the sequences of human interleukin-2.111 These compounds have significant antitumor activity but also significant toxicity, including elevated hepatic amino-transferases, hypoalbuminemia, fever, chest tightness, rashes, increased serum creatinine and thrombocytopenia, and clearly would have to be administered with great caution in the older patient. Studies have also been done with radioimmunoconjugates, in which a MoAb is coupled to a radionuclide (32P or 131I). By binding to CLL cells in the bone marrow as well as the peripheral blood, these compounds deliver radiation not only to their intended targets, but also to normal cells in the bone marrow, and myelosuppression results. Overall, MoAbs armed with immunotoxins or radionuclides do possess significant activity against CLL cells, but their place—if any—in therapy is undetermined. Possibly they may be of value for the eradication of minimal residual disease—for example after a complete remission has been obtained with fludarabine or other intensive chemotherapy. Recent studies with two monoclonal antibodies, rituximab (anti-CD20) and alemtuzumab (anti-CD52) suggest that these more recent additions to the therapeutic armamentarium are capable of palliating CLL even after the onset of resistance to chemotherapeutic agents.112,113 New drugs Novel drug therapies continue to be studied in CLL. The macrocyclic lactone bryostatin 1 has shown activity in low-grade lymphoid neoplasms, and in patients with CLL has induced differentiation of the CLL cells to a hairy cell phenotype.114 A randomized study in 229 patients with untreated CLL compared cladribine plus prednisone with chlorambucil plus prednisone.115 The rates of complete remission and of overall response were significantly higher in patients who received cladribine (47% and 87%, respectively) than in the patients who received chlorambucil (12% and 57%, respectively). Unfortunately, this higher rate of response did not translate into an improved overall survival for those who received cladribine. Hematopoietic stem cell transplantation (HSCT) Allogeneic HSCT is generally felt to be too hazardous for the older (over 70) patient with CLL, and will not be discussed here. Autologous HSCT has fewer complications and is undergoing evaluation. A French group has studied autologous HSCT as salvage therapy in patients with refractory or relapsed CLL.116 Patients aged up to 66 received intensive chemotherapy to induce remission and autologous HSCT as consolidation treatment. Only 8 of 20 (40%) of patients were able to complete the protocol, either because a new remission was not obtained or because not enough stem cells could be collected. Of the eight grafted patients, six were alive and in complete clinical remission a median of 30 months after ASCT. The eight transplanted patients were aged 54–63, and these promising results cannot be extrapolated with confidence to patients aged over 70. If autologous HSCT is useful for salvage therapy, it can be expected to be more effective when used earlier in the course of CLL, and a German group has tested this in

Comprehensive Geriatric Oncology

1024

18 patients aged 29–61.117 Only 4 patients had received no treatment and 16 had recognized adverse prognostic features. Initial chemotherapy was followed by stem cell harvesting, intensive chemotherapy and radiotherapy, and HSCT. Of 18 patients, 13 (72%) underwent HSCT and achieved complete remission; 1 relapsed at 36 months and 12 remain in remission at 12–48 months after HSCT. These early results are of great interest, particularly the absence of procedure-related deaths. If longer follow-up shows durable complete remissions, then the procedure could be considered—as a formal randomized study—for carefully selected older patients with recently diagnosed CLL and poor prognostic features. Chronic myeloid leukemias in the older person Introduction The following sections will consider the diagnosis, clinical features, and management of a diverse group of disorders that have, for reasons historical rather than scientific, been grouped together as chronic myeloid leukemias (Tables 46.1 and 46.12). The principal focus will be the least rare member of the group, namely Philadelphiachromosome-positive chronic granulocytic leukemia (CGL). For this disease, the potential role of biological therapy with interferon-α, the use of the tyrosine kinase inhibitor imatinib, and the likely impact of recent advances in molecular genetics upon its future management will be explored. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only known curative therapy for CGL, and in younger patients this is an important mode of treatment. In the older person, allogeneic HSCT by currently available techniques is proscribed because of lethal toxicity. Treatment in the older person thus is with palliative, not curative, intent. Terminology and classification of CML As in many other fields of pathology and clinical medicine, terminology has long been a problem in the leukemias. The same disease may have several names, and sometimes the name of a specific disease is also used as the name for a group of related diseases. For example, chronic granulocytic leukemia (CGL) is also named chronic myeloid leukemia (CML), chronic myelogenous leukemia, and chronic myelocytic leukemia. Each name emphasizes a particular feature of the disease: predominant involvement of the granulocytic series of cells, blood

Table 46.12 Chronic myeloid leukemiasa and related disorders • Chronic granulocytic leukemia (CGL)b • Atypical myeloproliferative syndromec • Chronic myelomonocytic leukemia (CMML) • Rarer subvarieties of chronic myeloid neoplasia:

Chronic leukemias in the elderly

1025

–

Chronic neutrophilic leukemia (CNL)

–

Chronic eosinophilic leukemia (CEL)

–

Chronic basophilic leukemia (CBL)/systemic mastocytosis

–

Granulocytic sarcomas without leukemia

a

Used as a generic term, cf. acute myeloid leukemias. A specific disease associated with the BCR-ABL translocation. c Formerly termed ‘Ph-negative CML’, but quite distinct from CGL b

that under the microscope resembles bone marrow, origin from marrow (as against lymphoid tissues), and a striking myelocytosis in the peripheral blood, respectively. In the present context, ‘chronic myeloid leukemias’ will be used as a generic term for the entire group of conditions, and unique names have been assigned to individual diseases within the group. This is comparable to the system that is accepted for the acute myeloid leukemias. The nomenclature and cardinal characteristics of these disorders are summarized in Table 46.12, and problems of nomenclature are discussed in more detail elsewhere.118 The diseases listed in Table 46.12 resemble one another in being more or less chronic leukemias that overtly involve the granulopoietic cells of the bone marrow. Cytogenetic, enzymatic, and more recently molecular genetic studies indicate that they represent monoclonal cell proliferations, and that the single cell of origin usually is a pluripotential hematopoietic stem cell, so that the megakaryocytic and erythropoietic cell series are also part of the neoplasm.119 In at least some cases, the B-cell lineage of lymphocytes is also implicated, and there are a few reports of the involvement of T lymphocytes in the neoplastic clone, indicating that it originated at a truly primordial stem cell level. Clinically, the different chronic myeloid leukemias show important differences in their frequency, age distribution, manifestations, hematologic findings, response to treatment, and prognoses. It is therefore very important to distinguish accurately between them in the assessment and management of the individual patient. Chronic granulocytic leukemia (CGL) Definition Chronic granulocytic leukemia (CGL) is a disease of unknown etiology characterized by leukocytosis in the peripheral blood, with a characteristic differential leukocyte count, and overgrowth of the granulocytic cell series in the bone marrow with essentially normal morphology and maturation but an abnormal preponderance of myelocytes. Whereas many other features are commonly encountered in CGL, for example splenomegaly, anemia, and a low neutrophil alkaline phosphatase (NAP) score, none is constant or essential to the diagnosis. Presentation

Comprehensive Geriatric Oncology

1026

The greatest incidence of CGL is in the age range 40–60 and there is a slight male preponderance. Unlike chronic lymphocytic leukemia (CLL), it is not rare for patients with CGL to be young adults. Although in the older person CLL is much more frequent than CGL, many individuals with CGL are also encountered, and their overall prognosis is worse than that of patients with CLL. Symptoms The most common presentation is with symptoms of anemia: loss of energy, fatigue, dyspnea, anorexia, weight loss, and pallor. Older patients with cardiac disease may present with cardiac failure or angina, and patients with peripheral vascular disease may complain of new, or more severe, claudication. Less commonly, the patient may complain of an abdominal mass (the spleen). This complaint is more frequent in women than in men; this may be a reflection of greater body awareness. Non-specific symptoms of splenomegaly—left upper quadrant discomfort, ‘dragging’ pain in the area of the spleen, bloating, and early satiety—are common. When the disease is in its chronic phase, neutropenia is absent and thrombocytopenia is uncommon: thus, unlike the acute leukemias, patients with CGL rarely present with symptoms of infection or hemorrhage. Because healthcare practices have altered in recent years, increasing numbers of patients are detected when asymptomatic, for example when blood tests are performed as part of a regular physical evaluation. Many but not all of these asymptomatic patients appear clinically to have early disease, in the sense that the physical and hematologic manifestations of CGL frequently fall short of the classical picture. In a biologic sense, the disease is not ‘early’, since in most cases all the dividing cells in the bone marrow carry the Philadelphia (Ph) chromosome and thus are part of the leukemic clone. Before the advent of chromosome studies, it was only possible to make the diagnosis of CGL with confidence in such cases after a period of observation had permitted the disease to evolve. The evolution is frequently slow: 1 or 2 years may be required before a typical picture of marked leukocytosis and splenomegaly is attained. It has been common practice not to offer treatment to these patients until symptoms appear, but this policy would change should definitive therapy for CGL become available; early treatment would then be indicated. The recent demonstration that the administration of interferon-α can at least temporarily suppress the Ph-positive clone in the bone marrow (see below) suggests that treatment immediately upon diagnosis may already be advisable, since durable suppression of the leukemia cells may be more readily achieved when they are not long-established and when adequate numbers of normal stem cells may persist. There are many atypical presentations of CGL: all are relatively uncommon. They include presentation with gout, or with renal colic due to urate calculi secondary to excessive urate production. Extreme leukocytosis (usually >500×109/l) can lead to hyperviscosity of the blood, with complications that include priapism, visual difficulty due to retinal bleeding, and mental confusion due to cerebral hypoxia. A particularly interesting presentation is with seemingly classical symptoms of thyrotoxicosis, including heat intolerance and night sweats. The explanation is that such patients are truly hypermetabolic (although not hyperthyroid) due to the active metabolism of a mass of granulocytic tissue that reaches 5kg or more. The hyper-metabolic symptoms resolve when the disease is treated.

Chronic leukemias in the elderly

1027

Occasional patients present with an apparent ‘surgical abdomen’ due to painful splenic infarction. Infarcts in the upper portion of the spleen, impinging upon the diaphragm, may be even more confusing, causing presentation with acute severe pain in the left shoulder tip. Rarely, spontaneous rupture of the spleen, or rupture through an area that is infarcted, leads to presentation with a genuine surgical emergency. The enlarged spleen of CGL is also readily ruptured by minor trauma, and injury is an occasional cause of initial presentation to medical attention. Some patients have no symptoms that they consider significant until their disease enters an acute phase, when they present with symptoms that are usually associated with the acute leukemias: bruising, bleeding, fever, and infections. Physical examination and features of the blood picture usually suggest the nature of the underlying disease, and demonstration of the Ph chromosome by cytogenetic study of the bone marrow is confirmatory. Clinically, such patients are quite different from those who present with genuine acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML), with no features of CGL, and who also possess the Ph chromosome in bone marrow cells. Patients with CGL, presenting in an acute phase of their disease, are usually distinguishable by the presence of massive splenomegaly, a finding that is very rare in the acute leukemias, although it does occur in some patients with AML that has arisen from a myeloproliferative syndrome. Patients in whom the spleen is congenitally absent120 and those who have undergone splenectomy, sometimes many years previously, are not immune from the development of CGL,121,122 and their presentation may be marked by pronounced thrombocytosis; the absence of a spleen is not routinely accompanied by the presence of marked hepatomegaly. The above account of clinical presentations of CGL is not exhaustive; other presentations have been described,123,124 and contribute to the complexity of this fascinating disease. Physical signs The most frequent physical findings are pallor and splenomegaly. The spleen is palpable in 80–90% of patients: splenomegaly was formerly regarded as a universal finding, but this is no longer true, because, with improved standards of medical care, some patients are detected with CGL at a relatively early stage and with no palpable splenic enlargement. Absence of splenomegaly commonly is associated with a leukocyte count of less than 100×109/l.3 In Western countries, CGL is the most frequent cause of massive splenomegaly that extends below the umbilicus. The spleen may be so large as to extend across the midline and have its lower pole in the pelvis; occasionally, these very large spleens are missed on abdominal examination because their lower edge is not found— they may, however, then be detected on rectal or vaginal examination! Splenomegaly of minor degree, or in an obese patient, may be detectable only by radionuclide scan or by computed tomography (CT) scan. If recent infarction has occurred, the spleen may be tender, and if the infarction is very recent, a friction rub may be heard with respiration. Rapid enlargement of the spleen, when the disease is accelerating, may also cause marked splenic tenderness due to acute stretching of the organ’s capsule. The liver may be enlarged, and in very advanced CGL, the liver and spleen fill the whole abdomen with the exception of the right midzone. The presence of lymphadenopathy, purpura, signs of

Comprehensive Geriatric Oncology

1028

infection, or bone pain and tenderness all suggest that CGL is no longer in its chronic phase, and should always be sought. When anemia is severe, conjunctival pallor may be accompanied by tachycardia, precordial hemic bruits, or frank congestive failure. In patients with very high leukocyte counts, usually exceeding 500×109/l, the retinal veins are dilated and the ophthalmoscopic appearances resemble those of Waldenstrom’s macroglobulinemia, with hemorrhages and ‘cattle-trucking’ of blood in the retinal vessels. The retina may show classical white-centered hemorrhages, which consist of extravasated blood with a central area of proliferating immature white cells. Increased bruisability, a frequent finding in the healthy elderly person, may take a different form in elderly patients with untreated CGL. The bruises may mirror, on a larger scale, the white-centered retinal hemorrhage. They develop central tumors, which on biopsy resemble the bone marrow in CGL. The reason is that many cells that normally reside only in the bone marrow are circulating in the peripheral blood; their extravasation into the tissues is followed by proliferation in their new location, with formation of a myeloid tumor that shows full differentiation. It is important to distinguish such manifestations from the much more ominous tumours of blast cells (variously termed chloromas, myeloblastomas, or granulocytic sarcomas) that occur in the skin and other tissues in AML or in CGL in an acute phase. Rarely, a patient with CGL in chronic phase has lymphadenopathy at presentation, and lymph node biopsy shows differentiating myeloid tissue in the node, not granulocytic sarcoma. Thus lymphadenopathy in untreated CGL is not always a sign that the disease is entering an acute phase. By contrast, the appearance of lymphadenopathy in a patient with CGL that is under treatment is extremely suspicious for the onset of a blastic phase of the disease. Many other physical signs occur in occasional patients with CGL.123,124 One of the most interesting is a mimicking of the stigmata of thyrotoxicosis, including tremor, tachycardia and hot sweaty hands, due to the hypermetabolic state associated with untreated CGL. It follows from the above that CGL may be suspected upon physical examination, but cannot with certainty be distinguished from other causes of anemia and splenomegaly. Laboratory findings The most characteristic finding is an extremely elevated leukocyte count, usually exceeding 100×109/l, and rarely less than 50×109/l. Low counts have been observed in very early cases, or in the presence of vitamin B12 or folate deficiency. Patients are recorded in whom CGL became apparent only after coexisting pernicious anemia had been diagnosed and treated, allowing the characteristic leukocytosis to develop. Anemia of mild to moderate degree is usual in CGL, but the hemoglobin concentration may be normal or elevated. Occasional patients have shown markedly elevated hemoglobin and modestly elevated leukocyte counts, and have been diagnosed initially as having polycythemia rubra vera (PRV). In the elderly patient with CGL, anemia due to the leukemia may be rendered more severe by comorbid conditions (e.g. peptic ulcer disease, diverticulitis, or colon cancer). Thrombocytopenia is uncommon in CGL, and moderate to marked thrombocytosis is the usual finding. Rare patients have gross thrombocytosis as the major abnormality in the blood, and are diagnosed initially as having essential

Chronic leukemias in the elderly

1029

thrombocythemia (ET). Demonstration of the Ph chromosome in bone marrow cells is the most rapid and conclusive means for excluding the diagnosis of PRV or ET. The appearances of the peripheral blood are diagnostic.125 There is a complete spectrum of granulocytic forms, ranging from blast cells to mature polymorphonuclear cells, thus justifying the older name for CGL, ‘chronic myeloid leukemia’ (i.e. blood that resembles bone marrow). The differential leukocyte count is characterized by two peaks—myelocytes and mature neutrophils—with lesser numbers of metamyelocytes. The morphologic features of the blood cells are usually normal, in sharp contrast to the picture seen in the myelodysplasias. Occasional poorly granulated myelocytes or neutrophils are seen, and moderately abnormal platelets, particularly large forms, are not uncommon. An absolute excess of basophil granulocytes is a uniform finding, and its absence always casts doubt on the diagnosis. The majority of patients show an absolute eosinophilia and monocytosis, and approximately half have an increased absolute lymphocyte count.125 All of these changes are best appreciated when absolute cell counts, rather than percentages of the differential count, are considered. The diagnosis of CGL hinges upon these characteristic findings in the peripheral blood. If they are not present, several explanations are possible: (i) the diagnosis is incorrect; (ii) the disease is at an early stage, usually with a leukocyte count well below 50×109/l; (iii) progression beyond the chronic phase has already occurred; (iv) factors such as folate or vitamin B12 deficiency have prevented development of the characteristic blood picture; (v) the quality of the staining of the blood film has been poor (this may mask the presence of basophilia, particularly if the pH of the stain has deviated from 6.8); (vi) the differential count has been performed by an inexperienced observer, or upon too few cells (e.g. 100 instead of 500), so that the more subtle features have been masked by sampling error. CGL is unusual among the leukemias in that the appearances of the blood are diagnostic, whereas those of the bone marrow are not. Hypercellularity, increased granulopoiesis with normal maturation and a left shift, increased megakaryocytes, and relatively reduced erythropoiesis without dysplasia—the usual findings126—are characteristic but not specific for CGL. Despite this, it is routine practice to examine both an aspirate and a biopsy of the marrow, for the following reasons: (i) occasionally, conversion to an accelerated or a blastic phase may be apparent from examination of the marrow when not yet manifest in the peripheral blood; (ii) the marrow aspirate provides optimal material for cytogenetic studies, which should be performed in every patient; (iii) the marrow biopsy enables assessment of cellularity and also may reveal the presence of associated myelofibrosis. Occasionally, the marrow biopsy may show islets composed entirely of blast cells, denoting the occurrence of transformation of CGL at a time when neither the blood film nor the marrow aspirate reveal this information. Serial examinations of the bone marrow usually show that many of the initial abnormalities persist, even when the health of the patient and the appearances of the blood have been restored to normal by effective treatment.126 This is a reflection of the overall inadequacy of standard chemotherapy for CGL, a disease of stem cells. Characteristically, several other laboratory findings are abnormal in CGL: low NAP, elevated serum levels of vitamin B12 and its binding protein transcobalamin I, and hyperuricemia. None is specific for the disease, and any of these findings can be absent in occasional cases of true CGL, so they are not of value in establishing the diagnosis. A

Comprehensive Geriatric Oncology

1030

low NAP score, once thought to be strongly suggestive of CGL, is also found in paroxysmal nocturnal haemoglobinuria and in some 30% of cases of myelofibrosis and related disorders. The chromosomal findings in CGL are of major importance, not only with respect to the disease itself, but also because of the insights that they provide into cancer biology as a whole. At least 95% of cases that meet the diagnostic criteria outlined above possess the Ph chromosome, a reciprocal translocation that involves the long arms of chromosomes 9 and 22, in 90–100% of dividing bone marrow cells. The uniform Ph-positivity of the bone marrow is usually not altered by conventional therapy, illustrating yet again the shortcomings of the palliative treatment of this disease. The advent of an immunofluorescent technique, fluorescence in situ hybridization (FISH), has enabled the demonstration of the t(9; 22) translocation in interphase cells that do not provide chromosome spreads for direct examination. In the reciprocal translocation, the terminal portion of the long arm of chromosome 9 is transferred to the long arm of chromosome 22. This portion of chromosome 9 carries the cellular proto-oncogene, c-ABL, which becomes juxtaposed to the break that occurred in chromosome 22. The breakpoints in chromosome 22 are not constant, but nor are they random: all are congregated in a short segment of DNA designated the breakpoint cluster region, BCR. The normal function of the gene at this site (the BCR gene) is unknown. The proximal, or 5′, portion of BCR (that part closer to the centromere of chromosome 22) joins with c-ABL to form a new, chimeric, oncogene, BCR–ABL. This gene encodes messenger (m)RNA that specifies a novel protein, p210BCR-ABL, that possesses tyrosine kinase activity and is thought to be a regulator of cell replication. Thus, the genetic events underlying the formation of the Ph chromosome may play a key role in the manifestations of the disease. Techniques now exist for the detection of the BCR-ABL DNA sequence, of its mRNA, and of p210BCR-ABL The presence of the BCR-ABL hybrid gene has now been demonstrated in cases of hematologically typical CGL in which the Ph chromosome has not been detected. Thus, as suggested by Baikie many years ago, the rare cases of CGL that lack a visible Ph chromosome but are in all other respects typical may have the same molecular genetic lesion as the Ph-positive cases. The finding of the BCR-ABL chimera in the absence of the Ph chromosome indicates that in some cases there occurs a translocation of genetic material far more subtle than the relatively huge segments of DNA that can be resolved by the light microscope. This finding not only explains the rare cases of Ph-negative but otherwise typical CGL, but may also explain the even rarer cases in which the Ph has first appeared during the course of CGL, or disappeared late in the course of the disease, without any loss of neoplastic behavior. The molecular event, formation of BCR-ABL, appears to be a crucial step. Why it should be frequently, but not invariably, associated with a visible chromosomal abnormality is unexplained. The development of the polymerase chain reaction (PCR) for greatly amplifying selected segments of the genome has made it possible to detect the presence of very small amounts of BCR-ABL, of the order of less than one cell in 10000. This places in our hands a very powerful tool for the detection of minimal residual disease when CGL has been treated with curative intent (e.g. by HSCT). Continuing molecular genetic studies in CGL may throw much light not only on this singular disease, but also on the nature of neoplas- tic disorders in general. There may be other ramifications to the Ph translocation, because it places c-ABL close to the gene that encodes for the λ, light

Chronic leukemias in the elderly

1031

chains of immunoglobulin, which is situated on the long arm of chromosome 22, proximal to the BCR. Similar translocations that shift another oncogene, c-MYC, from chromosome 8 in close proximity to an immunoglobulin gene on chromosome 2, 14, or 22 are seen in Burkitt lymphoma, suggesting that immunoglobulin genes or their regulatory sequences may in some way enhance the transcriptional activity of oncogenes. The occurrence of CGL that is BCR-ABL-positive but Ph-negative suggests that mediation of an immunoglobulin gene may not be an essential part of the process, but the tendency for Ph-positive disease to predominate suggests that the translocation may further enhance the proliferation of BCR-ABL-positive cells. When the Ph chromosome is formed, another oncogene, c-SIS, is transferred from the long arm of chromosome 22 to the long arm of chromosome 9. This event has not thus far been shown to play a role in the pathophysiology of CGL. Natural history and prognosis of CGL CGL was formerly described as having two phases: an initial chronic phase in which progression was slow and the patient might live for years even without treatment, and a ‘blastic crisis’, characterized by a sudden transition to a picture resembling acute leukemia. The clinical course then became one of hectic deterioration, with death within 4–6 weeks regardless of any attempts at treatment. This description is an oversimplification that arose many years ago when there was a lack of close follow-up of patients and also a failure to appreciate more subtle deviations from the true chronic phase of CGL. When physical examinations, blood counts, and examination of the bone marrow are more frequent, it is apparent that there are many states intermediate between the chronic phase and a true blastic phase. Baikie127 introduced the term ‘metamorphosis’ to describe the transitions that occur in CGL, and the protean features of this process have been described in detail.128,129 Most patients first progress from the chronic phase to an ‘accelerated myeloproliferative’ phase, usually characterized by the failure of one or more aspects of hematopoiesis, and sometimes by the development of myelofibrosis. The diagnosis of metamorphosis in CGL can be quite difficult because its onset is frequently subtle. Symptoms Insidious deterioration of health without specific symptoms is common. Fatigue, anorexia and malaise may occur without obvious cause. More definite symptoms—night sweats, splenic pain, and bone pain—may not arise until the process is well advanced. Physical signs Weight loss, fever, and the reappearance of a spleen that had become impalpable with treatment are common. A very tender spleen, denoting rapid enlargement, is extremely suspicious. When metamorphosis is more advanced, bone tenderness, lymphadenopathy, bruises, and purpura make the diagnosis obvious.

Comprehensive Geriatric Oncology

1032

Hematologic findings Usually there is a need for larger doses of cytotoxic drugs to control the leukocyte count. Typically, the ‘cost of treatment’ rises: whereas in the chronic phase it is possible to maintain a normal blood picture with non-intensive single-agent chemotherapy, in the accelerated phase the leukocyte count can be maintained within normal limits only at the price of anemia, or thrombocytopenia, or both. A marked increase in the circulating basophil count is common. Thrombocytosis with many abnormal platelets also may be an early change. Red cell changes suggestive of marrow fibrosis may be noted. Appearance of immature cells, particularly myeloblasts, in the peripheral blood makes the diagnosis obvious, but frequently occurs only as a late manifestation. Examination of the bone marrow sometimes is unhelpful because there is no obvious change in its appearance although its functional capacity has clearly altered. A marked excess of blast cells in the bone marrow is diagnostic but frequently a late finding. Cytogenetic studies of the marrow are sometimes helpful, showing the appearance of chromosomal changes additional to the Ph chromosome before morphologic changes are seen. Marrow biopsy is sometimes of value—for example, islands of blast cells may be seen when the aspirate fails to show an excess of immature cells, or the progressive accumulation of fibrous tissue may be demonstrated. Should the bone marrow become inaspirable (a ‘dry tap’), biopsy is essential and is likely to demonstrate marked fibrosis, with or without an excess of blast cells. Occasionally, a marrow biopsy in a patient with CGL whose health is deteriorating yields an unexpected finding: infiltration with carcinoma cells from a cancer of the lung, breast, or prostate. Second malignancies are uncommon in young patients, but are a relatively frequent problem in the elderly. Progression The accelerated myeloproliferative phase occurs in most patients—i.e. an abrupt transition to a blastic phase is the exception rather than the rule. It may last for months or even for more than a year, and for the first time it may become necessary to administer blood transfusions. There may at this stage be a role for the administration of recombinant human erythropoietin to enhance red cell production, but evidence on this point is as yet inadequate. If the patient survives the accelerated myeloproliferative phase, an acute-leukemia-like illness eventually supervenes and survival thereafter is a matter of weeks in most cases. Chemotherapy is far less effective than in de novo AML and not infrequently may shorten survival in the older patient, producing severe toxicity without securing a remission of the leukemia. A minority of patients experience true ‘blastic crisis’, manifesting a blastic phase abruptly, with no premonitory transitional phase: note that one cannot be certain that the onset was truly abrupt unless the patient is being followed at intervals not greater than 4 weeks. In cases of abrupt transition to a blastic phase, the blast cells frequently, but not always, resemble lymphoblasts in morphologic, cytologic, and immunologic features.129 These lymphoblastoid cells may in some cases arise from a Ph-positive clone that was never committed to granulocytic differentiation;130 in other cases, cytogenetic evidence suggests an evolution from the original CGL clone. Surface marker studies usually

Chronic leukemias in the elderly

1033

indicate a B-cell phenotype; T-cell characteristics are extremely rare. In general, the features of lymphoid morphology, presence of terminal deoxynucleotidyl transferase (TdT) in the cell nucleus, and presence of CALLA (common acute lymphocytic leukemia antigen, J5 or CD10) on the surface of the blast cells correlate with one another and also with responsiveness (in the short term) to vincristine and corticosteroids—drugs that are effective in ALL. Since TdT positivity and responsiveness to these drugs occasionally occur in cells with myeloid appearances, the test for TdT is a useful supplement to morphologic study. Prognosis of CGL Although there is no doubt that treatment improves the quality of life for patients with CGL, it has been questioned whether it increases its duration. The only substantial series of untreated patients131 was collected nearly 80 years ago, and this cannot, of course, be repeated. This paper is widely quoted, usually in an erroneous fashion, because, not surprisingly, few have read the original publication from 1924. Almost certainly, not all the patients in this study had true CGL by modern criteria, the diagnoses were probably made at a later stage than would now be the case, and some patients were not entirely untreated. In 1924, proper cytogenetic studies could not be performed. These individuals cannot therefore be accurately compared with any modern series. The median survival of these patients was calculated from onset of symptoms—a date of doubtful accuracy—and was 32 months: median survival from diagnosis was apparently 20 months. In modern series, median survival has always been calculated from diagnosis, because this time point can be determined with certainty, whereas time of onset cannot. As long ago as 1954, Tivey’s132 analysis of 1090 patients treated with radiotherapy showed a median survival of 32 months from diagnosis, or approximately 12 months longer than the corrected median survival for untreated patients. In 1968, the British Medical Research Council (MRC)133 reported a median survival of 39.5 months for patients treated with busulfan. In more recent series, the median survival has been in the range 40–45 months, and was 51 months for a subset of patients with known Ph-positive disease diagnosed since 1970.134 More recent studies with interferon-α, to be discussed later, show further significant increases in survival. A reasonable conclusion is that the median survival of untreated patients with CGL, based on suboptimal data that cannot be checked by a new study, is approximately 20 months from diagnosis, while that of patients with known Ph-positive disease who receive appropriate chemotherapy exceeds 50 months. It follows that treatment does prolong life in CGL, but the effect is modest. In older series of treated patients, the median survival is approximately 30 months, suggesting that modern treatment is measurably more effective than older therapy. Some of this improvement may be spurious and attributable to earlier diagnosis (‘lead time bias’) and to the exclusion of patients with CGL already in accelerated phase and those with disorders not acceptable as CGL by modern criteria. There was little evidence of improvement in median survival since the introduction of busulfan about 50 years ago, until recent studies with interferonα therapy showed promising results (see below). The failure of conventional chemotherapy to greatly improve the survival of patients with CGL contrasts sharply with the steady progress being made in the management of the acute leukemias. Its causes

Comprehensive Geriatric Oncology

1034

appear to be: (i) because CGL apparently arises at the stem cell level, it may not be eradicable by measures that are successful in the acute leukemias; (ii) palliative treatment with conventional chemotherapy does not greatly postpone the onset of metamorphosis of the disease; (iii) no treatment has greatly increased survival in a majority of patients (and thus improved the median survival) once metamorphosis has become established. The scatter of individual survival times in CGL is wide, ranging from less than a year to 20 or more years. Metamorphosis of the disease may occur at any time, and has proved extremely unpredictable. Thus, it has been difficult to give a meaningful prognosis, and this adds greatly to the distress of the unfortunate patient, who may suffer severely from this sense of ‘living with a time bomb’. Newer approaches have provided valuable assistance with this problem. In 1982, it was reported that a significant correlation exists between survival and the amount of busulfan required for control of the disease in its first year: patients who require 300mg or less of busulfan in the first year have a significantly better prognosis than those who require more intensive treatment.135 The reason for this correlation may be that the requirement for busulfan is a measure both of the initial bulk of disease and of the cell proliferation rate characteristic for each patient. It is not known whether this simple predictive device applies to other types of drug therapy, and as busulfan is no longer the chemotherapy of choice in CGL, the clinical application of this interesting observation is limited. In 1984, Sokal et al136 showed that certain features at diagnosis—age, spleen size, percentage of blast cells in the bone marrow, and platelet count—may be used to develop a ‘hazard function’ that successfully divides patients into three prognostic groups with widely differing median survivals. Of significance in geriatric oncology is that older age was proved to be a risk factor for shorter survival in CGL. Criteria that indicate the likely survival from diagnosis of patients with CGL are now well documented,136,137 but the prediction of survival in ‘late chronic phase’, defined as more than 12 months from diagnosis, is more uncertain. Survival after 12 months of disease is relevant because many patients with CGL are referred to tertiary centers at that stage, and to assess the benefits (or otherwise) of new therapies, an accurate prognosis is desirable. From an analysis of 257 patients with CGL in late chronic phase, the group at the MD Anderson Cancer Center found an overall median survival of 43 months.138 By multivariate analysis, characteristics associated with shorter survival were age of 60 or older, time from diagnosis of 3 years or greater, performance status of 1 or greater, blood basophils 7% or greater, spleen 10cm or greater, blood blasts 3% or greater, and albumin less than 40g/l. A model that included age, duration of chronic phase, performance status, and peripheral blood basophil cells was generated. Patients with 0, 1, 2, or 3–4 adverse factors had median survivals of 71, 49, 26, and 19 months respectively. The ability to divide patients with CGL into prognostic categories is of assistance not only in advising the patients, but also in the selection of therapy. For example, patients with adverse prognostic features are potential candidates for early HSCT or other innovative therapies that might not be recommended for, or accepted by, patients who can expect a lengthy survival with more conservative measures. Currently, allogeneic HSCT is rarely performed in patients older than 55–60 years and thus has not affected the management of the elderly patient with CGL, but other investigational therapies, including autologous HSCT, may be appropriate in carefully selected older patients.

Chronic leukemias in the elderly

1035

The classification of patients into risk groups by mainly clinical criteria has certainly improved prognostication in CGL. A study from Germany has demonstrated that the pathology of the pretreatment bone marrow in CGL exerts a significant impact on prognosis, and that the clinically based multivariate risk classification can be improved by consideration of morphologic variables.139 In a study of 495 patients with Ph-positive CGL, examination of the pretreatment bone marrow showed that a doubling of fiber content and a reduction of erythropoiesis predicted a shorter survival—even in patients classified clinically as low-risk. In patients with myelofibrosis, there was no significant difference in survival rates under hydroxyurea or interferon-α treatment; if confirmed, this observation could be most important in planning treatment strategies for individual patients. Treatment of chronic-phase CGL CGL is responsive to ionizing radiations of several types and to a great variety of alkylating agents and antimetabolite drugs. Special measures, including leukapheresis and splenectomy, are indicated in a few specific situations. Thanks to recent advances, some methods of treatment are of historical interest only and will not be considered here. The subject has been reviewed at length elsewhere.140 The focus of the following discussion of treatment is the patient aged 70 or older. Hydroxyurea In the majority of cases, my preference is for hydroxyurea as the initial drug therapy. Its advantages include rapid control of the leukocyte count and relatively rapid reversal of the drug’s effects, which minimizes the hazards of overdosage. Hydroxyurea also lacks the chronic toxic effects that may occur with the long-term administration of busulfan (see below). If aggressive therapy at some later date is envisaged (e.g. autologous HSCT), then it will be to the patient’s advantage not to have had exposure to busulfan, which is radiomimetic, inflicting chronic tissue damage, and may thus enhance the toxic sequelae of intensive treatment, particularly pulmonary fibrosis. Furthermore, since 1982, there has been evidence that the survival of patients treated with hydroxyurea is longer than that of busulfan-treated patients.141 More recently, a meta-analysis of the data from 690 patients in three randomized trials confirmed the superiority of hydroxyurea: survival at 4 years was 45.1% with busulphan and 53.6% with hydroxyurea (p=0.01).142 Another study indicates that, in a minority of patients, very intensive therapy with hydroxyurea results in the emergence of Ph-negative, presumably non-leukemic, cells in the bone marrow.143 It is not yet known if this stratagem can improve the survival of patients with CGL, and in the older patient it should be considered a high-risk treatment. Disadvantages of hydroxyurea, compared with the older drug busulfan, include greater cost, the need for continuous therapy in most patients, and occasional difficulty in finding the dose that will maintain the leukocyte count in the desired range of 5−10×109/l. Hydroxyurea is begun at a dose of 1g twice daily, with a good fluid intake and concurrent allopurinol (300mg once daily). A blood count is performed not less than once weekly. The dose is halved when the leukocyte count reaches 20×109/l, and subsequent adjustments are made to secure a stable leukocyte count below 10×109/l. Allopurinol is

Comprehensive Geriatric Oncology

1036

discontinued when the leukocyte count is controlled. For maintenance therapy, most patients require between 1 and 1.5g of hydroxyurea daily, and once stability has been secured, a blood count every 3–4 weeks is usually sufftcient for good control. Relative resistance to hydroxyurea can arise while CGL remains in its chronic phase and usually can be countered by increasing the dose. Side-effects are uncommon, but they include nausea and stomatitis, usually only at high doses, and skin rashes. Rarely, prolonged administration of hydroxyurea (2 years or more) causes hyperkeratosis of the palms, soles, and knuckles, with flaking of the skin, and sometimes ulceration. Busulfan Although it is now rarely indicated, busulfan is the least expensive and most convenient drug therapy for CGL. It is begun in a once-daily dose of 3mg/m2 body surface area, and it is seldom necessary to exceed a daily dose of 6mg. The effects of busulfan are principally upon relatively early precursor cells in the bone marrow, and, as a result, changes in the blood count are both delayed in their onset and persist longer than those induced by other alkylating agents. The leukocyte count may not fall until 10–14 days of treatment have elapsed, and may not cease falling for a similar period after the drug has been discontinued. For this reason, it is wise to interrupt therapy when the leukocyte count falls to 20×109/l and resume it when the count begins to rise once more. When the count is stable in the 5–10×109 range, busulfan is discontinued and the patient observed. A normal platelet count and haemoglobin concentration usually are attained 2–6 weeks after correction of the leukocytosis, but splenomegaly resolves more slowly. Massive splenic enlargement may require 6–9 months and more than one course of busulfan for its resolution. The duration of response to an initial 4–8 week (approximately 120–240mg) course of busulfan varies widely. If the threshold for beginning a further course of busulfan is set at a leukocyte count of 30×109/l, occasional patients require no further treatment for up to 24 months (a good prognostic sign), but most require retreatment within 6–12 months. The value of close control of the leukocyte count in the patient with CGL has not been proven, although there is some evidence that patients who are retreated only when the leukocyte count rises once more to over 100×109/l have a shorter survival. Most physicians prefer to keep the count below 20×109/l. Early in the course of CGL, this may be achieved by intermittent treatment, but later a progressively increasing requirement for busulfan leads to the use of regular maintenance therapy, which may vary from as little as 4mg once a week to as much as 2mg daily. In the latter situation, with a busulfan requirement exceeding 700mg annually, it is better and safer to change to hydroxyurea. The appearance of resistance to busulfan, defined as the need for a continuing daily dose of 4mg or more to control the leukocyte count, usually is associated with a change in the course of CGL; often it is the earliest sign of the onset of metamorphosis. Unlike the situation with hydroxyurea, where the emergence of relative resistance to the drug generally has no ominous significance, an increasing need for busulfan is almost always a bad sign. Management of CGL with busulfan has the advantages of a high response rate (approximately 98%) and the possibility, in the early stages, of intermittent therapy with relatively few clinic visits and blood counts. It carries the disadvantages of a sustained

Chronic leukemias in the elderly

1037

duration of effects, so that overdosage may lead to prolonged life-threatening pancytopenia. Injudicious overuse of busulfan may produce severe marrow hypoplasia with a mortality rate as high as 50%, or higher in the older patient. For this reason, a prescription for busulfan should be for only sufficient drug to last until the next clinic visit, and refills of the prescription should never be authorized. Chronic ingestion of busulfan has numerous adverse effects,140 of which the most serious, particularly for the older patient, is pulmonary fibrosis. Skin pigmentation (melanosis) is common, and is most pronounced in darker-skinned individuals and least noticeable in the very fair-skinned, presumably because of a constitutional inability to produce large quantities of melanin. Busulfan causes cellular atypia in many tissues, and the results of cervical smears are not fully reliable during its administration. Occasional patients develop a wasting syndrome superficially resembling Addison’s disease but without hypoadrenalism.140 In patients without leukemia, busulfan has induced AML:144 this hazard is virtually impossible to assess in patients with CGL, because there is a high incidence of conversion to a more acute disorder even when no therapy is given. In fact, busulfan is used very rarely. It has been recommended when control with hydroxyurea is poor, when no aggressive form of therapy is contemplated later in the disease, or when age, infirmity, poverty, or geographic considerations dictate a treatment that causes little inconvenience or expense for the patient. Thus, busulfan is not indicated in the management of the younger patient with CGL, but occasionally can be a valuable option in the older patient. Other drugs in the chronic phase of CGL Many other agents, including melphalan, cyclophosphamide, uracil mustard, dibromomannitol, mercaptopurine, and thioguanine, are effective in chronic-phase CGL, but none has a proven advantage over hydroxyurea, and nowadays they are seldom prescribed. Mercaptopurine is a useful substitute for hydroxyurea in the few patients who develop nausea or skin rashes with the former drug. If the patient is concurrently receiving allopurinol, thioguanine is preferable to mercaptopurine, because allopurinol retards the metabolic degradation of mercaptopurine by xanthine oxidase and thus potentiates its effects and also its toxicity. Because the degree of potentiation is variable, selection of an appropriate dose of mercaptopurine during the administration of allopurinol is very difficult. Irradiation of the spleen Splenic irradiation was for 50 years the favored method of treatment for CGL in its chronic phase, and has been discussed elsewhere.140 With the introduction of busulfan, and the demonstration that the median survival of patients who receive busulfan is superior to that of those who receive radiation therapy,133 the use of splenic irradiation as an initial treatment for CGL in chronic phase declined, and now has virtually ceased.

Comprehensive Geriatric Oncology

1038

Hyperleukocytosis with hyperviscosity Occasional patients with CGL present with leukocyte counts exceeding 500×109/l and resultant blood hyper-viscosity. The complications of this state include cerebral dysfunction, respiratory compromise, priapism, angina with cardiac failure,145 and retinal hemorrhages. Examination of the optic fundus reveals changes resembling those seen in macroglobulinemia. It is worth noting that, in the patient with hyperleukocytosis, measurements of arterial blood gases are apt to yield values for pO2 that are incompatible with life. This is due to the consumption, in vitro, of oxygen by the excessive numbers of leukocytes. A correct value for pO2 can be obtained by performing the blood gas analysis at the bedside or, more conveniently, by collecting the specimen in a syringe primed with sodium azide, which terminates the respiratory activity of the leukocytes. The most effective emergency treatment for hyperleukocytosis in CGL is leukapheresis, which brings about a rapid (though temporary) reduction in the leukocyte count. In order to maintain this reduction, treatment is begun with hydroxyurea, 1g every 4 hours for the first few days. Allopurinol is administered at a dose of 300mg every 12 hours, since the large leukemic cell mass and the rapid cytolytic effect of the high-dose chemotherapy are apt to cause hyperuricemia. Intravenous hydration is advisable and the urine output should be monitored. In AML, problems related to leukostasis in the cerebral and pulmonary circulations may be encountered when the total leukocyte count is in the region of 100×109/l. Familiarity with this problem may give rise to needless apprehension when a patient with CGL has a leukocyte count that exceeds this value. In fact, leukostatic lesions are relatively rare in CGL in its chronic phase, because their occurrence depends principally on the absolute blast cell count, which is relatively low compared with that in AML. Problems attributable to a high leukocrit and hyperviscosity are not seen in CGL unless the total leukocyte count greatly exceeds 100×109/l. Hyperuricemia and renal failure Presentation with hyperuricemia and obstructive urate nephropathy is an uncommon but life-threatening manifestation of CGL. Such patients commonly have a marked leukocytosis, prominent splenomegaly, and a high leukemic cell mass. The problem is more frequent in the elderly and in those with a history of renal disease. Measures that have proved valuable are the immediate institution of treatment with allopurinol, alkalinization of the urine with intravenous sodium bicarbonate, cystoscopy with ureteric irrigation to remove urate sludge, and rapid treatment of the disease, initially by leukapheresis and then with hydroxyurea after 24 hours of exposure to the action of allopurinol. The pH of the urine should be monitored; if it does not become alkaline with intravenous sodium bicarbonate alone, then acetazolamide should be administered. Severe cases require hemodialysis, and this can with profit be combined with leukapheresis, passing the plasma that returns from the cell separator through a dialysis coil before its return to the patient.

Chronic leukemias in the elderly

1039

Special problems in initial management In the elderly patient with CGL, management may be complicated by diseases of multiple other systems. For example, the effects of anemia are more severe in the presence of cardiovascular or cerebrovascular disease; metabolic abnormalities are enhanced in the presence of renal or liver disease; the administration of busulfan is unwise in the presence of chronic pulmonary disease; and deficiencies of folate or vitamin B12 may confuse the hematologic picture and also impair the expected response to treatment. Iron deficiency may occur at any age, and should always be suspected when control of the leukocyte count is not accompanied by a return of the hemoglobin concentration to normal: the identification of iron deficiency dictates a careful search for its cause, especially in elderly male patients, who frequently may be suffering from a gastrointestinal malignancy. The psychotic patient with CGL poses special problems—for example, treatment with lithium elevates the leukocyte count in CGL, just as it may in normal individuals, and makes accurate control of the disease more difficult. For a mentally disturbed or intellectually impaired patient who is not in a hospital, unreliability in taking medications may be a problem. It is best countered by administering busulfan in large single doses (e.g. 20–50mg once every 2 weeks), taken under direct supervision in the clinic. Pregnancy at the time of diagnosis of CGL has been the subject of significant discussion,146 but fortunately this at least is not a problem for the geriatric oncologist. Psychosocial aspects of management A diagnosis of any form of leukemia inevitably causes much anxiety and grief. The patient with CGL can be reassured that the short-term prognosis is excellent and that the treatment is both innocuous and highly effective, but this initial relief may soon be replaced by chronic anxiety about the future, particularly in more thoughtful and intelligent patients. Many patients with CGL are in the age group with developing careers, young children, and major financial and social commitments. Some will be faced with onerous decisions, for example whether to agree to HSCT, which offers cure of the disease if successful, but also carries the risk of early death from complications of the procedure. By contrast, in the elderly patient, young children are seldom a problem and HSCT is not an issue, but other problems frequently loom large—for example, when CGL is diagnosed in a patient who is the caregiver for a chronically ill spouse, or when CGL develops in a widowed patient who lacks good support systems. An honest and strongly supportive attitude on the part of the physician is the first essential of management, but many patients will require in addition the advice of a social worker. A minority of patients develop major depression or other disturbances and require the help of a psychiatrist. It is important to involve the patient’s immediate family in the process of support and counselling, and to be on the alert for anxiety-depression and other problems that are common in the spouse or other relatives.

Comprehensive Geriatric Oncology

1040

Attempts to prolong the chronic phase of CGL Conventional approaches have failed to cure CGL, and treatment of the disease after metamorphosis is difficult and relatively unrewarding, particularly in the older patient who may tolerate intensive therapy poorly. Measures that would prolong the chronic phase of the disease, when treatment is simple and highly effective, thus seem a worthwhile approach to improving the duration and the quality of life for the patient. An uncontrolled trial of splenectomy early in the course of CGL suggested that the procedure prolonged the chronic phase and improved survival,147 but a randomized controlled trial failed to demonstrate prolongation of the median duration of the chronic phase, of median survival, or of median survival after the onset of metamorphosis.148 The same negative result followed the use, during the chronic phase and following splenectomy, of pulses of therapy with drugs active in AML or ALL.149 A more promising approach, not yet tested by a controlled study, is regular cytogenetic monitoring of the bone marrow, every 3–4 months, and intervention with aggressive therapy (usually cytarabine and an anthracycline antibiotic) at the earliest sign of clonal evolution, a known harbinger of metamorphosis. By this means, the evolving clones can be suppressed150 and the chronic phase may be prolonged. This stratagem merits more extensive study, but has no value in those cases in which metamorphosis is not preceded by cytogenetic evolution. This is particularly frequent in the ‘lymphoid’ variety of metamorphosis. Exploration of the potential value of molecular genetic, rather than cytogenetic, monitoring of CGL during the chronic phase has some promise. Intermittent intensive therapy should be studied first in younger patients with CGL. In the older patient, aggressive intervention that aims to abort the development of metamorphosis may be poorly tolerated; the cardiotoxicity of the anthracycline antibiotics and the gastrointestinal and central nervous system toxicity of cytarabine may pose major obstacles to their use. Study of the in vitro cultural characteristics of cells aspirated from the bone marrow during the chronic phase sometimes gives advance warning of the onset of metamorphosis. Unfortunately, the method is costly and relatively too insensitive to be of great clinical value. Overall, attempts to lengthen the life of the unfortunate patient with CGL by prolonging the chronic phase of the disease met with no major success so long as standard cytotoxic agents were employed. It seems probable that this lack of achievement is attributable to the failure of conventional treatments to achieve true remission of the disease with suppression of the leukemic clone(s). Certainly, this is the major difference between the outcomes of therapy in CGL versus the acute leukaemias. A highly significant advance has been made. Recent studies with interferon-α, to be discussed later, suggest that this biologic agent can produce major suppression of Phpositive cells, accompanied by the appearance of normal, Ph-negative, dividing cells in the bone marrow—a result that is rarely achieved with non-biologic chemotherapeutic agents. Mounting evidence shows that these changes translate into prolongation of the chronic phase and of survival.

Chronic leukemias in the elderly

1041

Diagnosis of metamorphosis Metamorphosis to an acute-leukemia-like state is usually readily diagnosed. Even when immature cells do not appear in the peripheral blood, development of cytopenias will prompt examination of the bone marrow, and the diagnosis will be established. Occasionally, the marrow aspirate suggests that the disease remains in chronic phase, but a biopsy specimen obtained at the same time demonstrates foci of blast cells scattered through the marrow. Greater difficulty arises when neither blood nor bone marrow reflect the change that is occurring, as when metamorphosis arises in the spleen, lymph nodes, or as initially localized tumors (granulocytic sarcomas) in bone or soft tissues at any one of a great variety of sites. In the past, there were many reports of ‘malignant lymphoma’ arising in patients with CGL: improved histopathologic techniques and the use of Romanowsky stains rather than the traditional hematoxylin and eosin now show these to be myeloid, not lymphoid, tumors.151 They are instances of metamorphosis arising at an extramedullary site. Two rare initial manifestations of metamorphosis are spinal cord compression due to an epidural granulocytic sarcoma, and development of meningeal symptoms with cerebrospinal fluid that contains numerous myeloblasts. These complications are clinically important because of the serious morbidity they engender. Occasional patients develop malaise and fever of obscure origin that remain unexplained—sometimes for months—before metamorphosis can be documented pathologically. Such patients frequently improve if their treatment is changed, empirically, to a regimen appropriate for the refractory phase of CGL. It is well known— and overemphasized—that when CGL progresses beyond its chronic phase, the NAP score may rise to normal or high levels. This finding is non-specific and frequently is absent—thus, it is of very little help in establishing or refuting a diagnosis of metamorphosis. Diagnosis of metamorphosis that takes the form of an accelerated myeloproliferative phase commonly is made retrospectively, because the onset is frequently insidious and clinical and hematologic deterioration may be very gradual. A usefiil working rule is that when the condition of a patient with CGL deteriorates without obvious explanation, metamorphosis should always be suspected and sought. Intercurrent unrelated disease should of course be considered, particularly in the older patient, but unfortunately this less sinister alternative is frequently not the explanation. Treatment of CGL in metamorphosis Accelerated myeloproliferative phase When failure of one or more aspects of hematopoiesis, with or without fibrosis of the bone marrow and refractory splenomegaly, signals the occurrence of this phase, it is generally recommended to discontinue busulfan and institute hydroxyurea152 (patients already receiving hydroxyurea may benefit from a change to mercaptopurine). Beyond this, treatment is tailored to the needs of the individual patient. Most require blood transfusion. Patients with marked hypersplenism are often improved by splenectomy, but the risks of removing a massively enlarged spleen in a patient with failing health must be

Comprehensive Geriatric Oncology

1042

weighed carefully against the potential benefits. In the older patient, the risks of splenectomy are increased, particularly in the presence of chronic pulmonary or cardiac disease. Morphologic and cytogenetic study of the bone marrow is indicated before splenectomy: imminent blastic change may contraindicate the operation because the patient’s life-expectancy is short. Constitutional symptoms (fever, night sweats, and malaise) may be relieved by controlling leukocytosis, or may respond to the administration of indomethacin or other non-steroidal anti-inflammatory agents. Anecdotally, treatment with anabolic steroid hormones has improved erythropoiesis. The value of recombinant human erythropoietin, with or without an anabolic agent, in the transfusion-dependent patient with CGL in an accelerated myeloproliferative phase remains to be elucidated. There has been little experience with intensive drug therapy in the accelerated myeloproliferative phase of CGL. Because such therapy carries a major risk of doing only harm, whereas the patient may have many months of relative comfort with supportive and palliative therapy only, physicians are naturally reluctant to recommend such treatment, especially in the older patient, in whom the risk:benefit ratio may be unacceptably high. In my experience, low doses of cytarabine, 20mg/m2 every 12 hours by subcutaneous injection for 10–20 days, have improved the symptoms and blood counts of some patients, but even this non-intensive treatment can cause serious pancytopenia, and caution must be exercised, particularly in older patients. HSCT may be considered at this stage in younger individuals, but this is not an option for the older patient. Transformation to a picture resembling acute leukemia This type of metamorphosis is usually obvious and poses no diagnostic problem. The onset is relatively abrupt, and hematopoietic failure and clinical deterioration are accompanied by the appearance of numerous blast cells in the bone marrow and peripheral blood. The initial effort is directed toward defining the cellular phenotype of the new clone—‘lymphoid’ or ‘myeloid’—because this affects the choice of treatment and its likely outcome.153 Careful examination of the peripheral blood film, supplemented by special stains, enables the differentiation of ‘lymphoid’ (approximately 20%) and ‘myeloid’ forms in many cases. Further refmement is achieved by determining whether the blast cells contain TdT in their nuclei or have surface expression of CALLA; in some cases, these features are more reliable than morphology alone in determining the likely response to therapy.130,153,154 Lymphoid blastic change It has long been recognized that when the cell phenotype resembles that of lymphoblasts, there is a 50% or greater incidence of favourable response to vincristine with prednisone.155 Such treatment is relatively non-toxic and is the initial chemotherapy of choice. Major problems are that the remissions achieved are brief, effective maintenance therapy has not been found, and the median survival of patients who respond to this therapy is of the order of 8 months only. In the older patient, the neurotoxicity of

Chronic leukemias in the elderly

1043

vincristine, including constipation and peripheral neuropathy, and the metabolic effects of prednisone (hyperglycemia, hypertension, and cardiac failure) may cause serious problems, so even this non-intensive therapy may not be altogether benign. Myeloid blastic change Approximately 75% of cases are of this variety. Their treatment has been extensively reviewed.156,157 The results may be summarized thus: regimens that are effective in de novo AML (an anthracycline with cytarabine, or high-dose cytarabine) are rarely of substantial benefit to patients with CGL in myeloid blastic metamorphosis, and the more intensive treatments may actually shorten survival by causing prolonged pancytopenia with fatal complications. The intensive eight-drug TRAMPCOL regimen156 appears to be an exception, producing good responses in over 40% of cases, but control of the disease for more than a year is exceptional. Despite the daunting list of component drugs— thioguanine, daunorubicin, cytarabine, methotrexate, prednisolone, cyclophosphamide, vincristine and L-asparaginase—TRAMPCOL has fewer subjective toxic effects than some more recent regimens (e.g. high-dose cytarabine). The TRAMPCOL regimen has been modernized, substituting a continuous infusion of cytarabine for the original daily bolus injections (Table 46.13), and continues to be an active therapy for CGL in myeloid blastic phase.

Table 46.13 An updated version of the TRAMPCOL regimen, used in the treatment of CGL in blastic metamorphosis of the myeloid type (the regimen may also be used in lymphoblastic metamorphosis that is unresponsive to vincristine with corticosteroid) Thioguanine

100mg/m2/12 h×10 doses, days 1–5

Daunorubicin

60mg/m2/day, i.v. bolus, days 1–3

Cytarabine

200mg/m2/day, i.v. infusion, days 1–5

Methotrexate

7.5mg/m2/day, i.v. bolus, days 1–3

Prednisolone

200mg/day, by mouth, days 1–5

Cyclophosphamide

100mg/m2/day, i.v. bolus, days 1–5

Vincristine

2mg, i.v. bolus, day 1

L-Asparaginase

6000 U/m2, s.c., every other day for 28 days

The doses are those for an initial course of therapy and may be modified in subsequent courses. The frequency of courses depends on response and varies on average from 14 to 28 days.

In practice, the majority of patients require two courses, begun on days 1 and 15, for initial control of their disease, and the subsequent pancytopenia may persist for 4–6

Comprehensive Geriatric Oncology

1044

weeks. Because of this, TRAMPCOL must be considered a hazardous regimen, particularly in patients aged over 70. A 1985 report suggested that mithramycin (plicamycin), a cytotoxic drug not used in the treatment of leukemia, may induce cell differentiation in vivo in patients with CGL in myeloid blast phase, with a median duration of response exceeding 9 months.158 Unfortunately, several later studies failed to reproduce these results, and this treatment cannot be recommended. Limited studies suggest that amsacrine, 5-azacytidine, mitoxantrone, high-dose cytarabine, and razoxane all possess some activity in myeloid blastic metamorphosis of CGL,157 but none of these has won a definite place in management. Workers in Houston have reviewed their experience in treating large numbers of patients with CGL in blastic phase, utilizing a variety of regimens.159 Considering only treatments that were tested in 20 or more patients, the best complete response rate was 43% with the VAD regimen, a 4-day infusion of vincristine and doxorubicin, together with high-dose dexamethasone by mouth. A phase II study of carboplatin by continuous infusion (300mg/m2/day for 5 days) indicated that this compound may possess useful activity in the blastic phase of CGL.160 The Eastern Cooperative Oncology Group (ECOG) reported on 36 patients with CGL in accelerated or blastic phase who received 5-day infusions of carboplatin.161 The median age of the patients was 54 (range 31–74). There were five complete responses (13.9%) and the median remission duration was 3 months (range 1.4–8.9 months). The median survival for all patients was 3.5 months and that of responders was 12.8 months; six patients died within the first 30 days on study. Thus, carboplatin has activity in blastic CGL but most responses are brief and toxicity is severe. Two publications have described experience with the potent purine antagonist cladribine (2-chlorodeoxyadenosine) in CGL in accelerated or blastic phase. Gollard et al162 treated three patients with CGL in a myeloid blast phase with single-agent cladribine. Two patients aged 53 and 67 had responses for 14 and 3 months, respectively, and survived for 19 and 6 months; the non-responding patient, aged 65 years, survived 2 months. Of note, drug-induced anemia and thrombocytopenia were mild and reversible. Dann et al163 treated 19 patients with high-dose cladribine by 5-day infusions. Their median age was 55 (range 30–73) and eight had been heavily pretreated; four had lymphoid cytologic features. There were one complete and seven partial responses (42%); the median survival was 34 weeks for all patients and 56 weeks for the eight responders. Fever and neutropenia were frequent, and there were two early deaths. It appears that cladribine provides effective palliation for a minority of patients with CGL in refractory phase, even after extensive pretreatment. An Italian group treated 15 patients with CGL in blastic phase with the FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor (G-CSF)) regimen.164 Seven patients (46.7%) achieved a complete remission, and two a partial response. Three patients were primarily resistant to FLAG and three died during remission induction therapy. The median overall survival and disease-free survival were 7.5 and 4.5 months, respectively; thus, a favorable complete remission rate did not secure improved survival. Elderly or otherwise frail patients with myeloid metamorphosis of CGL frequently are unsuitable for any form of intensive therapy. Useful palliation may be secured by blood transfusion and small doses of corticosteroid to decrease purpura. Systemic symptoms, particularly fever, may respond to indomethacin and also to moderation of the

Chronic leukemias in the elderly

1045

leukocytosis by non-intensive therapy. A useful and generally well-tolerated regimen for achieving this is the combination of hydroxyurea 500mg with thioguanine 40mg, each drug being given 2–4 times daily, depending on the leukocyte count. Concurrent administration of allopurinol, 300mg daily, is advisable to prevent hyperuricemia (unlike mercaptopurine, the action of thioguanine is not potentiated by allopurinol). Treatment by autologous hematopoietic stem cell transplantation (HSCT) The principles of this form of palliative therapy165,166 are as follows: (i) hematopoietic stem cells are harvested from the peripheral blood in the early stages of CGL, preferably before treatment; (ii) the stem cells are cryopreserved in liquid nitrogen (they can be stored for years without loss of viability); (iii) metamorphosis is treated by prompt ablation of the entire bone marrow with intensive chemotherapy; (iv) hematopoiesis is reconstituted by the intravenous infusion of the cryopreserved stem cells; (v) a second chronic phase of CGL is established, as if the clock had been turned back. Successful engraftment and re-establishment of the chronic phase are the rule, but a major drawback has been the rapid recurrence of blastic disease, sometimes within a few weeks, in most patients. Cytogenetic studies indicate that the recurrence is with the original blastic cell clone, i.e. the ablative regimens are inadequate. There is also the philosophical objection that the entire procedure is only palliative and cure is never an expected outcome. Autografting as a treatment for CGL in transformation is not widely practised. It may be overly ambitious to attempt the destruction of an entire blastic clone with a single pulse of chemotherapy, even when the doses administered approach the maximum dictated by the tolerance of tissues other than the bone marrow. Preliminary studies suggest that deliberate repetition of the chemotherapy and the autografting procedure, early in the second chronic phase, may secure longer responses. A most interesting observation is that in some patients, Ph-negative metaphases appear after a single marrow ablation and autografting. This raises the question whether the procedure should be evaluated for treatment of CGL while still in chronic phase, as a potential means for eradication of the Ph-positive clone. Although the procedure of autologous HSCT is less hazardous than an allogeneic transplant, it is still an intensive therapy, and many older patients would be unable to tolerate the high-dose chemotherapy that is required to ablate the bone marrow before grafting. The problem of refractoriness in late-phase CGL It was with good reason that the metamorphosis of CGL to an acute-leukemia-like state was termed the ‘refractory phase’. As discussed above, it is extremely difficult to obtain remissions in this phase of the disease, and even more difficult to secure responses that are durable. At least three mechanisms (there may be more) explain why the results of treatment for CGL in blastic phase are so much worse than those seen in the treatment of de novo AML. Absence of normal hematopoietic stem cells

Comprehensive Geriatric Oncology

1046

By the time of metamorphosis, CGL usually has been present for several years and large cumulative doses of cytotoxic agents have been administered. Cytogenetic studies during the chronic phase rarely demonstrate any normal, Ph-negative, cells. The combination of the effects of the CGL clone itself, and of the agents that have been administered to control it, may have eradicated, or permanently suppressed, any residual normal stem cells. When the blastic phase responds favorably to treatment, usually the best result seen is the re-emergence of a Ph-positive but chronic-phase clone. In many patients, intensive chemotherapy is followed only by the recrudescence of blast cells and the apparent extinction of any ‘useful’ chronic-phase cells (i.e. cells retaining the capacity to differentiate) that remained. Still more intensive treatment may be followed by seemingly interminable bone marrow hypoplasia with fatal consequences. These outcomes, which are regularly reproducible, suggest the absence of a significant population of stem cells that might repopulate the bone marrow and produce a remission. Multiple cell lines Clinically, it is frequently observed that when CGL has undergone metamorphosis to an acute-leukemia-like state, treatment with single cytotoxic drugs generally produces a transient effect, with rapid development of resistance to the agent being administered: the leukocyte count may fall for a few days only and then rapidly rebound despite continued administration of the drug. This process is repeated when other agents are employed. Cytogenetic studies reveal that in the blastic phase, multiple cell lines are present, generally representing a stepwise evolution from the original Ph-positive clone. These cell lines possess differing sensitivities to cytotoxic drugs, and serial cytogenetic studies—a very labor-intensive undertaking—have shown that the fluctuation from sensitivity to resistance to a particular drug corresponds to a simultaneous change in the nature of the predominant cell line, as identified by its chromosomal constitution. The situation is comparable to the changes observable in a mixed microbial flora when exposed to different single antibiotics to which some organisms are sensitive and others resistant. In this setting, durable control of the leukemic process by single-agent therapy is certain to be elusive. Multiple drug resistance The phenomenon of multiple drug resistance (MDR) in mammalian cells was first described in 1970,167 and was shown in 1976 to be mediated by a surface glycoprotein of 170kDa molecular weight, now termed gp170 or P-glycoprotein (P-gp), encoded by the MDR1 gene.168 The gp170 protein functions as a transmembrane efflux pump that decreases the intracellular concentration of a variety of stmcturally unrelated complex natural products by binding with them at the cell surface. Presumably the biological role of gp170, which also occurs in normal tissues, is to protect the cell from natural toxins. Unfortunately, this mechanism confers upon neoplastic cells resistance to many of the best anticancer drugs because they are derived from natural products (e.g. the vinca alkaloids, the anthracycline antibiotics, and etoposide). When CGL is in its chronic phase, expression of the MDR1 gene is minimal or absent, but in the refractory phase, it is usually expressed at high levels.169 By contrast, in AML, only a minority of cases

Chronic leukemias in the elderly

1047

express MDR1, usually at low levels.170 This would explain the relative inefficacy in transformed CGL of many drugs (e.g. daunorubicin) that are valuable in AML. Other forms of drug resistance, unrelated to the MDR1 gene, are under study: their role in refractory CGL remains to be demonstrated. Laboratory and clinical research aimed at circumventing the activity of gp170 is at an early stage: agents that interfere with calcium transport, including verapamil and quinine, have shown minor activity, but have not found a place in therapy other than in a research setting. Newer approaches to therapy of CGL Intensive therapy with intent to cure This stratagem is based on the concept that with appropriate chemotherapy, administered soon after the diagnosis of CGL is made, the entire clone of Ph-positive cells could be eradicated, and that there exists a population of non-leukemic stem cells that is capable of expanding and repopulating the bone marrow, normal hematopoiesis being restored and the patient cured. Suppression of CGL cells that was less than total would not be curative, but could be expected to produce very long clinical remissions of the disease, since there is evidence that reconversion of the bone marrow to 100% Ph-positive cells would require several years.171 Potential flaws in this approach are the failure, in most instances, to demonstrate large numbers of surviving normal stem cells in patients with CGL, and doubt as to the reliability of the Ph chromosome as a marker for eradication of the leukemia. There is evidence that the Ph chromosome may arise as a secondary phenomenon in the leukemia clone:172 thus, elimination of Ph-positive cells may not denote cure of the disease. With modern techniques of molecular genetics, the strictest definition of eradication of the leukemia clone would be inability to demonstrate the presence of the BCR-ABL hybrid gene by PCR. It remains to be proved that this can be equated with cure of CGL. Intensive therapy is frequently curative in the acute leukemias, and this justified its use in CGL in the setting of clinical trials.173,174 The results of chemotherapy studies thus far may be summarized as follows: (i) it is possible to reduce the percentage of Ph-positive cells in the bone marrow but difficult to achieve 100% Ph-negativity; (ii) repopulation with Ph-positive cells is the rule, with or without maintenance chemotherapy, and usually is quite rapid; (iii) no cures have been reported; (iv) it has not been proved by a controlled trial that overall survival is enhanced, and the risks and discomforts of intensive therapy are considerable. It follows that this approach cannot be recommended for patients in general—and certainly not for older patients, who are at greater risk for complications of intensive therapy. Controlled trials with new chemotherapeutic regimens and with biologic agents should continue; patients with CGL and poor prognostic features136 are particularly suitable for such studies because the results of conventional therapy are so unsatisfactory. Sokal et al,175 after demonstrating that cytarabine produces preferential inhibition of leukemic colony-forming units when CGL cells are cultured in vitro, found that prolonged infusions of low doses of cytarabine could produce up to 92% Ph-negativity when administered to patients with CGL in chronic phase. This therapy, which is less

Comprehensive Geriatric Oncology

1048

intensive than many that had previously been explored, merits further investigation— particularly since it might be applicable to the older patient with CGL. Treatment of bone marrow in culture A further investigational approach is the treatment of bone marrow in vitro, by prolonged culture with or without the addition of drugs or biologic agents, to produce a leukemiafree population of autologous stem cells. After treatment to eradicate the patient’s bone marrow—both leukemic and normal—hematopoiesis would be reconstituted by reinfusion of the cells that had been maintained in culture. The role of such therapy, and particularly its applicability to the older patient, is uncertain. Allogeneic HSCT Interest in the application of allogeneic HSCT to the management of CGL continues to increase, since the results are improving176,177 and because no other form of therapy has succeeded in curing this disease. If allogeneic HSCT remains restricted to younger patients who possess a related HLA-identical donor, the procedure will not alter the overall mean survival in CGL, because only a small fraction of patients will be eligible. Progress in pushing back the age limit for allogeneic HSCT, in the use of partially matched related donors, and in the use of matched, but unrelated, donors (see Chapter 40 of this volume178), should improve this situation, but it is unlikely that allogeneic HSCT will become a treatment for the older patient with CGL in the near future. Interferon-α therapy for CGL The introduction of the biologic response modifier interferon-α (IFN-α) into the treatment of CGL179 appears to be the most significant therapeutic advance since the beginnings of cytotoxic chemotherapy for this disease. There are now many reports, encompassing several hundred patients, on the use of IFN-α in the chronic phase of CGL.1,180–182 A complete hematologic response of the disease is obtained in up to 80% of patients, and a cytogenetic response, with the appearance of Ph-negative dividing cells in the bone marrow, is seen in up to 25%. Complete suppression of the Ph-positive clone may occur, the bone marrow being entirely repopulated by cells with a normal chromosomal constitution. IFN-α delays, but does not prevent, the eventual progression of CGL to a refractory phase. It is less effective in advanced CGL, and ineffective in a fully developed blastic phase. IFN-γ is also active in CGL, but less so than IFN-α. The median survival of patients who are treated with IFN-α in the chronic phase of CGL exceeds 60 months (i.e. 15–20 months longer than what is observed with conventional cytotoxic drugs), and a survival advantage has been shown both for historical control patients and in randomized controlled studies that compared patients treated with IFN-α directly with others who received hydroxyurea. The effectiveness of IFN-α is dose-dependent, and the best results are seen with doses not less than 5×106 units/m2 body surface area, administered by subcutaneous injection once daily. At these doses, IFN-α may produce a severe influenza-like syndrome. This can be mitigated by beginning at a low dose, e.g. 106 units daily, and increasing the dose

Chronic leukemias in the elderly

1049

by 106 units daily once a week. For convenience and their own independence, it is usually best to teach patients to administer their own IFN-α, but this may be difficult in older patients, particularly in the presence of impaired vision. The symptoms of chills, shivering, and fever can be mitigated by injecting the IFN-α at bedtime and taking a dose of acetaminophen (paracetamol) before the injection. Some patients find additional relief from symptoms by taking 50mg of diphenhydramine by mouth before injecting IFN-α. The side-effects of IFN-α tend to decrease with repeated administration (tachyphylaxis), but anorexia and severe lassitude may persist. Some patients sustain severe weight loss, and a minority feel so unwell that they refuse to continue with IFN-α treatment. Other side-effects include abnormal liver function tests, pancytopenia, and neurotoxicity. IFN-α appears to be particularly effective at lowering the platelet count, and in some patients with CGL and thrombocytosis, it is more effective than hydroxyurea. Occasional patients cannot tolerate full doses of IFN-α because of thrombocytopenia. We have observed thrombocytopenia, morphologic changes in the bone marrow, and prolonged disease control without maintenance therapy in some of our patients who received IFN-α for CGL.183 The marrow became hypocellular or the biopsies showed an extraordinary alternation of hypercellular and hypocellular areas, while megakaryocytes were depleted and frequently immature. One patient maintained a normal blood count and normal NAP score more than a year after discontinuing IFN-α treatment, although the bone marrow remained 100% Ph-positive. The mechanism underlying the beneficial effects of IFN-α in CGL is uncertain: it has been shown to increase the (usually deficient) attachment of CGL progenitor cells to bone marrow stromal cells in vitro: this might bring the CGL cells under more normal regulatory control.184 Clinically, IFN-α exerts an antiproliferative effect; for example, periodic cytogenetic studies of the bone marrow during treatment with IFN-α frequently yield very few dividing cells unless treatment is interrupted for a few days before the marrow is sampled. Hematologic control of CGL with IFN-α alone may take several weeks, and many physicians prefer to administer hydroxyurea initially to obtain more rapid symptomatic and hematologic improvement before beginning treatment with IFN-α. Cytogenetic responses in the bone marrow may require several months of therapy. If cytogenetic conversion to at least partial Ph-negativity has not occurred by 9 months of treatment, it is unlikely to be achieved. It is uncertain whether continued treatment with IFN-α, in the absence of cytogenetic conversion, confers any survival advantage upon the patient; certainly, the most marked increase in survival is correlated with the suppression of Phpositive dividing cells. A French study of 116 patients with newly diagnosed CGL who received IFN-α in myelosuppressive doses showed that the most significant factor associated with improved survival was the occurrence of a major or a complete cytogenetic response.185 Furthermore, the achievement of a complete hematologic response within 3 months of beginning IFN-α was strongly correlated with the later occurrence of a major cytogenetic response and subsequent long survival. It follows that failure of a hematologic response to IFN-α in 3 months should prompt consideration of other therapy. These interesting results also suggest that the administration of hydroxyurea should be restricted to a short period (e.g. for 2 weeks after diagnosis)—otherwise the hematologic response to IFN-α will be inevaluable.

Comprehensive Geriatric Oncology

1050

Several studies have explored the efficacy of IFN-α in combination with hydroxyurea, busulfan, cytarabine, or multiple-agent chemotherapy, but it has not yet been proven that these approaches are superior to the use of IFN-α alone. IFN-α is also being studied as an adjuvant therapy after CGL has been treated by. HSCT, to determine if the incidence of relapse can be reduced. Of particular interest is a preliminary report of the efficacy of IFN-α when administered in an adjuvant fashion after patients with CGL in a blastic phase had received intensive chemotherapy and developed a hypoplastic bone marrow.186 Any maneuver that will increase the durability of a response to chemotherapy in the blastic phase of CGL merits serious attention. A trial of therapy with IFN-α should now be considered a standard approach to the patient with newly diagnosed CGL. This agent can at least partially suppress the Phpositive clone, with reappearance of Ph-negative dividing cells and the restoration of normal, polyclonal hematopoiesis.187 Controlled studies confirm that patients who are treated with IFN-α have a significant prolongation of median survival compared with those who receive chemotherapy. The hope exists that a combined approach, perhaps with IFN-α to induce a state of minimal residual disease and intensive chemotherapy to eradicate the residuum, might be curative for CGL. On the other hand, treatment with IFN-α is inconvenient, has unpleasant side-effects, and is costly. It does prolong survival, but thus far there is no suggestion that patients have been cured by the use of IFN-α alone. Even in the presence of complete cytogenetic remissions induced by IFN-α, studies using PCR have detected the BCR-ABL rearrangement in small populations of bone marrow cells. It is clear that continuing clinical and laboratory studies of this powerful biologic tool are of great importance, but it is too early to recommend categorically that IFN-α should in all situations be the standard therapy for CGL in its chronic phase. IFN-α and the elderly patient Some elderly patients are very susceptible to the side-effects of IFN-α, particularly the chronic fatigue and weight loss that it engenders, and may suffer a significant decline in performance status during treatment.188 The fever induced by IFN-α has been observed to provoke angina in patients with coronary artery disease. As a result of these adverse effects, older patients may never attain the desired therapeutic dose of IFN-α, or may be unable to tolerate it for long enough to obtain a significant survival advantage. Coexisting renal, hepatic, or cardiac disease may contraindicate the use of IFN-α. Some elderly patients may be able to continue IFN-α, but with a reduced quality of life, which renders this a poor choice of therapy. Some oncologists have stated categorically that patients aged 60 or older with CGL should receive hydroxyurea or busulfan, and not IFN-α.1 Studies in Austria have included patients with CGL who were aged 60–73; they comprised 41 out of 213 patients on study.189 Treatment was with IFN-α alone, in a relatively low dose of 3.5×106 units daily, or IFN-α in combination with hydroxyurea or with low-dose cytarabine. The older group contained more patients with advanced-stage CGL, received IFN-α for a shorter period (42 weeks versus 57 weeks), and had more anemia, thrombocytopenia, and gastrointestinal symptoms. Other adverse effects, including influenza-like symptoms, depression, and disturbed liver and renal function, were evenly distributed between the age groups. The incidence of hematologic and

Chronic leukemias in the elderly

1051

cytogenetic responses was not signif- icantly different, but there was a trend in favor of the younger patients. It is reasonable to attempt management with IFN-α in the older patient with CGL, but it should be done cautiously, with gradual dose increments, and with the realization that some patients will be unable to tolerate IFN-α at an appropriate dose and must receive chemotherapy, preferably with hydroxyurea. Investigational therapies for CGL All-trans-retinoic acid Prompted by observations that all-trans-retinoic acid (ATRA), especially in combination with IFN-α, suppressed Ph-positive cells in vitro, an Italian group has studied ATRA in combination with hydroxyurea in patients with CGL in chronic phase.190 After initial treatment with hydroxyurea had lowered the white blood cell count (WBC) to less than 10×109/l, the patients received intermittent courses of ATRA. Of 18 patients, 11 went off study, 8 due to inadequate control of the blood count. Of 7 patients who continued therapy, 2 maintained the normal WBC that had been induced by hydroxyurea. Clearly ATRA is not highly active in CGL as a single agent, but its combination with IFN-α merits study. Homoharringtonine Following the observation that the plant alkaloid homoharringtonine produced a complete hematologic remission in 72% of patients with CGL in late chronic phase,191 the group at the MD Anderson Cancer Center investigated the drug in early chronic-phase CGL.192 Ninety patients with CGL diagnosed less than 1 year previously received six courses of homoharringtonine in 6 months, followed by IFN-α therapy. With homoharringtonine, there were 92% complete hematologic responses, 60% cytogenetic responses, and 27% major cytogenetic responses: these results were significantly better than those seen in historical control patients after 6 months of IFN-α therapy. In the maintenance phase after homoharringtonine, patients required lower doses of IFN-α (median 2.4×106 units/m2) to maintain a complete remission and had a lower incidence of IFN-α side-effects. The overall incidence of cytogenetic responses was 66%, compared with 61% in historical controls treated with IFN-α. It is clear that homoharringtonine is very active in CGL and produces cytogenetic responses at least as frequently as IFN-α and much more frequently than standard drugs. There is scope for much further evaluation of this promising drug in patients with CGL. Tyrosine kinase inhibitors BCR-ABL

The protein p210 encoded by the BCR-ABL chimeric gene has kinase activity: specifically, it causes phosphorylation of tyrosine residues. Although the precise mechanism is unknown, the transduction of murine stem cells with retroviral vectors containing the BCR-ABL fusion gene induces a disease closely resembling human CGL,193 and there seems to be no doubt that p210BCR-ABL is intimately concerned in

Comprehensive Geriatric Oncology

1052

leukemogenesis. A logical approach to therapy of CGL is to block the activity of p210BCR-ABL. The phenylaminopyrimidine derivative imatinib (originally called CGP 57– 148B and then STI 571) has such activity and promises to be a major advance in the management of CGL.194 Clinical studies of imatinib began in 1998, and early results are striking.195 Of 31 patients with chronic-phase CGL who received 300mg or more daily, all went into hematologic remission; of 20 who were treated for 5 months or longer, 9 showed some cytogenetic response, which was complete in three patients. Remarkably, imatinib proved to be active in the blastic phase of CGL, in both myeloid and lymphoid cases. Based on this limited evidence, imatinib appears to be the most active agent known in CGL. The long-term results of therapy and chronic toxic effects of the drug remain to be demonstrated. At present, there is no reason to suppose that imatinib has curative potential in CGL. Although the long-term results of treatment with imatinib remain to be explored, it is now generally considered to be the treatment of choice for newly diagnosed CGL in its chronic phase and has even been referred to as the ‘gold standard’.196 An international cooperative study of 1106 patients compared treatment with imatinib alone with treatment with a combination of IFN-α and cytarabine.197 In terms of hematologic and cytogenetic responses, tolerability, and the likelihood of progression to accelerated phase or blastic phase, imatinib was significantly superior. As the median follow-up at the time of publication was only 19 months, further observation is necessary to ascertain the longterm results. The antibiotic herbimycin A also inhibits tyrosine kinase,198 and might prove to be a useful alternative to, or a supplementary therapy with, imatinib. Antisense oligonucleotides Other potential approaches to the control of CGL include the use of antisense oligonucleotides to inhibit either BCR-ABL199 or c-MYB.200 These avenues are exciting because they are based on agents that, like the tyrosine kinase antagonists, are derived rationally rather than empirically. Molecular genetics and management of CGL For many years, the therapy of CGL was monitored in the traditional way, by serial studies of the peripheral blood, which generally reverted to near-normal values and appearances, and usually could be maintained in that state by simple therapy, judiciously prescribed. When parallel morphologic studies of the bone marrow were performed, it was obvious that control of the disease was in fact minimal, the marrow continuing to be hypercellular and showing granulocytic hyperplasia. With the introduction of serial cytogenetic studies, it became apparent that with conventional therapy, CGL almost never entered a true remission; the marrow cells remained 100% Ph-positive and thus entirely leukemic. Various newer treatments—intensive chemotherapy, allogeneic HSCT, and IFN-α—were found to induce in some patients cytogenetic complete remissions, with 100% Ph-negativity of the bone marrow. Yet in all of these situations, relapse of CGL could occur—occasionally after HSCT and routinely after other therapies. Molecular genetic studies then demonstrated that, in many instances, even when the marrow was

Chronic leukemias in the elderly

1053

100% Ph-negative, the BCR-ABL rearrangement was still detectable. Most recently, use of PCR has demonstrated minute quantities of BCR-ABL that persist in bone marrow samples that are Ph-negative and also BCR-ABL-negative by standard techniques. PCR can thus detect very small numbers of surviving leukemia cells that may lead to relapse at a (possibly remote) date. Currently, the clinical standard for cure of CGL is the achievement of a normal lifespan and death without evidence of leukemia—i.e. cure can only be proved in retrospect. It is not yet known if cure can be predicted from the attainment of a BCR-ABL-negative state, (e.g. by FISH), or if negativity by the very sensitive PCR is a necessary precondition for this desirable clinical outcome. Summary It is The management of the patient with CGL continues to pose major problems for the clinician and scientist. apt to be more difficult in the older patient because the disease carries a poorer prognosis with advancing age, the side-effects of therapy may be more severe, and intensive, potentially curative therapies, such as allogeneic HSCT are not an available option. Until recently, progress has been exceedingly slow, particularly in comparison with that achieved in the acute leukemias. Research in molecular genetics is now greatly increasing our understanding of CGL and also our ability to study the disease and the effects of treatment. Therapeutic developments, including autologous and allogeneic HSCT and the use of IFN-α, are important advances in the control and cure of this unique neoplasm, but their benefits are at present restricted in the older patient. The recently licensed tyrosine kinase inhibitor imatinib may prove to be a major advance in the treatment of CGL in patients of all ages. Philadelphia-chromosome-negative CGL During the 1960s, some authors reported that as many as 30% of cases of CGL lacked the Ph chromosome, whereas in modern series it is usually less than 5%. This difference is due in part to better cytogenetic techniques, but the major factor has been the adoption of a much stricter, and more standardized, hematologic definition of CGL. Most of the cases initially reported as ‘Ph-negative CGL’ would not now be accepted as being CGL at all, so the absence of the Ph chromosome requires no special explanation. It is now generally considered that Ph-negative CGL is an extremely rare condition. Some have said that it is non-existent, but this is usually because they have included presence of the Ph chromosome in their working definition of CGL. Since the condition is so rare, knowledge about the clinical course and responsiveness to treatment of Ph-negative CGL is understandably limited. To qualify as Ph-negative CGL, a case must possess hematologic findings that are acceptable for CGL, as described earlier in this chapter, and the Ph chromosome must be absent from the metaphases of bone marrow cells. It has long been recognized clinically that in a few of these cases, the course of disease and responsiveness to treatment with busulfan were indistinguishable from those observed in Ph-positive disease, and the prognosis was relatively good, with median survivals of 40–45 months. Baikie speculated that in such cases the genetic lesion in the leukemic cells was the same as in the more common Ph-positive cases, but the visible structural change in chromosome 22 was

Comprehensive Geriatric Oncology

1054

lacking. These cases were thus compared with those Ph-positive cases that possessed a variant form of translocation yet did not differ in their natural history from the more frequent cases that possess the t(9; 22) translocation. Molecular genetic techniques have now demonstrated the BCR-ABL rearrangement in many, but not all, cases of Ph-negative CGL. This appears to confirm Baikie’s original hypothesis, although there are not yet sufficient data to indicate whether all the Ph-negative cases that behave like Ph-positive cases are BCR-ABL-positive. Parenthetically, BCR-ABL has also been demonstrated in several cases with variant and complex translocations, indicating that genetic material that originates from chromosome 9 is involved in the disease process even when that chromosome is not visibly altered. Rare cases of CGL meet all the diagnostic criteria previously outlined but, in addition to their Ph-negativity, respond poorly to busulfan and have a relatively short survival, with early termination in a blast-cell leukemia. In one such case, isoenzyme studies demonstrated that the disease was of clonal origin, thus resembling Ph-positive CGL.201 Thus, cases of ‘Ph-negative CGL’ really represent a different disease, which is not separable by hematologic criteria but is distinguishable cytogenetically and clinically. It is not yet known if all of these cases are BCR-ABL-negative. To summarize, when the diagnosis of CGL is established hematologically and the Ph chromosome is not demonstrable in marrow cells, this indicates a poorer overall prognosis, which is the result of a group with median survivals of 40–45 months (behaving like true CGL) being admixed with a group with median survivals of approximately 12–18 months (behaving in atypical fashion). A poor response to busulfan separates these groups in retrospect, and it appears probable that testing for the BCR-ABL rearrangement will separate them prospectively. Atypical myeloproliferative syndrome (AMS) The older literature implied that Ph-negative CGL was relatively common. However, several reports made it clear that the patients with Ph-negative disease differed both clinically and hematologically from the picture of CGL.202,203 Variant features included lesser degrees of splenomegaly, lower leukocyte counts, differential counts atypical of CGL (e.g. without basophilia), and thrombocytopenia. Such cases do not meet the current criteria for the diagnosis of CGL, and thus are relegated to the category of ‘Ph-negative non-CGL’. Most of mankind can be thus classified! More recent reports have included some in which the diagnostic criteria for CGL are not specified,204 and others in which they are too lax.205 In one series, leukocytosis was not a criterion for making the diagnosis.205 The 10 patients were older than is usual in CGL (range 46–79 years, with 8 patients over 67), the leukocyte count varied from 5.5 to 65.9×109/l, the platelet count from 20 to 570×109/l, and the NAP score from zero through the normal range to elevated. Survival also varied widely, and these patients seem to have suffered from a heterogeneous collection of disorders with only slight similarities to each other and to true CGL. In order to avoid the misleading implications of ‘Ph-negative CGL’, Gunz and Baikie206 proposed the term ‘atypical myeloproliferative syndrome’ (AMS) to encompass those cases with a superficial resemblance to CGL, obvious variant features, and without the Ph chromosome. The group is not sharply demarcated, grading into chronic

Chronic leukemias in the elderly

1055

myelomonocytic leukemia and into agnogenic myeloid metaplasia and also myelodysplasia, and seems not to be a single disease. Thus the initial features, the pattern of evolution, the clinical course, and the response to treatment are all variable. Leukocytosis is common, but seldom reaches 100×109/l, and basophilia is less prominent than in CGL and often absent. Relative and absolute monocytosis are common, whereas in CGL only absolute monocytosis (i.e. relative to the total monocyte count in normal blood) is regularly observed. The characteristic differential leukocyte count of CGL is absent, and the percentage of blast cells in the blood may be elevated in comparison with CGL. Thrombocytopenia and morphologic abnormalities of the leukocytes are frequent in AMS and rare in CGL. The NAP score in AMS is variable, but normal or elevated values are considerably more frequent than they are in true CGL. The response of AMS to busulfan is almost uniformly poor, and information regarding other forms of therapy is inadequate. There is a need for cooperative studies in AMS, to assess methods of treatment other than busulfan and to better characterize the syndrome in order to identify those cases with a particularly poor prognosis that might be improved by intensive chemotherapy. Since many patients with AMS are elderly and unfit, conservative management with packed red blood cell transfusion is often the best course. Unlike the situation in CGL, control of the leukocytosis in AMS with chemotherapy is often not accompanied by correction of anemia or thrombocytopenia, although usually it is worthwhile to assess this with a trial of an agent that does not seriously or irreversibly compromise erythropoiesis or platelet production (hydroxyurea or mercaptopurine). Splenectomy is beneficial in occasional patients with AMS and hypersplenism, but is usually valueless when pancytopenia is due to hematopoietic failure. The median survival in AMS is approximately 12–18 months, and progressive monocytosis or a steadily increasing blast cell count in the peripheral blood indicate an especially poor outlook, with the probability of early conversion to a picture resembling a refractory AML. As in true CGL, granulocytic sarcomas occasionally arise at extramedullary sites (e.g. bone and lymph nodes) as harbingers of more generalized blastic disease. AMS is more frequent, and consequently more important, in the older patient, and it is necessary to distinguish it from true CGL because the treatment and the expected results of therapy are so different. Chronic myelomonocytic leukemia (CMML) CMML has been classified as a myeloproliferative disorder, as a preleukemic condition, and as a leukemia in its own right. The French-American-British (FAB) group207 included CMML in the category of idiopathic myelodysplastic syndromes (MDS), a heterogeneous group of disorders with a variable tendency to transform into blast cell leukaemias. CMML is here considered as one of the chronic myeloid leukemias, since its hematologic manifestations resemble the leukemias rather than the refractory anemias, and the incidence of conversion to an acute leukemia is higher in CMML than in the other myelodysplasias.208 Most patients with CMML are middle-aged or elderly and there is a slight female preponderance. Splenomegaly is not uncommon, but is much less marked than in CGL. The peripheral blood shows absolute neutrophilia and monocytosis, and serum and urinary lysozyme are increased. Immature granulocytes and monocytes are scarce or

Comprehensive Geriatric Oncology

1056

absent in the chronic phase of CMML, so the blood film appearances are quite different from those of true CGL. Dysplastic abnormalities of the neutrophils, including hypogranular and agranular forms and pseudo-Pelger-Hüet cells, are common. The NAP score is variable. Morphologically abnormal platelets are common, as are micromegakaryocytes in the bone marrow. Cytogenetic studies of the bone marrow208 do not show the Ph chromosome, but do reveal abnormalities similar to those observed in de novo AML. Occasionally, CGL in transformation may mimic the picture of CMML, but is usually distinguishable on the grounds of marked splenomegaly, basophilia, and Phpositivity in the bone marrow. CMML may grade into other myelodysplastic disorders: some patients with refractory anemia develop a gradually progressive monocytosis, with or without neutrophilia, and over the course of months or years may attain the full picture of CMML, with termination in a blast cell leukemia. The natural history of CMML is very variable. Occasionally, the chronic phase persists for many years, but sometimes there is progression to an acute leukemia in less than a year. Guidelines have been proposed for separating patients with CMML into ‘good-risk’ and ‘bad-risk’ groups.209 The Bournemouth scoring system, which may be applicable to all myelodysplasias, is based on the presence of anemia, thrombocytopenia, neutropenia, and bone marrow blast cell counts of 5% or greater.210 The ability to recognize, at an early stage, patients with CMML who are at high risk of developing overt acute leukemia would facilitate the choice of therapy—either conservative or more intensive. At a later stage in CMML and other myelodysplasias, the appearance in the bone marrow of cells with Auer rods—even in very small numbers—usually denotes imminent progression. Treatment for CMML in its chronic phase is unsatisfactory. The response to busulfan is poor, but there have been occasional good results with mitobronitol (dibromomannitol). My practice is to treat with hydroxyurea, because adverse effects of treatment (increased anemia and thrombocytopenia) are less pronounced, and more rapidly reversible, than they are with busulfan. Mercaptopurine may be substituted if the response to hydroxyurea is unsatisfactory, or the two agents may be given together, in the ratio of 50mg of mercaptopurine to every 500mg of hydroxyurea. There are anecdotal reports of favorable responses of CMML and other myelodysplasias to the administration of IFN-α. Control of the leukocytosis in CMML may decrease the symptoms of hypermetabolism and correct hyperuricemia, but often fails to improve red cell production, so there may be a continuing need for transfusion. The role of erythropoietin in CMML has yet to be adequately evaluated, but it is occasionally beneficial. Intensive chemotherapy or HSCT in the chronic phase of CMML have not received extensive evaluation; many patients are too elderly for such aggressive therapy. A phase II study has demonstrated that the topoisomerase I inhibitor topotecan has activity in both CMML and MDS.211 Thirty patients with CMML and a median age of 66 were treated with single-agent topotecan; there were eight complete responses (27%). A history of chemotherapy and the presence of monocytosis in blood or marrow predicted a lower response rate to treatment. The median remission duration was 7 months and the median survival was 9.3 months; mucositis and myelosuppression were severe. Topotecan has activity in CMML, and its combination with other agents, including topoisomerase II inhibitors, merits study.

Chronic leukemias in the elderly

1057

Acute leukemia develops in one-third to one-half of patients with CMML, and responds poorly to treatment—as do other acute leukemias that arise secondary to a preexisting bone marrow disorder. Even when allowance is made for the greater age of most patients with CMML, the response to treatment is less favorable than that seen in de novo AML. Once CMML has evolved into an acute leukemia, life-expectancy is a matter of weeks only, and a trial of a regimen that is effective in AML and with which the physician is familiar is indicated in carefully selected patients whose general condition will permit it. Rarely, complete remission lasting longer than a year has been obtained. Chronic neutrophilic leukemia (CNL) This extremely rare disease has been classified both as a leukemia and as a myeloproliferative disorder. The patients are usually elderly and the sex ratio is equal. Splenomegaly, hepatomegaly, and bruising are common, and gout has been described. The leukocyte count at presentation has ranged from 27 to 98×109/l.212 The differential leukocyte count is notable for extreme neutrophilia, the segmented and band forms comprising 79–99% of the total. Immature granulocytic forms are infrequent or absent. The NAP score is usually high and serum levels of vitamin B12 and uric acid are characteristically elevated. The bone marrow is hypercellular, but the granulocytic: erythroid ratio is sometimes normal, owing to concurrent erythroid hyperplasia. Cytogenetic studies have consistently failed to show the Ph chromosome, but Pane et al213 have described three cases with a Ph chromosome and an unusual BCR-ABL fusion with a breakpoint between exons c3 and c4 of the BCR gene. Other cytogenetic findings in CNL have varied widely from case to case214—possibly the patients described by Pane et al have a different disease. CNL is readily distinguished from CGL because of the striking difference in the differential leukocyte count. The lower total leukocyte count and elevated NAP score provide additional evidence of the difference between these disorders. The major differential diagnosis of CNL is from a reactive neutrophilia: distinction is usually made by the exclusion of infection, tumors, and collagen disease as a cause of leukocytosis and by demonstrating the persistence of neutrophilia over a period of observation. A few patients with CNL have been treated with busulfan or splenic irradiation, or with hydroxyurea and cytarabine, and do not appear to have benefited greatly: treatment has been complicated by hyperuricemia.214 In a series of 13 patients, survival from the apparent onset of disease ranged from 7 months to 5 years: seven patients died within 33 months and two were alive when reported.212 Only one patient was considered to develop an acute-leukemia-like disease; three died of infections, and three after abdominal surgery. Of these 13 patients, 4 had significant problems with hemorrhage, and conventional tests of coagulatiom were normal: thus, CNL appears to be associated with an uncharacterized coagulopathy, and surgical procedures must be considered potentially dangerous in these patients. More information is required about this rare disease. The apparent rarity of transition to an acute leukemia suggests that CNL, despite its name, may be a form of myeloproliferative disease with a relatively low liability to malignant transformation. Further cytogenetic studies, and molecular genetic evaluation, would be of great interest in CNL.

Comprehensive Geriatric Oncology

1058

Chronic eosinophilic leukemia (CEL) This is a rare condition and frequently is difficult to diagnose with confidence. Distinction must be made from the following conditions: 1. Idiopathic chronic eosinophilia: This appears to be a non-neoplastic condition that sometimes has a benign clinical course or may be associated with the cardiac, pulmonary, cerebral and thromboembolic complications of the hypereosinophilic syndrome (HES).215,216 2. Reactive eosinophilia: This may be a response to parasitic infestation, collagen disease, malignant lymphoma (particularly Hodgkin lymphoma), or an underlying carcinoma. Eosinophilia has also been reported in association with ALL,217 usually of T-cell variety,218 and occurs in cutaneous T-cell lymphomas. These phenomena may correlate with the observation that normal T lymphocytes may induce eosinophilia.219 3. Acute myelomonocytic leukemia with eosinophilia: There is a well-established association of acute myelomonocytic leukaemia (M4 in the FAB classification) with a pericentric inversion of chromosome 16 and pronounced eosinophilia in the bone marrow.220 The dysplastic morphology of the eosinophils suggests that they are part of the neoplastic process, and not a reactive phenomenon. 4. CGL with eosinophilia: A moderate degree of absolute eosinophilia is the rule in CGL,125 but occasional cases have relatively marked eosinophilia. Sometimes this occurs at the onset of metamorphosis, although increasing basophilia is more common. Rarely, vast numbers of cells with a mixture of eosinophil and basophil granules, including blast cells with such granules, are released into the blood in the terminal stages of CGL. Very rarely, true cases of CGL have predominant eosinophilia, rather than neutrophilia: usually they have been reported as cases of CEL with the Ph chromosome.221,222 The great majority of patients with eosinophilia do not possess the Ph chromosome. 5. Myeloproliferative disease with marked eosinophil component: The dividing line between such cases and true CEL is not sharp. Major involvement of other cell lines in the bone marrow, with abnormalities of erythropoiesis, platelet production, the neutrophil series, and increased marrow reticulin, characterizes this group. The diagnosis of CEL is established by excluding the above conditions as far as is possible, and by the following positive features: morphologic abnormalities of the eosinophils and of their granules, increased eosinophilic promyelocytes, the occurrence of eosinophil granules in cells that otherwise have the appearances of myeloblasts, and the demonstration of cytogenetic abnormalities in the bone marrow. The latter finding is the most reliable way of ruling out a reactive eosinophilia. In some cases, the diagnosis of CEL remains uncertain, but is confirmed in retrospect when transformation to a blastic leukemia occurs.223,224 Only a minority (4 of 14) of cases of eosinophilia investigated by Chusid et al215 were considered to have a true neoplastic process; i.e. CEL is one of the rarer causes of ersistent eosinophilia.225,226 Typically, CEL shows a male predominance, a poor prognosis, and the clinical findings of hepatosplenomegaly and lymphadenopathy.227 The pathophysiology of CEL is complex. In addition to the hematologic complications of anemia, thrombocytopenia, and granulocytopenia, cardiovascular complications are very frequent, especially

Chronic leukemias in the elderly

1059

intractable congestive heart failure. Autopsy examination reveals endocardial fibrosis and eosinophilic infiltration of the myocardium, with areas of scarring and necrosis, and mural thrombi in 15% of cases.226 Pulmonary infiltration with opacified areas on chest radiographs occurs in 20% of patients. Neurologic complications are common. Cerebral lesions with paralysis, confusion, or coma are associated with thromboembolic events or with eosinophilic infiltration. Peripheral neuropathy also occurs. There is thus a strong resemblance to the clinical pictures produced by vasculitic collagen diseases. Although subacute or chronic endomyocardial fibrosis and restrictive cardiac physiologic features are the classical characteristics of heart disease in HES, another form of eosinophilic heart disease is characterized by acute onset, severe systolic ventricular failure, and death within days or weeks.228 Autopsy reveals extensive necrosis of myocytes, with a striking eosinophilic inflammatory infiltrate. Severe cardiac damage can occur in hypereosinophilic states of any cause, which suggests that its mechanism involves the eosinophils themselves, rather than the underlying condition that caused the eosinophilia. Major basic protein (MBP), the most abundant protein in eosinophil granules, is toxic to parasites and to human cells in vitro, and is deposited in the necrotic and thrombotic myocardial lesions of typical hypereosinophilic cardiomyopathy and also in the lesions of acute necrotizing eosinophilic myocarditis.228 The natural history of CEL is variable. The disease may remain in a chronic stable phase for months or years. During this period, the patient may be well, or develop lesions attributable to HES, or myelofibrosis may develop and increase the hematopoietic compromise.229 Eventually a blastic leukemia may develop after a stable phase that has varied from 2 to 11 years.230 Occasional patients present with eosinophilia and an acuteleukemia-like picture, with an excess of blasts in the bone marrow, without a preceding phase of CEL.227,231 Some doubt has existed as to whether such cases should be considered to be acute eosinophilic leukemia or AML with an eosinophil reaction,231 but later studies suggest that the eosinophils are part of the leukemia, not a reaction to it.220 When CEL is suspected, but no complications are apparent, and no chromosomal abnormality is present in the bone marrow, distinction from a chronic benign eosinophilia cannot be made—in pragmatic terms, no real difference exists at that stage, and observation without treatment is advisable. Development of hematopoietic compromise, or of lesions attributable to HES, are indications for treatment. Adrenal corticosteroids are effective in 40% of cases with HES,215,216 where the eosinophilia is usually reactive in nature, but their efficacy in true CEL is unproved. CEL in its chronic phase responds well to both busulfan and hydroxyurea, and some lengthy remissions have been observed.215,232 We have seen two patients with CEL benefit from the combination of prednisolone, erythropoietin and IFN-α. The blastic phase of CEL responds poorly to treatment, but in selected patients a trial of therapy that is effective in AML is justified. As stated above, a major problem in CEL is establishing the diagnosis. Careful study of the morphology of cells in the peripheral blood and the bone marrow, coupled with cytogenetic studies of the marrow, may resolve the issue. In doubtful cases, there is no proven disadvantage to withholding therapy until the first sign of complications appears.

Comprehensive Geriatric Oncology

1060

Chronic basophilic leukemia (CBL) This very rare condition is also termed mast cell leukemia or acute mast cell leukemia. It has also been classified as a form of systemic mastocytosis, although most instances of the urticaria pigmentosa/systemic mastocytosis syndromes appear not to have a neoplastic basis. CBL must be distinguished from the following conditions: 1. Myeloproliferative disease (MPD) with marked basophilia: The distinction is easy if there has been a long history of MPD before the appearance of basophilia. If marked basophilia exists at the time of presentation, it rarely dominates the clinical picture: other stigmata of MPD, including neutrophilia, abnormal NAP score, thrombocytopenia or thrombocytosis, anaemia, and fibrosis of the bone marrow will indicate the correct diagnosis. 2. CGL with basophilia: In the usual case, severe basophilia develops months or years after the initial diagnosis of CGL, and there is no diagnostic problem. In CGL, the onset of marked basophilia is a well-known harbinger of metamorphosis; occasionally, basophilia in CGL is sufficiently severe to produce those symptoms of hyperhistaminemia usually associated with systemic mastocytosis.233 When marked basophilia is detected at the time of presentation with CGL, a diagnostic problem may arise, but features of CGL, including neutrophilia, circulating myelocytes, and a low NAP score, will usually suggest the correct diagnosis, and demonstration of the Ph chromosome in the bone marrow will confirm it. 3. Systemic mastocytosis: Differentiation of true CBL from systemic mast cell disease presents a more difficult problem, comparable to distinguishing CEL from chronic non-neoplastic eosinophilias. A long history of urticaria pigmentosa before the appearance of systemic basophilia is indicative of a reactive process. Hallmarks of true CBL are invasion of the blood, heavy involvement of the bone marrow, and hematopoietic failure. The finding of a clonal chromosomal abnormality in the bone marrow is the most conclusive evidence of the neoplastic nature of the condition. 4. AML with basophilia: There have been numerous case reports of AML that is associated with pronounced basophilia in the bone marrow and an unusual chromosomal translocation, t(6; 9) (p23; q34). The FAB subtype of the AML has been quite variable, but M2 has been the most frequent diagnosis. There has often been a symptomatic myelodysplastic phase before the development of overt AML. Most, but not all, cases with the translocation have shown an excess of basophils in a hypercellular bone marrow—basophilia has been absent in some, so the association is not absolute. The translocation has been demonstrated in cases of acute myelofibrosis and MDS, in addition to AML, which suggests that the chromosomal aberration occurs at the level of the multipotent stem cell.234 Absence of basophilia in the peripheral blood, an excess of blast cells with features of AML, and (perhaps) demonstration of t(6; 9) serves to differentiate these cases from CBL. It remains to be determined if modern cytogenetic techniques with high-resolution banding will disclose t(6; 9) (p23; q34) in any cases of true CBL.

Chronic leukemias in the elderly

1061

Clinical features of CBL These include skin infiltrates, hepatosplenomegaly, bone lesions, and the occurrence of systemic symptoms due to release of mast cell products. These features are not of value in distinguishing CBL from non-neoplastic mastocytosis, because they can occur in either condition. Mast cell granules contain the ‘three Hs’—heparin, histamine, and 5hydroxytryptamine (serotonin)—and their release can cause findings attributable to each substance. Release of endogenous heparin can cause temporary prolongation of the clotting time and hemorrhage. Symptoms of histamine excess include flushing, urticaria, pruritus, bronchospasm, and gastric hypersecretion with peptic ulceration. Release of excess serotonin produces flushing, abdominal pain, diarrhea, hypotension, and mental confusion—symptoms that are usually associated with the carcinoid syndrome. Patients with CBL may in addition develop the symptoms of anemia, thrombocytopenia, and granulocytopenia. These are not typical of systemic mastocytosis, but further confusion may arise because patients with mast cell disease are prone to the development of hematologic neoplasms other than CBL, including AML and non-Hodgkin lymphoma.235 The cells of CBL vary in appearance: forms resembling mature tissue mast cells may be intermingled with more primitive cells resembling basophilic promyelocytes and forms resembling abnormally lobated basophils.236 Reactions with PAS and for naphthol AS-D chloroacetate esterase and lactate dehydrogenase are usually positive, and proliferative activity determined by [3H]thymidine uptake is low. Those symptoms of CBL that are due to mast cell products respond to a variety of agents, including epinephrine (adrenaline), adrenal corticosteroids, and H1 and H2 antihistamines, and to cyproheptadine, which possesses both antihistamine and antiserotonin activities. More recently, it has been shown that the oral administration of disodium cromoglycate, an agent that inhibits the calcium-dependent coupled activationsecretion response of mast cells, effectively controls most of the symptoms.237 Information regarding the treatment of the underlying CBL is sparse. Older reports describe the use of a variety of alkylating agents and corticosteroids with generally poor results.236,238 Responses have been obtained with daunorubicin,239 and a rapidly progressive downhill course in a patient with CBL warrants a trial of an intensive regimen known to be effective in AML. It has been suggested236 that effective cytotoxic treatment for CBL might carry the risk of massive release of mast cell products—a situation comparable to the exacerbation of disseminated intravascular coagulation when treatment is begun for acute promyelocytic leukaemia (FAB M3)—and prophylactic administration of cyproheptadine, diphenhydramine, and cimetidine or ranitidine should be considered. Acute leukemias arising in patients with pre-existing CML When an acute leukemia arises in a patient who suffers from any of the chronic myeloid leukemias, it usually has a rapid course and is singularly refractory to therapy. This refractoriness has become very obvious in an era when intensive chemotherapy is proving relatively successful in securing remissions in cases of AML that arise de novo. Leukemias that supervene upon polycythemia vera or other myeloproliferative disorders,

Comprehensive Geriatric Oncology

1062

or upon the myelodysplastic syndromes, and those arising after chemotherapy and radiotherapy for a wide variety of neoplastic diseases, are similarly unresponsive. All of these secondary AMLs are more frequent in the older patient, and the problems of older age and multiple medical conditions complicate their management. There is not yet a complete explanation for these findings. The greater age of patients with pre-existing neoplastic disorders is an insufficient reason by itself, because secondary AML proves less responsive to therapy than de novo AML in patients who are matched for age and who receive the same modern treatment regimens. Further, when secondary AML arises in a younger patient (e.g. after successful treatment for Hodgkin lymphoma), the outcome of treatment usually is no better. Previous exposure to cytotoxic drugs might explain a poor response to therapy in terms of the acquisition of resistance to various chemotherapeutic agents being part of the genesis of the secondary AML, but even intensive regimens that produce profound hypoplasia of the bone marrow frequently fail to secure a remission of the leukemia.240 A very high incidence of cytogenetic aberrations—frequently those that are associated with a poor prognosis when they occur in de novo AML—is characteristic of secondary AML, particularly when it is thought to arise as a result of radiotherapy and chemotherapy. This may in part explain the very poor results of treatment. The most tenable explanation, although incompletely proved, is that during the previous chronic disease process, there is a progressive attrition of the normal hematopoietic stem cells of the bone marrow, so that few or none are surviving at the time of onset of the secondary AML, and possibly none may survive subsequent chemotherapy that is sufficiently intensive to suppress the highly resistant cells of the leukemic process. This hypothesis, and the exceptionally poor results of current treatment, both suggest that very different strategies need to be developed for the control of AML that is secondary to other disease or to its treatment. Conclusions Chronic leukemias in the older person present the geriatric hematologist-oncologist with many problems. Curative therapy with allogeneic HSCT is not at present an option for these patients, who cannot tolerate the severe morbidity of such intensive treatment. Similarly, intensive chemotherapy at levels below those used for transplantation is hazardous in the older patient, and the risk increases with advancing age. Tolerance to many drugs, particularly anthracyclines, IFN-α, and corticosteroids, is poor in many older patients. The presence of multiple medical problems, particularly chronic degenerative diseases, complicates the care of many patients. The correct approach is that which prevails in all of geriatric medicine: a detailed global assessment of each patient, careful attention to all of the patient’s problems, and the assignment of a priority to the chronic leukemia in terms of its importance in the overall picture of performance status and life-expectancy for that individual. That done, the individual and the leukemia are treated with the best skills, compassion, and insight that can be marshalled by the physician for the patient’s benefit.

Chronic leukemias in the elderly

1063

References 1. Quaglino D, Di Leonardo G, Furia N et al. Therapeutic management of hematological malignancies in elderly patients. Biological and clinical considerations. Aging Clin Exp Res 1997; 9:383–90. 2. Spiers ASD, Davis MP, Levine M et al. T-cell chronic lymphocytic leukaemia: anomalous cell markers, variable morphology, and marked responsiveness to pentostatin (2′-deoxycoformycin). Scand J Haematol 1985; 34:57–67. 3. Linet MS, Devesa SS. Descriptive epidemiology of the leukemias. In: Leukemia, 5th edn (Henderson ES, Lister TA eds). Philadelphia: Saunders, 1990:207–24. 4. Linet MS. The Leukemias: Epidemiologic Aspects. New York: Oxford University Press, 1985. 5. Samuels LE, Kaufman MS, Morris RJ et al. Open heart surgery in patients with chronic lymphocytic leukemia. Leuk Res 1999; 23: 71–5. 6. Baer MR, Stein RS, Dessypris EN. Chronic lymphocytic leukemia with hyperleukocytosis. The hyperviscosity syndrome. Cancer 1985; 56:2865–9. 7. Cash J, Fehir KM, Pollack MS. Meningeal involvement in early stage chronic lymphocytic leukemia. Cancer 1987; 59:798–800. 8. Case Records of the Massachusetts General Hospital. (Case 45–1988). N Engl J Med 1988; 319:1268. 9. Cheson BD, Bennett JM, Rai KR et al. Guidelines for clinical protocols for chronic lymphocytic leukemia (CLL). Recommendations of the NCI-Sponsored Working Group. Am J Hematol 1988; 29: 152–63. 10. Juliusson G, Gahrton G. Chromosome abnormalities in B-cell chronic lymphocytic leukemia. In: Chronic Lymphocytic Leukemia, (Cheson BD, ed). New York: Dekker, 1993:83–103. 11. Geisler CH, Philip P, Christensen BE et al. In B-cell chronic lymphocytic leukaemia chromosome 17 abnormalities and not trisomy 12 are the single most important cytogenetic abnormalities for the prognosis: a cytogenetic and immunophenotypic study of 480 unselected newly diagnosed patients. Leuk Res 1997; 21:1011–23. 12. Dohner H, Stilgenbauer S, Benner A et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000; 343:1910–16. 13. Enno A, Catovsky D, O’Brien M et al. ‘Prolymphocytoid’ transformation of chronic lymphocytic leukemia. Br J Haematol 1979; 41:9–18. 14. Gujral S, Jain P, Bhutani M et al. Prolymphocytic transformation in chronic lymphocytic leukemia presenting as bilateral periorbital swelling. Am J Hematol 1998; 58:98–9. 15. Shimoni A, Shvidel L, Shtalrid M et al. Prolymphocytic transformation of B-chronic lymphocytic leukemia presenting as malignant ascites and pleural effusion. Am J Hematol 1998; 59:316–18. 16. Richter MN. Generalized reticular cell sarcoma of lymph nodes associated with lymphatic leukemia. Am J Pathol 1928; 4:285. 17. Han T, Rai KR. Chronic lymphocytic leukemia. In: Leukemia, 5th edn (Henderson ES, Lister TA, eds). Philadelphia: Saunders, 1990: 565–611. 18. Fermand JP, James JM, Herait P et al. Associated chronic lymphocytic leukemia and multiple myeloma: origin from a single clone. Blood 1985; 66:291–3. 19. Laurent G, Gourdin MF, Flandrin G et al. Acute blast crisis in a patient with chronic lymphocytic leukemia: immunoperoxidase study. Acta Haematol 1981; 65:60–6. 20. Whipham T. Splenic leukemia with carcinoma. Trans Pathol Soc Lond 1878; 29:313. 21. Gunz FW, Angus HB. Leukemia and cancer in the same patient. Cancer 1965; 18:145–52. 22. Moayeri H, Han T, Stutzman L et al. Second neoplasms with chronic lymphocytic leukemia. NY State J Med 1976; 76:378–81.

Comprehensive Geriatric Oncology

1064

23. Binet JL, Auquier A, Dighiero G et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 1981; 48:198–206. 24. Zippin C, Cutler SJ, Reeves WJ et al. Survival in chronic lymphocytic leukemia. Blood 1973; 42:367–76. 25. Rozman C, Montserrat E, Vinolas N. Serum immunoglobulins in B-chronic lymphocytic leukemia. Natural history and prognostic significance. Cancer 1988; 61:279–83. 26. Rundles RW, Moore JO. Chronic lymphocytic leukemia. Cancer 1978; 42:941–5. 27. Hansen MM. Chronic lymphocytic leukemia clinical studies based on 189 cases followed for a long time. Scand J Haematol Suppl 1973; 18:1–286. 28. Galton DAG. The pathogenesis of chronic lymphocytic leukemia. Can Med Assoc J 1966; 94:1005–10. 29. Vinolas N, Reverter JC, Urbano-Ispizua A et al. Lymphocyte doubling time in chronic lymphocytic leukemia: an update of its prognostic significance. Blood Cells 1987; 12:457–70. 30. Han T, Barcos M, Emrich L et al. Bone marrow infiltration patterns and their prognostic significance in chronic lymphocytic leukemia: correlations with clinical, immunologic, phenotypic, and cytogenetic data. J Clin Oncol 1984; 6:562–70. 31. Baldini L, Mozzana R, Cortelezzi A et al. Prognostic significance of immunoglobulin phenotype in B cell chronic lymphocytic leukemia. Blood 1985; 65:340–4. 32. Shatt B, Child JA, Karrgish SM et al. Behaviour of serum β2-microglobulin and acute phase reactant proteins in chronic lymphocytic leukaemia. Acta Haematol 1980; 64:73. 33. Simonsson B, Wiw L, Nilsson K. β2-Microglobulin in chronic lymphocytic leukaemia. Scand J Haematol 1980; 24:174–80. 34. Juliusson G, Karl-Henrik R, Nilsson B et al. Prognostic value of B-cell mitogen-induced and spontaneous thymidine uptake in vitro in chronic B-lymphocytic leukaemia cells. Br J Haematol 1985; 60: 429–36. 35. Kallander CFR, Simonsson B, Hagberg H et al. Serum deoxythymidine kinase gives prognostic information in chronic lymphocytic leukemia. Cancer 1984; 54:2450–5. 36. Chandra P, Sawitsky A, Chanana AD et al. Correlation of total body potassium and leukemic cell mass in patients with chronic lymphocytic leukemia. Blood 1979; 53:594–603. 37. Boggs DR, Sofferman SA, Wintrobe MM et al. Factors influencing the duration of survival of patients with chronic lymphocytic leukemia. Am J Med 1966; 40:243–54. 38. Dameshek W. Chronic lymphocytic leukemia—an accumulative disease of immunologically incompetent lymphocytes. Blood 1967; 29:566–84. 39. Rai KR, Sawitsky A, Cronkite EP et al. Clinical staging of chronic lymphocytic leukemia. Blood 1975; 46:219–34. 40. International Workshop on CLL. Proposal for a revised prognostic staging system. Br J Haematol 1981; 48:365–7. 41. Spiers ASD. Chronic lymphocytic leukemia. In: Leukemia, 4th edn (Gunz FW, Henderson ES, eds). New York: Grune & Stratton, 1983:709–40. 42. Rai KR, Sawitsky A, Jagathambal K et al. Chronic lymphocytic leukemia. Med Clin North Am 1984; 68:697–711. 43. Rai KR. An outline of clinical management of chronic lymphocytic leukemia. In: Chronic Lymphocytic Leukemia (Cheson BD, ed). New York: Dekker, 1993:241–51. 44. Digheiro G, Binet J-L. When and how to treat chronic lymphocytic leukemia. N Engl J Med 2000; 343:1799–801. 45. Kalil N, Cheson BD. Management of chronic lymphocytic leukemia. Drugs Aging 2000; 16:9– 27. 46. Keating MJ. Chemotherapy of chronic lymphocytic leukemia. In: Chronic Lymphocytic Leukemia (Cheson BD, ed). New York: Dekker, 1993:297–336. 47. Kempin S, Shank B. Radiation in chronic lymphocytic leukemia. In: Chronic Lymphocytic Leukemia: Recent Progress and Future Direction (Gale RP, Rai KR, eds). New York: Alan R Liss, 1987:337.

Chronic leukemias in the elderly

1065

48. Thornton PD, Hamblin M, Treleaven JG et al. High dose methyl prednisolone in refractory chronic lymphocytic leukemia. Leuk Lymphoma 1999; 34:167–70. 49. Kennedy BJ. Androgenic hormone therapy in lymphatic leukemia. JAMA 1964; 190:1130–3. 50. Presant CA, Safdar SH. Oxymethalone in myelofibrosis and chronic lymphocytic leukemia. Arch Intern Med 1973; 132:175–8. 51. West WO. The treatment of bone marrow failure with massive androgen therapy. Ohio State Med J 1965; 61:347. 52. Narasimhan P, Amaral L. Lymphopenic response of patients presenting with chronic lymphocytic leukemia associated with carcinoma of the prostate to diethylstilbestrol: correlation of response to the in vitro synthesis of RNA by patient lymphocytes and its relationship to transcortin. Am J Hematol 1980; 8:369–75. 53. Narasimhan P, Glasberg S. Responses to diethylstilbestrol in a patient with refractory chronic lymphatic leukemia associated with non-Hodgkin’s lymphoma (Richter’s syndrome). In: Proceedings of the Second International Congress on Hormones and Cancer. New York: Pergamon Press, 1983 (abst). 54. Galton DAG, Israel LG, Nabarro JDN et al. Clinical trials of p-(di-2chloroethylamino)phenylbutyric acid (CB1348) in malignant lymphoma. BMJ 1955; ii: 1172–6. 55. Han T, Ezdinli EZ, Shimaoka K et al. Chlorambucil vs. combined chlorambucil-corticosteroid therapy in chronic lymphocytic leukemia. Cancer 1973; 31:502–8. 56. Huguley CM Jr. Treatment of chronic lymphocytic leukemia. Cancer Treat Rev 1977; 4:261. 57. Knospe WH, Loeb V Jr, Huguley CM Jr. Biweekly chlorambucil treatment of chronic lymphocytic leukemia. Cancer 1974; 33: 555–62. 58. Sawitsky A, Rai KR, Glidewell O et al. Comparison of daily versus intermittent chlorambucil and prednisone therapy in the treatment of patients with chronic lymphocytic leukemia. Blood 1977; 50: 1049–59. 59. Digheiro G, Maloum K, Desablens B et al. Chlorambucil in indolent chronic lymphocytic leukemia. N Engl J Med 1998; 338: 1506–14. 60. Khong HT, McCarthy J. Chlorambucil-induced pulmonary disease: a case report and review of the literature. Ann Hematol 1998; 77: 85–7. 61. Lai R, Arber DA, Brynes RK et al. Untreated chronic lymphocytic leukemia concurrent with or followed by acute myelogenous leukemia or myelodysplastic syndrome. Am J Clin Pathol 1999; 111: 373–8. 62. Spiers ASD, Chikkappa G, Wilbur HJ. Haemorrhagic cystitis after low-dose cyclophosphamide. Lancet 1983; i: 1213–14. 63. French Cooperative Group on Chronic Lymphocytic Leukaemia. Effectiveness of ‘ChOP’ regimen in advanced untreated chronic lymphocytic leukaemia. Lancet 1986; i: 1346–9. 64. Kempin S, Lee BJ, Thaler HT et al. Combination chemotherapy of advanced chronic lymphocytic leukemia: the M-2 protocol (vincristine, BCNU, cyclophosphamide, melphalan and prednisone). Blood 1982; 60:1110–21. 65. Keating MJ, Scouros M, Murphy S et al. Multiple agent chemotherapy (POACH) in previously treated and untreated patients with chronic lymphocytic leukemia. Leukemia 1988; 2:157–64. 66. Delpero JR, Gastout JA, Letreut YP et al. The value of splenectomy in chronic lymphocytic leukemia. Cancer 1987; 59:340–5. 67. Ferrant A, Michaux JL, Sokal G. Splenectomy in advanced chronic lymphocytic leukemia. Cancer 1986; 58:2130–5. 68. Merl SA, Theodarakis ME, Goldberg J et al. Splenectomy for thrombocytopenia in chronic lymphocytic leukemia. Am J Hematol 1983; 15:253–9. 69. Pegourie B, Sotto J-J, Hollard D et al. Splenectomy during chronic lymphocytic leukemia. Cancer 1987; 59:1626–30. 70. Stein RS, Weikert D, Reynolds V et al. Splenectomy for end-stage chronic lymphocytic leukemia. Cancer 1987; 59:1815–18.

Comprehensive Geriatric Oncology

1066

71. Binet JL, Catovsky D, Dighiero G et al. Chronic lymphocytic leukemia: recommendations for diagnosis, staging and response criteria. Ann Intern Med 1989; 110:236–8. 72. Frederickson S. Specificity of adenosine deaminase toward adenosine and 2′-deoxyadenosine analogues. Arch Biochem Biophys 1966; 113:383. 73. Malspeis L, Grever MR, Staubus AE et al. Pharmacokinetics of 2-F-ara-A (9-β-Darabinofuranosyl-2-fluoroadenine) in cancer patients during the phase I clinical investigation of fludarabine phosphate. Semin Oncol 1990; 17:18. 74. Plunkett W, Huang P, Gandhi V. Metabolism and action of fludarabine phosphate. Semin Oncol 1990; 17:3. 75. Von Hoff DD. Phase I clinical trials with fludarabine phosphate. Semin Oncol 1990; 17:33. 76. Chun HG, Leyland-Jones B, Caryk SM et al. Central nervous system toxicity of fludarabine phosphate. Cancer Treat Rep 1986; 70:1225–8. 77. Grever MR, Kopecky KJ, Coltman CA et al. Fludarabine monophosphate: a potentially useful agent in chronic lymphocytic leukemia. Nouv Rev Franc Hematol 1988; 30:457. 78. Keating MJ, Kantarjian H, Talpaz M et al. Fludarabine: a new agent with major activity against chronic lymphocytic leukemia. Blood 1989; 74:19–25. 79. Keating MJ, Kantarjian H, O’Brien S et al. Fludarabine: a new agent with marked cytoreductive activity in untreated chronic lymphocytic leukemia. J Clin Oncol 1991; 9:44–9. 80. Keating MJ, O’Brien S, Kantarjian H et al. Long-term follow-up of patients with chronic lymphocytic leukemia treated with fludarabine as a single agent. Blood 1993; 81:2878–84. 81. Keating MJ, Kantarjian H, O’Brien S et al. Fludarabine (FLU)-prednisone (PRED): a safe, effective combination in refractory chronic lymphocytic leukemia. Proc Am Soc Clin Oncol 1989; 8:201. 82. Keating MJ, O’Brien S, Lerner S et al. Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy. Blood 1998; 92:1165–71. 83. French Cooperative Group on CLL. Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. Lancet 1996; 347:1432–8. 84. French Cooperative Group on CLL. Comparison of fludarabine (FDB), CAP and CHOP in previously untreated stage B chronic lymphocytic leukemia (CLL). First interim results of a randomized clinical trial in 247 patients. Blood 1994; 83:461a. 85. Rai KR, Peterson B, Elias L. A randomized comparison of fludarabine and chlorambucil for patients with previously untreated chronic lymphocytic leukemia. A CALGB, SWOG, CTG/NCI-C and ECOG inter-group study. Blood 1996; 88:141a. 86. Rai KR, Peterson BL, Appelbaum FR et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 2000; 343:1750–7. 87. Zaja F, Rogato A, Russo D et al. Combined therapy with fludarabine and cyclophosphamide in relapsed/resistant patients with B-cell chronic lymphocytic leukaemia and non-Hodgkin’s lymphomas. Eur J Haematol 1997; 59:327–8. 88. Rummel MJ, Kafer G, Pfreundschuh M et al. Fludarabine and epirubicin in the treatment of chronic lymphocytic leykaemia: a German multicenter phase II study. Ann Oncol 1999; 10:183– 8. 89. Weiss MA, Glenn M, Maslak P et al. Consolidation therapy with high-dose cyclophosphamide improves the quality of response in patients with chronic lymphocytic leukemia treated with fludarabine as induction therapy. Leukemia 2000; 14:1577–82. 90. Cheson BD, Bennett JM, Grever M et al. National Cancer Institute-Sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87:4990–7. 91. Robak T, Blasinska-Morawiec M, Blonsky JZ et al. 2-Chlorodeoxyadenosine (cladribine) in the treatment of elderly patients with B-cell chronic lymphocytic leukemia. Leuk Lymphoma 1999; 34:151–7.

Chronic leukemias in the elderly

1067

92. Spiers ASD, Ruckdeschel JC, Horton J. Effectiveness of pentostatin (2′-deoxycoformycin) in refractory lymphoid neoplasms. Scand J Hematol 1984; 32:130–4. 93. Johnson SA, Catovsky D, Child JA et al. Phase I/II evaluation of pentostatin (2′deoxycoformycin) in a five day schedule for the treatment of relapsed/refractory B-cell chronic lymphocytic leukaemia. Invest New Drugs 1998; 16:155–60. 94. Di Raimondo F, Guistolisi R, Cacciola E et al. Autoimmune hemolytic anemia in chronic lymphocytic leukemia patients treated with fludarabine. Leuk Lymphoma 1993; 11:63–8. 95. Myint H, Copplestone A, Orchard J et al. Fludarabine-related autoimmune haemolytic anaemia in patients with chronic lymphocytic leukaemia. Br J Haematol 1995; 91:341–4. 96. Gonzalez H, Leblond V, Azar N et al. Severe autoimmune hemolytic anemia in eight patients treated with fludarabine. Hematol Cell Ther 1998; 40:113–18. 97. Taha HM, Narasihman P, Venkatesh L et al. Fludarabine-related hemolytic anemia in chronic lymphocytic leukemia and lymphoproliferative disorders. Am J Hematol 1998; 59:316–19. 98. Rosenkrantz K, Dupont B, Flomenberg M. Relevance of autocytotoxic and autoregulatory lymphocytes in the maintenance of tolerance. Concepts Immunopathol 1987; 4:24–41. 99. List AF, Kummet TD, Adams JD et al. Tumor lysis syndrome complicating treatment of chronic lymphocytic leukemia with fludarabine phosphate. Am J Med 1990; 89:388–90. 100. Cheson BD, Frame JN, Vena D et al. Tumor lysis syndrome: an uncommon complication of fludarabine therapy of chronic lymphocytic leukemia. J Clin Oncol 1998; 16:2313–20. 101. Schlaifer D, Rigal-Huguet F, Pris J et al. Secondary neoplasms in two patients treated with purine analogues. Nouv Rev Franc Hematol 1994; 36:341. 102. Frewin RJ, Provan D, Smith AG. Myelodysplasia occurring after fludarabine treatment for chronic lymphocytic leukaemia. Clin Lab Haematol 1997; 19:151–2. 103. Coppelstone JA, Mufti GJ, Hamblin TJ et al. Immunological abnormalities in myelodysplastic syndromes II. Coexistent lymphoid or plasma cell neoplasms: a report of 20 cases unrelated to chemotherapy. Br J Haematol 1986; 63:149–59. 104. Silber R, Potmesil M. Drug resistance in chronic lymphocytic leukemia. In: Chronic Lymphocytic Leukemia (Cheson BD, ed.) New York: Dekker, 1933:221–39. 105. Potmesil M, Bank B, Grossberg H et al. Resistance of human leukemic and normal lymphocytes to DNA cleavage by drugs correlates with low levels of DNA topoisomerase. Cancer Res 1988; 49:4385. 106. Holmes JA, Jacobs A, Carter G et al. Is the mdr1 gene relevant in chronic lymphocytic leukemia? Leukemia 1990; 4:216–18. 107. Friedenberg WR, Spencer SK, Musser C et al. Multi-drug resistance in chronic lymphocytic leukemia. Leuk Lymphoma 1999; 34: 171–78. 108. Bosanquet AG, Johnson SA, Richards SM. Prognosis for fludarabine therapy of chronic lymphocytic leukaemia based on ex vivo drug response by DiSC assay. Br J Haematol 1999; 106:71–7. 109. Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia. Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia. A randomized, controlled clinical trial. N Engl J Med 1988; 319:902. 110. Kontoyianis DP, Anaissie EJ, Bodey GP. Infection in chronic lymphocytic leukemia: a reappraisal. In: Chronic Lymphocytic Leukemia (Cheson BD, ed). New York: Dekker, 1993:399–417. 111. Rabinowe SN, Grossbard ML, Nadler LM. Innovative treatment strategies for chronic lymphocytic leukemia: monoclonal antibodies, immunoconjugates, and bone marrow transplantation. In: Chronic Lymphocytic Leukemia (Cheson BD, ed). New York: Dekker, 1993:337–67. 112. Byrd JC, Rai KR, Weiss RB. What choices are available for treatment of the patient with chronic lymphocytic leukemia who is fludarabine-refractory? Semin Oncol 2000; 27: xii–xvi.

Comprehensive Geriatric Oncology

1068

113. Herold M, Schulze A, Hartwig K et al. Successful treatment and retreatment of resistant B-cell chronic lymphocytic leukemia with the monoclonal anti-CD20 antibody rituximab. Ann Hematol 2000; 79: 332–5. 114. Varterasian ML, Mohammad RM, Shurafa MS et al. Phase II trial of bryostatin 1 in patients with relapsed low-grade non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Clin Cancer Res 2000; 6:825–8. 115. Robak T, Blonski JZ, Kasznicki M et al. Cladribine with prednisone versus chlorambucil with prednisone as first-line therapy in chronic lymphocytic leukemia: report of a prospective, randomized, multicenter trial. Blood 2000; 96:2723–9. 116. Sutton L, Maloum K, Gonzalez H et al. Autologous hematopoietic stem cell transplantation as salvage treatment for advanced B cell chronic lymphocytic leukemia. Leukemia 1998; 12:1699– 707. 117. Dreger P, von Neuhoff N, Kuse R et al. Early stem cell transplantation for chronic lymphocytic leukaemia: a chance for cure? Br J Cancer 1998; 77:2291–7. 118. Spiers ASD. Philadelphia-chromosome-negative chronic myeloid leukaemias. In: Chronic Granulocytic Leukaemia (Shaw MT, ed). Eastbourne: Praeger, 1982:231–44. 119. Fialkow PJ. Clonal development and stem cell origin of leukemias and related disorders. In: Leukemia, 4th edn (Gunz FW, Henderson ES, eds). New York: Grune & Stratton, 1983:63–76. 120. Ramachandran A, Mathur BP, Madhukar S et al. Chronic myeloid leukaemia with asplenism. J Assoc Physicians India 1978; 26: 541–42. 121. Galton DAG, Spiers ASD. Development of chronic granulocytic leukaemia in the absence of a spleen. Lancet 1989; ii: 805. 122. Cervantes F, Rozman M, Rozman C. Chronic granulocytic leukaemia in asplenic patients. Eur J Haematol 1990; 45:177. 123. Thompson RB, Stainsby D. The clinical and haematological features of chronic granulocytic leukaemia in the chronic phase. In: Chronic Granulocytic Leukaemia 1982 (Shaw MT, ed). Eastbourne: Praeger, 1982:137–167. 124. Spiers ASD. The clinical features of chronic granulocytic leukemia. Clin Haematol 1977; 6:77–95. 125. Spiers ASD, Bain BJ, Turner JE. The peripheral blood in chronic granulocytic leukaemia. Study of 50 untreated Philadelphia-positive cases. Br J Haematol 1977; 18:25–38. 126. Spiers ASD, Ermidou-Sazeidis C, Richards HGH. Chronic granulocytic leukaemia: clinical course, blood and bone marrow changes after chemotherapy and splenectomy. Haematologica 1979; 64: 616–34. 127. Baikie AG. Chronic granulocytic leukaemia: the metamorphosis of a conditioned neoplasm to an autonomous one. In: Proceedings of the 4th Congress of the Asian Pacific Society of Haematology, 1969: 197. 128. Spiers ASD. Metamorphosis of chronic granulocytic leukaemia: diagnosis, classification and management. Br J Haematol 1979; 41: 1–7. 129. Shaw MT. Clinical and haematological manifestations of the terminal phase. In: Chronic Granulocytic Leukaemia (Shaw MT, ed). Eastbourne: Praeger, 1982:169–88. 130. Greaves MF. Target cells, differentiation and clonal evolution in chronic granulocytic leukaemia: a model for understanding the biology of malignancy. In: Chronic Granulocytic Leukaemia (Shaw MT, ed). Eastbourne: Praeger, 1982:15–47. 131. Minot JB, Buckman TE, Isaacs R. Chronic myelogenous leukemia. Age incidence, duration and benefit derived from irradiation. JAMA 1924; 82:1489–94. 132. Tivey H. The prognosis for survival in chronic granulocytic and lymphocytic leukemia. AJR 1954; 72:68–93. 133. Medical Research Council. Chronic granulocytic leukaemia: comparison of radiotherapy and busulphan. BMJ 1968; i: 201–8. 134. Kardinal CG, Bateman JR, Weiner J. Chronic granulocytic leukemia. Review of 536 cases. Arch Intern Med 1976; 136:305–13.

Chronic leukemias in the elderly

1069

135. Wareham NJ, Johnson SA, Goldman JM. Relationship of the duration of the chronic phase in chronic granulocytic leukaemia to the need for treatment during the first year after diagnosis. Cancer Chemother Pharmacol 1982; 8:205–10. 136. Sokal JE, Cox EB, Baccarani M et al and the Italian Cooperative CML Study Group. Prognostic discrimination in ‘good risk’ chronic granulocytic leukemia. Blood 1984; 63:789–99. 137. Kantarjian HM, Keating MJ, Smith TL et al. Proposal for a simple synthesis prognostic staging systewm in chronic myelogenous leukemia. Am J Med 1990; 88:1–8. 138. Rodriguez J, Cortes J, Smith T et al. Determinants of prognosis in late chronic-phase chronic myelogenous leukemia. J Clin Oncol 1998; 16:3782–7. 139. Kvasnicka HM, Thiele J, Schmitt-Graeff A et al. Prognostic impact of bone marrow erythropoietic precursor cells and myelofibrosis at diagnosis of Ph1+ chronic myelogenous leukaemia—a multicentre study on 495 patients. Br J Haematol 2001; 112:727–39. 140. Spiers ASD. Chronic granulocytic leukemia. In: Leukemia, 4th edn (Gunz FW, Henderson ES, eds). New York: Grune & Stratton, 1983:663–708. 141. Lamas I, Sanjuan P, Zabala P et al. Leucemia mieloide cronica. Estudio clinico y analisis de resultados terapeuticos en 55 casos. Sangre 1982; 27:493–507. 142. Chronic Myeloid Leukaemia Trialists’ Collaborative Group. Hydroxyurea versus busulphan for chronic myeloid leukaemia: an individual patient data meta-analysis of three randomized trials. Br J Haematol 2000; 110:573–6. 143. Kolitz JE, Kempin S, Clarkson BD et al. Phase II trial of high-dose hydroxyurea in chronic myelogenous leukemia. Blood 1989; 74(Suppl 1): 155a. 144. Stott H, Fox W, Girling GJ et al. Acute leukaemia after busulphan. BMJ 1977; ii: 1513–17. 145. McCormick J, Henderson SO. Leukemic hyperleukocytosis-induced unstable angina and congestive heart failure. Am J Emerg Med 1999; 17:217–19. 146. Richards HGH, Spiers ASD. Chronic granulocytic leukaemia in pregnancy. Br J Radiol 1975; 48:261–4. 147. Spiers ASD, Baikie AG, Galton DAG et al. Chronic granulocytic leukaemia: effect of elective splenectomy on the course of disease. BMJ 1975; i: 175–9. 148. Medical Research Council’s Working Party for Therapeutic Trials in Leukaemia. Randomized trial of splenectomy in Ph1-positive chronic granulocytic leukaemia, including an analysis of prognostic features. Br J Haematol 1983; 54:415–30. 149. Italian Cooperative Study Group on Chronic Myeloid Leukaemia. Effect of early splenectomy and cyclic acute leukaemia-like chemotherapy on the course of chronic myeloid leukaemia. Boll Inst Sieroterap Milan 1978; 57:360–9. 150. Brodsky I, Fuscaldo KE. Chronic myelocytic leukemia: the use of cytogenetics and aggressive therapy in management. In: Clinical Interpretation and Practice of Cancer Chemotherapy (Greenspan EM, ed). New York: Raven Press, 1982:565–76. 151. Garfinkel LS, Bennett DE. Extramedullary myeloblastic transformation in chronic myelocytic leukemia simulating a coexistent malignant lymphoma. Am J Clin Pathol 1969; 51:638–45. 152. Schwartz JH, Canellos GP. Hydroxyurea in the management of the hematologic complications of chronic granulocytic leukemia. Blood 1975; 46:11–16. 153. Goldman JM. The treatment of chronic granulocytic leukaemia. In: Chronic Granulocytic Leukaemia (Shaw MT, ed). Eastbourne: Praeger, 1982:189–216. 154. Bertazzoni V, Brusamolino E, Isernia P et al. Prognostic significance of terminal transferase and adenosine deaminase in acute and chronic myeloid leukemia. Blood 1982; 60:685–92. 155. Canellos GP. The treatment of chronic granulocytic leukaemia. Clin Haematol 1977; 6:113– 28. 156. Spiers ASD, Goldman JM, Catovsky D et al. Multiple-drug chemotherapy for acute leukemia. The TRAMPCOL regimen: results in 86 patients. Cancer 1977; 40:20–9. 157. Wiernik PH. The current status of therapy for and prevention of blast crisis of chronic myelocytic leukemia. J Clin Oncol 1984; 2: 329–35.

Comprehensive Geriatric Oncology

1070

158. Koller CA, Miller DM. Long-term followup of a novel effective regimen for the treatment of myeloid blast phase of chronic granulocytic leukemia: mithramycin and hydroxyurea. Blood 1985; 66:203a. 159. Kantarjian HM, Keating MJ, Talpaz M et al. Chronic myelogenous leukemia in blast crisis. Analysis of 242 patients. Am J Med 1987; 83:445–54. 160. Martinez JA, Martin G, Sanz GF et al. A phase II clinical trial of carboplatin infusion in highrisk acute nonlymphoblastic leukemia. J Clin Oncol 1991; 9:39–43. 161. Dutcher JP, Lee S, Paietta E et al. Phase II study of carboplatin in blast crisis of chronic myeloid leukemia: Eastern Cooperative Oncology Group study E1992. Leukemia 1998; 12:1037–40. 162. Gollard R, Miller WE, Piro LD et al. 2-Chlorodeoxyadenosine administration to patients with the myeloid blast phase of chronic myelogenous leukemia. Leuk Lymphoma 1997; 28:183–5. 163. Dann EJ, Anastasi J, Larson RA. High-dose cladribine therapy for chronic myelogenous leukemia in the accelerated or blast phase. J Clin Oncol 1998; 16:1498–504. 164. Tedeschi A, Montillo M, Ferrara F et al. Treatment of chronic myeloid leukemia in the blastic phase with fludarabine, cytosine arabinoside and G-CSF (FLAG). Eur J Haematol 2000; 64:182–7. 165. Goldman JM, Catovsky D, Hows J. Cryopreserved peripheral blood cells functioning as autografts in patients with chronic granulocytic in transformation. BMJ 1979; i: 1310–13. 166. Marcus RE, Goldman JM. Autografting for patients with chronic granulocytic leukemia: current status and future possibilities. In: Autologous Bone Marrow Transplantation (Dicke KA, Spitzer G, Zander AR, eds). Houston: University of Texas, 1985:11–15. 167. Beidler JL, Riehm H. Cellular resistance to actinomycin D in Chinese hamster cells in vitro: cross-resistance, radioautographic, and cytogenetic studies. Cancer Res 1970; 46:1174–84. 168. Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochem Biophys Acta 1976; 455:152–62. 169. Kuwazura Y, Yoshimura A, Hanada S et al. Expression of the multidrug transporter, Pglycoprotein, in chronic myelogenous leukaemia cells in blast crisis. Br J Haematol 1990; 74:24–29. 170. Goldstein LJ, Galski H, Fojo A et al. Expression of multi-drug resistant gene in human tumors. J Natl Cancer Inst 1989; 81:116–24. 171. Kamada N, Uchino H. Chronologic sequence in appearance of clinical and laboratory findings characteristic of chronic myelocytic leukemia. Blood 1978; 51:843–50. 172. Fialkow PJ, Martin PJ, Najfeld V et al. Evidence for a multistep pathogenesis of chronic myelogenous leukemia. Blood 1981; 58: 158–63. 173. Cunningham I, Gee T, Dowling M et al. Results of treatment of Ph1+ chronic myelogenous leukemia with an intensive treatment regimen (L-5 protocol). Blood 1979; 53:375–95. 174. Sharp JC, Joyner MV, Wayne AW et al. Karyotypic conversion in Ph1-positive chronic myeloid leukaemia with combination chemotherapy. Lancet 1979; i: 1370–2. 175. Sokal JE, Gockerman JP, Bigner SH. Evidence for a selective antileukemic effect of cytosine arabinoside in chronic granulocytic leukemia. Blood 1987; 70:237a. 176. Goldman JM, Apperley JF, Jones L et al. Bone marrow transplantation for patients with chronic myeloid leukaemia. N Engl J Med 1986; 314:202–7. 177. McGlave PB. Bone marrow transplants in chronic myelogenous leukemia: an overview of determinants of survival. Semin Hematol 1990; 27:23–30. 178. Fields KK, Djulbegovic B. Hematopoietic stem cell transplantation in the older patient. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:489–501. 179. Talpaz M, Kantarjian H, McCredie KB et al. Chronic myelogenous leukemia: hematologic remissions and cytogenetic improvement induced by recombinant oc A interferon. Blood 1985; 66:209a.

Chronic leukemias in the elderly

1071

180. Alimena G, Morra E, Lazzarino M et al. Interferon α-2b as therapy for Ph1-positive chronic myelogenous leukemia: a study of 82 patients treated with intermittent or daily administration. Blood 1988; 72:642–7. 181. Ozer H. Biotherapy of chronic myelogenous leukemia with interferon. Semin Oncol 1988; 15:14–20. 182. Talpaz M, Kantarjian H, Kurzrock R et al. Update on therapeutic options for chronic myelogenous leukemia. Semin Hematol 1990; 27:31–6. 183. Spiers ASD, Saba HI, Ballester OF et al. Interferon (IFN) therapy for chronic granulocytic leukemia (CGL): thrombocytopenia, morphologic and cytogenetic changes in bone marrow, and prolonged disease control after discontinuing treatment. Blood 1990; 76:323a. 184. Osterholz J, Siczkowski M, Gordon MY et al. Interferon-α increases attachment of CML progenitor cells to stromal cells. Blood 1990; 76:265a. 185. Mahon FX, Faberes C, Pueyo S et al. Response at three months is a good predictive factor for newly diagnosed chronic myeloid leukemia patients treated by recombinant interferon-α. Blood 1998; 92:4059–65. 186. Burke PJ, Rowley SD. Remission of aggressive phase chronic myelocytic leukemia (CML) with timed sequential therapy (TST) and interferon (I) given in aplasia. Blood 1990; 76:258a. 187. Claxton D, Gooch G, Deisseroth A et al. Hematopoiesis is nonclonal in interferon induced cytogenetic remissions in CML. Blood 1990; 76:262a. 188. Chang AYC, Fisher HAG, Spiers ASD et al. Toxicities of human recombinant interferon-α2 in patients with advanced prostate carcinoma. J Interferon Res 1986; 6:713–15. 189. Hilbe W, Apfelbeck U. Fridrik M et al. Interferon-α for the treatment of elderly patients with chronic myeloid leukaemia. Leuk Res 1998; 22:881–6. 190. Russo D, Regazzi M, Sacchi S et al. All-trans retinoic acid (ATRA) in patients with chronic myeloid leukemia in chronic phase. Leukemia 1998; 12:449–54. 191. O’Brien S, Kantarjian H, Keating M et al. Homoharringtonine therapy induces responses in patients with chronic myelogenous leukemia in late chronic phase. Blood 1995; 86:3322. 192. O’Brien S, Kantarjian H, Koller C et al. Sequential homoharringtonine and interferon-α in the treatment of early chronic phase chronic myeloid leukemia. Blood 1999; 93:4149–53. 193. Daley GQ, van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the p210BCR/ABL gene of the Philadelphia chromosome. Science 1990; 247:824–30. 194. Goldman JM. Tyrosine-kinase inhibition in treatment of chronic myeloid leukaemia. Lancet 2000; 355:1031–2. 195. Druker BJ, Talpaz M, Resta D et al. Clinical efficacy and safety of an abl specific tyrosine kinase inhibitor as targeted therapy for chronic myelogenous leukemia. Blood 1999; 94(Suppl 1): 369a. 196. Peggs K, Mackinnon S. Imatinib mesylate—the new gold standard for treatment of chronic myeloid leukemia. N Engl J Med 2003; 348:1048–50. 197. O’Brien SG, Guilhot F, Larson RA et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348: 994–1004. 198. Okabe M, Uehara Y, Miyagishima T et al. Effect of herbimycin A, an antagonist of tyrosine kinase, on bcr/abl oncoprotein-associated cell-proliferations: abrogative effect on the transformation of murine hematopoietic cells by transfection of a retroviral vector expressing oncoprotein p210bcr/abl and preferential inhibition on Ph1-positive leukemia cell growth. Blood 1992; 80:1330. 199. Szczylik C, Skorski T, Nicolaides NC et al. Selective inhibition of leukemia cell proliferation by BCR-ABL antisense oligodeoxynucleotides. Science 1991; 235:262. 200. Ratajczak MZ, Hijiya N, Catani L et al. Acute- and chronic-phase chronic myelogenous leukemia colony-forming units are highly sensitive to the growth inhibitory effects of c-myb antisense oligodeoxynucleotides. Blood 1992; 79:1956.

Comprehensive Geriatric Oncology

1072

201. Fialkow PJ, Jacobson RJ, Singer JW et al. Philadelphia chromosome (Ph1-negative chronic myelogenous leukemia (CML): a clonal disease with origin in a multipotent stem cell. Blood 1980; 56:70–3. 202. Krauss S, Sokal JE, Sandberg AA. Comparison of Philadelphia chromosome-positive and negative patients with chronic myelocytic leukemia. Ann Intern Med 1964; 61:625–35. 203. Ezdinli EZ, Sokal JE, Crosswhite L et al. Philadelphia-chromosome-positive and -negative chronic myelocytic leukemia. Ann Intern Med 1970; 72:175–82. 204. Hays T, Morse H, Peakman D et al. Cytogenetic studies of chronic myelocytic leukaemia in children and adolescents. Cancer 1979; 44: 210–14. 205. Mintz U, Vardiman J, Golomb HM et al. Evolution of karyotypes in Philadelphia (Ph1) chromosome-negative chronic myelogenous leukaemia. Cancer 1979; 43:411–16. 206. Gunz F, Baikie AG. The pathology and pathophysiology of the leukemia cell. In: Leukemia, 3rd edn (Gunz FW, Baikie AG, eds). New York: Grune & Stratton, 1974:133–74. 207. Gralnick HR, Galton DAG, Catovsky D et al. Classification of acute leukemia. Ann Intern Med 1977; 87:740–53. 208. Sultan C, Pierre RV, Hast R et al. Refractory anemias and dysmyelopoietic syndromes (DMPS). In: Educational Program of the American Society of Hematology, Montreal, 1980:22– 6. 209. Storniolo AM, Moloney WC, Rosenthal DS et al. Myelodysplasia with monocytosis: the chronic myelodysplastic syndromes. Blood 1986; 68:206a. 210. Mufti GJ, Stevens JR, Oscier DG et al. Myelodysplastic syndromes: a scoring system with prognostic significance. Br J Haematol 1985; 59:425–33. 211. Beran M, Kantarjian H. Topotecan in the treatment of hematologic malignancies. Semin Hematol 1998; 35:26–31. 212. You W, Weisbrot IM. Chronic neutrophilic leukemia. Report of two cases and review of the literature. Am J Clin Pathol 1979; 72: 233–42. 213. Pane F, Frigeri F, Sindona M et al. Neutrophilic-chronic myeloid leukemia: a distinct disease with a specific molecular marker (BCR/ABL with c3/a2 junction). Blood 1996; 88:2410–14. 214. Terre C, Garcia I, Bastie JN et al. A case of chronic neutrophilic leukemia with deletion(11) (q23). Cancer Genet Cytogenet 1999; 110:70–1. 215. Chusid MJ, Dale DC, West BC et al. The hypereosinophilic syndrome. Medicine 1975; 54:1– 27. 216. Parrillo JE, Fauci AS, Wolff SM. Therapy of the hypereosinophilic syndrome. Ann Intern Med 1978; 89:167–72. 217. Spitzer G, Garson OM. Lymphoblastic leukemia with marked eosinophils: a report of two cases. Blood 1973; 43:377–84. 218. Catovsky D, Bernasconi C, Verdonck PJ et al. The association of eosinophilia with lymphoblastic leukaemia or lymphoma: a study of seven patients. Br J Haematol 1980; 45:523– 34. 219. Bass DA. The functions of eosinophils. Ann Intern Med 1979; 91: 120–1. 220. Tantravahi R, Schwenn M, Henkle C et al. A pericentric inversion of chromosome 16 is associated with dysplastic marrow eosinophils in acute myelomonocytic leukemia. Blood 1984; 63:800–2. 221. Kauer GL, Engle RL. Eosinophilic leukaemia with Ph1-positive cells. Lancet 1964; ii: 1340. 222. Gruenwalk H, Kiossoglou KA, Mitus WJ et al. Philadelphia chromosome in eosinophilic leukemia. Am J Med 1965; 39:1003–10. 223. Gershwin ME, Fajardo LP, Gurwith M et al. Eosinophilia terminating in myeloblastoma. Am J Med 1972; 53:348–53. 224. Huang CS, Gomez GA, Kohno S et al. Chromosomes and causation of human cancer and leukemia. XXXIV. A case of ‘hypereosinophilic syndrome’ with unusual cytogenetic findings in a chloroma, terminating in blastic transformation and CNS leukemia. Cancer 1979; 44:1284– 9.

Chronic leukemias in the elderly

1073

225. Hardy WR, Anderson RE. The hypereosinophilic syndromes. Ann Intern Med 1968; 68:1220– 9. 226. Yam LT, Li CY, Necheles TF et al. Pseudoeosinophilia, eosinophilic endocarditis and eosinophilic leukemia. Am J Med 1972; 53: 193–202. 227. Benvenisti DS, Ultmann JE. Eosinophilic leukemia. Ann Intern Med 1969; 71:731–45. 228. Parrillo JE. Heart disease and the eosinophil. N Engl J Med 1990; 323:1560–1. 229. Flannery EP, Freeman MVR, D’Ambrosio U et al. Eosinophilic leukemia with fibrosing endocarditis and short Y chromosome. Ann Intern Med 1972; 77:223–8. 230. Resnick M, Myrrson RM. Hypereosinophilic syndrome. Am J Med 1971; 51:560–4. 231. Weinger RS, Andre-Schwartz J, Desforges JF et al. Acute leukaemia with eosinophilia or eosinophilic leukaemia: a dilemma. Br J Haematol 1975; 30:65–70. 232. Hamilton PJ, Dawson AA. Successful treatment of apparent eosinophilic leukaemia. BMJ 1977; i: 1195. 233. Youman JD, Taddeini L, Cooper T. Histamine excess symptoms in basophilic chronic granulocytic leukemia. Arch Intern Med 1973; 131:560–2. 234. Cuneo A, Kerim S, Vandenberghe E et al. Translocation t(6;9) occurring in acute myelofibrosis, myelodysplastic syndrome, and acute nonlymphocytic leukemia suggests multipotent stem cell involvement. Cancer Genet Cytogenet 1989; 42:209–19. 235. Sagher F, Even-Paz Z. Mastocytosis and the Mast Cell. Basel: Karger, 1967. 236. Coser P, Quaglino D, De Pasquale A et al. Cytobiological and clinical aspects of tissue mast cell leukaemia. Br J Haematol 1980; 45: 5–12. 237. Sater NA, Austen KF, Wasserman SI. Oral disodium cromoglycate in the treatment of systemic mastocytosis. N Engl J Med 1979; 301: 465–9. 238. Mutter RD, Tannenbaum M, Ultmann JE. Systemic mast cell disease. Ann Intern Med 1963; 59:887–906. 239. Daniel MT, Flandrin G, Bernard J. Leucemie aiguë a mastocytes. Nouv Rev Franc Hematol 1975; 15:319–32. 240. Foley HT, Bennett JM, Carbone PP. Combination chemotherapy in accelerated phase of chronic granulocytic leukemia. Arch Intern Med 1969; 123:166–70.

47 Hodgkin lymphoma in the elderly Paul Kaesberg Introduction Hodgkin lymphoma (HL, Hodgkin’s disease) is an infrequent malignancy, but has been heavily studied as a model for the cure of advanced malignancies. In younger persons, HL is notable for being among only a handful of tumors that is curable even in its most advanced stages and curable by salvage chemotherapy once relapse has occurred. In older patients, while the responsiveness to chemotherapy is still common, curability and tolerance to therapy take a sharp decline. Histologic subtype distribution alters with age toward more aggressive subtypes, and stage at presentation appears to be more advanced in older patients. The bimodal age distribution suggests different etiologies in different age groups. The combination of immune suppression that occurs with HL, with treatment, and with immune senescence causes a high susceptibility to opportunistic infections, making curative treatment more problematic. Despite this, clinical remissions, relief of symptoms, and prolongation of life can be achieved with treatment tailored toward the patient’s age and physical condition. Epidemiology of HL in the elderly HL in the USA has a bimodal age distribution.1,2 The early peak is between ages 20 and 30, while the later peak is between ages 60 and 80, with the incidence starting to increase at about age 50. The epidemiology is different in developed versus underdeveloped countries, with the early peak being smaller to absent in underdeveloped countries.3 In the younger age group, the epidemiology is similar to that of paralytic polio (higher socioeconomic class, first child in the family, and fewer siblings). Based on these pieces of evidence, McMahon4 proposed the possibility of a viral etiology, with HL being more likely to occur (but still rare) if the viral infection occurs later in childhood. Most evidence suggests that Epstein-Barr virus (EBV) is associated with HL. There is an increased risk of HL in patients with a history of mononucleosis,5,6 and EBV genomic elements are found in many cases of HL.7 The epidemiologic finding continues in age groups 40–54, but not in older age groups; however, EBV is found in HL cells throughout all age groups.8 With the obvious immunologic reaction that occurs against the malignant cell, combined with the senescence of the immune system, the increased incidence with increasing age may be due to decreased immune surveillance, although there is no experimental evidence to support this theory. In the older age group, men far out number women, while women are slightly more frequent in the lower age groups.

Hodgkin lymphoma in the elderly

1075

Clustering of HL, suggesting that the disease might be contagious, has now been discarded as a concern.9 Biology of HL The cellular origin of the Reed-Sternberg (RS) cell characteristic of HL remains unclear; however, most cases likely arise from germinal center B cells. It may be that the cell of origin is different in different types of HL. T- and B-cell gene rearrangements are occasionally found, but their significance has been hard to interpret.10–17 Many times, the immunoglobulin heavy-chain gene is rearranged in RS cells. It was found to be polyclonal in four patients with lymphocyte-predominant disease,18 monoclonal in some, and polyclonal in other patients with nodular sclerosis and mixed cellularity disease.19 RS cells from 12 patients with nodular sclerosis and mixed cellularity HL showed identical immunoglobulin heavy-chain gene rearrangements in 3, unrelated rearrangements in 6, and both identical and unrelated rearrangements in 3, suggesting that these cells can be derived from B-cell precursors or from memory cells.20 The polyclonal nature of HLderived RS cells could have several explanations, as outlined by Hummel et al,20 including continued recruitment of new cells, genetic instability, immune system abnormalities that prevent the destruction of abnormal cells, and viral or chemical transformation. B-cell-specific J-chain rearrangements have been limited to the nodular variant of lymphocyte-predominant HL, which is now largely

Figure 47.1 Possible pathogenetic scheme for Hodgkin lymphoma. Adapted from Haluska et al.138

Comprehensive Geriatric Oncology

1076

accepted as a separate B-cell malignancy.21 RS cells from this entity uniformly express CD20.22 Light-chain genes may also be rearranged.14 RS-cell-rich cell populations also have been found to be negative for immunoglobulin gene rearrangements, which appears to be a true heterogeneity, rather than a technical problem.16 There have been inconsistent reports of rearrangements at the sites of oncogenes, especially BCL2, but also c-MYC,28 RAS,28,29 and p53.30,31 Cell surface marker studies have been somewhat confusing, since uniform expression of markers has not been generally found, even within subclasses of HL. Some consistency has been seen. B-cell markers (CD19, CD20, CD138, and others) are found on almost all RS cells.32 T-cell markers (CD1, CD2, CD3, and CD4) have been found frequently on RS cells.17 It had been hoped that the Leu-M1 antibody, which recognizes CD15, would be a sensitive and specific marker for RS cells. RS cells are generally positive for CD15,33,34 suggesting a monocyte origin for them. T-cell non-Hodgkin lymphomas have now been commonly identified as expressing CD15.35–37 The Ki-1 antibody, raised against an RS cell line, and recognizing the CD30 antigen, again was thought to be specific for HL,38 but has now been found on peripheral T-cell lymphomas,39 lymphomatoid papulosis,39–41 and anaplastic large cell lymphoma,39,42–44 which can be difficult to distinguish from HL. Progressive growth of RS cells has been thought to be related to EBV infection in the majority of patients.8,14 Figure 47.1 represents a possible pathogenesis of HL. RS cells are nearly always aneuploid,45 and generally contain 4–8 times the normal amount of DNA.46 Chromosomal abnormalities are numerous and varied; however, gains or other abnormalities in chromosomes 1, 2, 5, 8, 11, 12, 14, and 21 are most common.11,46–50 Abnormalities involving 8q22–24, 11q23, and 14q32, which are associated with other lymphoid malignancies, have frequently been found.48–50 At present, these abnormalities have not been correlated with HL subtypes. Diagnosis of HL in the elderly Lymphadenopathy HL frequently presents with lymphadenopathy, often rubbery and fixed to underlying tissue. Because of the myriad causes of lymphadenopathy, deciding when to biopsy a lymph node can cause a considerable dilemma. The risk of a neoplastic etiology for lymphadenopathy increases progressively with age. The incidence of most viral infections leading to lymphadenopathy declines with age, and the incidence of malignancy increases. Lymph nodes greater than 2cm in diameter, progressively enlarging nodes, lymph nodes found in the absence of acute infectious symptoms, lymphadenopathy found in the presence of night sweats or weight loss, and supraclavicular lymph nodes are most likely to lead to neoplastic diagnoses.51–53 Solitary enlarged nodes, fixed or matted nodes, and supraclavicular nodes should almost always be biopsied. Inguinal lymph nodes frequently do not yield a diagnosis. Adenopathy in other areas should be sought, or, if the risk is high, multiple biopsies may be necessary. Sequential node biopsies often yield a diagnosis, when an initial biopsy is benign.54 In a study at Stanford,55 unexplained adenopathy was the presentation in 65% of patients over

Hodgkin lymphoma in the elderly

1077

the age of 60 with HL, while 29% presented with B symptoms. Diagnosis requires examination of the architecture of lymph nodes as well as the cytology. For that reason, needle biopsy is not adequate for diagnosis. HL frequently involves cervical, supraclavicular, axillary, mediastinal, hilar, splenic, para-aortic, iliac, and inguinal lymph nodes. It rarely involves Waldeyer’s ring, mesenteric, epitrochlear, or popliteal lymph nodes, suggesting that the initial site of HL is in central lymph node regions and that retrograde spread through the lymphatic system is rare. Pulmonary involvement is almost always related to hilar or mediastinal involvement, and hepatic involvement almost always related to extensive splenic involvement. Other presentations of HL While peripheral lymphadenopathy is the most common initial presentation of HL, it is certainly not the only one. Especially in older patients, unusual presentations are possible. Older patients are more likely to have abdominal masses as their only site of disease, and initial presentations in the bone marrow, spleen, or lung can be seen. B symptoms as an initial presentation are common in older patients, and somewhat less common in younger patients. In older patients, significant intercurrent illness is of major concern. In the Stanford study by Peterson et al,55 42% of patients over 60 had significant coronary artery disease, chronic obstructive pulmonary disease (COPD), diabetes mellitus, hypertension, or other illnesses that interfered with evaluation and management of the HL. Peterson et al considered 75% of older patients to have been adequately staged, and (although these have now largely been replaced by other diagnostic studies) they were able to perform staging laparotomies in 45% of patients with significant intercurrent disease. Histology of HL The diagnostic cell for HL is the Reed-Sternberg (RS) cell, which is a large binucleate cell with prominent nucleoli. Current understanding of the RS cell is that it is of pleomorphic origin, with cell surface positivity for CD30 (Ki-1 antigen), CD15 (Leu-M1 antigen), HLA-DR, and CD25 (interleukin-2 receptor).17,39,56–60 These markers are not conserved across all variants of HL or even within a single variant, possibly indicating differing etiologies of the disease. The RS cell is now considered the malignant cell in HL, despite the fact that it may make up less than 1% of the total cells in an involved node or organ. This has been a topic of debate for many years. The diagnosis of HL is still made on histologic examination of sections of lymph node tissue. While surface markings and genetic studies may serve to ‘rule in’ diagnoses other than HL, there are no unique markers for HL allowing a biochemical or cytogenetic diagnosis. Strict criteria require identification of an RS cell to make the diagnosis of HL. On occasion, the mononuclear form—the ‘Hodgkin cell’—is more prominent, or multilobed variants of the RS cell are found, and these may be used to make the diagnosis of HL. The RS cell may be present as a reactive cell in other disorders, so its presence, while considered necessary

Comprehensive Geriatric Oncology

1078

for the diagnosis of HL, is not sufficient. The neoplastic cell must be observed in the appropriate background setting.61,62 The Rye modification of the Lukes and Butler classification divides HL into four histologic categories: lymphocyte-predominant, nodular sclerosis, mixed cellularity and lymphocyte-depleted.62,63 Lymphocyte-predominant HL is characterized by an abundance of small round lymphocytes, and a small number of RS cells. The nodular variant of this is considered by many to be a follicular low-grade lymphoma, with an indolent and relapsing course. It may be difficult to distinguish from benign expansion of lymphoid follicles.64 It may be difficult to distinguish the diffuse form from well-differentiated lymphocytic lymphoma.65 Lymphocyte-depleted HL is generally distinguished by the relative paucity of reactive cells and prominence of the malignant RS cells. While different subgroups have been identified, most contain an amorphous background of fibrosis. In the differential diagnosis again are non-Hodgkin lymphomas, as well as a lymphocytedepleted form of nodular sclerosing HL. Mixed cellularity is often considered a midway point between lymphocytepredominant and lymphocyte-depleted HL, and contains a background of lymphocytes, plasma cells, eosinophils, and fibroblasts. Differentiation from a peripheral T-cell lymphoma may be difficult. Nodular sclerosis is typified by wide bands of fibrous material separating lymph nodes into nodules. Along with this, RS cells, lacunar cells, and a background of lymphocytes and other cells are found. Multiple subvariants have been identified, but it is unclear whether any prognostic significance can be attached to them.62,66,67 Distribution of HL histologies across age The distribution of histologic subclasses of HL varies with age. In general, it is thought that lymphocyte-predominant and nodular sclerosis HL are more common in younger patients, while mixed cellularity and lymphocytedepleted variants are more common in older patients. Nodular sclerosis HL is generally thought to be a disease of young women.67 According to Hellman et al,68 it is unusual in patients over the age of 50. Decreased eosinophil infiltration occurs in HL in older age groups.69 Again, this may be due to differing cellular reactions, or differing etiologies. The Finsen Institute in Copenhagen examined the distribution of histologic subtypes in 506 unselected patients with HL (about one-third of the cases of HL in Denmark from the years 1969–1983), finding that while nodular sclerosis HL was more common in younger patients, it still represented the most common subtype in patients over the age of 60.70 The frequency of lymphocyte-predominant disease remained stable, while the frequency of mixed cellularity increased with age. The notable rarity of lymphocytedepleted HL and the potential difficulty in distinguishing it from a lymphocytedepleted subvariant of nodular sclerosis HL may in part explain the discrepancy between this and other studies. Stanford University investigators found that 64% of their ‘older patients’ had nodular sclerosis subtype.71 Only 52 of 1169 patients were over the age of 60. It is possible that there was a referral bias in older patients toward healthier and lower-stage patients, who would be thought more to benefit from aggressive management. This selected population may have a higher proportion of better histologies, such as nodular sclerosis.

Hodgkin lymphoma in the elderly

1079

The Cancer and Leukemia Group B (CALGB) reported on 73 patients over the age of 60 on protocol therapy for advanced HL.55 Of these patients, 7% had nodular sclerosis HL, compared with 30% of patients under the age of 40. The lower percentage of nodular sclerosis HL in this study is explained by the selection of patients with advanced disease, unusual for nodular sclerosis HL. Our own tumor registry had similar distributions, with 64% of patients under the age of 51. Ten percent were unclassified, while 3% had lymphocyte-predominant, 67% nodular sclerosis, 15% mixed cellularity, and 5% lymphocyte-depleted. Of those aged over 50 (24 patients), 42% had nodular sclerosis, 33% mixed cellularity, and 8% lymphocyte-predominant, and 17% were unclassified (Meriter Hospital Tumor Registry, unpublished data). These studies suggest a shift from nodular sclerosis HL in younger patients to mixed cellularity and lymphocyte-depleted HL in older patients. The cause of this is unknown. The background cellularity is vital in distinguishing histologic types, such that the differences may be in the way older patients form a reaction to HL. This may be related to cellular immune senescence. It is notable that more aggressive forms of HL occur in older persons—at odds with other cancers, where often less aggressive forms predominate. The strong immune reaction in younger patients to HL and the well-defined senescence of the immune system may explain the differing histologies with advancing age, as well as the worsening stage and progno- sis. Another possible explanation of differing histologies can be derived from the bimodal age distribution of HL. The etiology may be different in older people, leading to differing cellular reactions and histologies. Immunology of HL Cellular immunity is depressed in all patients with HL, prior to commencement of treatment.72 Humoral immunity remains relatively intact. In patients with B symptoms, there is a reduction in the level of circulating T lymphocytes,73 while this is normal in patients with stage A disease. Helper:suppressor T-cell ratios remain normal in all stages of HL. There is also an abnormality in T-cell function in patients with B symptoms, while this is normal in patients without these.74 Increased T-cell susceptibility to suppression by normal monocyte interactions75 and suppressor T cells76 occurs in all stages of HL. Interleukin-2 production is also decreased.77 It is unknown whether the immune suppression is a result of the disease or whether the immune suppression is a predecessor of the HL. Older patients with HL are frequently anergic, as are younger patients with stage B disease.78 These immune defects are the cause of the increase susceptibility to opportunistic organisms such as tuberculosis and fungal infections.

Table 47.1 Staging classification of Hodgkin lymphoma Stage

Definition

I

Involvement of a single lymph node group (or spleen) on one side of the diaphragm

Comprehensive Geriatric Oncology

1080

II

Involvement of more than one lymph node group (or spleen) on one side of the diaphragm

III

Involvement of lymph node groups (or spleen) on both sides of the diaphragm

IV

Involvement of parenchymal organs (bone marrow, liver, lung, bone)

Subset E

Involvement of a single extranodal site (the differentiation between stage E and stage IV can be difficult)

Subset A

No constitutional symptoms

Subset B

Constitutional symptoms (drenching night sweats, fever >38°C, weight loss >10% of body weight; some investigators consider pruritus a symptom)

Stage III disease can be divided into subets 1 (involvement of only splenic hilar, celiac or portal nodes) and 2 (involvement of para-aortic, iliac, or mesenteric nodes)

Staging of HL HL is staged according to the Ann Arbor classification,79 developed in 1971 (Table 47.1). This system has both prognostic80 and therapeutic value. Precise staging of HL has an importance that is not seen in other lymphomas. Since HL spreads in an orderly manner (as opposed to many non-Hodgkin lymphomas), precise staging allows careful tailoring of therapy to a particular pattern of involvement. Treatment of stage III HL by radiation therapy is only possible because of precise staging, and because of the orderly manner of progression. Also, precise staging has allowed the comparison of results between studies to be much more reliable in this heavily investigated model disease. Extranodal HL comes in two forms. First is direct extension of disease from a nodal site. This is probably similar in prognosis and progression to nodal disease. Second is true non-contiguous extranodal disease. True extranodal disease represents a poorer prognosis than local extension from a nodal site into a single extranodal site.81 It is sometimes difficult to distinguish extranodal disease (what might be staged IIE or IIIE) from stage IV disease. There can be marked disagreement among experienced clinicians given identical scenarios as to what is E disease and what is stage IV disease.82 This is of significant import for therapy, since much more intensive therapy is needed for stage IV disease, at the expense of side-effects. Stages are subclassified A or B. The stage is subclass B if the patient has one or more of the following: unexplained weight loss of more than 10% of body weight over the last 6 months, unexplained fever of above 38°C, or drenching night sweats. The stage is subclass A if these are absent. Pruritus has been considered by some as a B symptom. In the Ann Arbor staging system, it is not considered a B symptom; however, recurrent generalized pruritus that ebbs and flows with the disease may be considered a B symptom. It is important to note whether a given stage is based on pathologic or clinical information. Enlarged lymph nodes are assumed to be involved, but if therapeutic options would change, they should be biopsied. The spleen is often the first site of involvement in the abdomen of HL arising above the diaphragm. Despite this, a homogenous, enlarged

Hodgkin lymphoma in the elderly

1081

spleen on computed tomography (CT) scan is often negative for involvement if there is no other evidence of disease below the diaphragm. Basic staging procedures A suggested plan for staging HL is shown in Table 47.2. History, in addition to looking for B symptoms, should concern unusual extranodal sites such as bone or gastrointestinal tract. Physical examination should include an assessment of Waldeyer’s ring and skin, as well as nodal sites, liver and spleen. Evaluation of thoracic disease is often accomplished with only a chest X-ray. If no abnormalities are seen, it is likely that the chest is grossly negative. If mediastinal disease obscures pulmonary parenchyma or if treatment will be altered by minimal findings in the chest, a CT scan of the chest is necessary.

Table 47.2 Suggested staging plan for Hodgkin lymphoma 1. History, with emphasis on B symptoms: weight loss, fever, and sweats 2. Physical examination, with emphasis on nodal areas, liver, spleen, and skin 3. Laboratory studies, including complete blood court, differential, platelet count, and erthrocyte sedimentation rate, creatinine, liver function studies, albumin, and total protein 4. Radiologic studies to include chest X-ray, with chest computed tomography (CT) scan if any abnormality, CT of abdomen and pelvis, lymphangiogram (bipedal), and consideration of galllium-67 scan 5. Percutaneous bone marrow biopsy, bilateral 6. Percutaneous or laparoscopic liver biopsy 7. In select patients, exploratory laparotomy with splenectomy, wedge liver biopsy, and sampling of nodes from para-aortic, mesenteric, portal, and splenic hilar nodes

Equivocal cases may benefit from gallium-67 scanning.83,84 Complete evaluation of abdominal disease requires at least CT of the abdomen to evaluate the upper abdomen and lymphangiography to evaluate the lower abdomen and pelvis. More recently, positron emission tomography (PET) scans have been used to stage HL and other lymphomas, with significant success in predicting active disease, and risk of relapse after treatment. One study showed no relapses in patients with residual masses and negative PET scan.85 Another study showed a relapse rate of 100% in patients with residual masses and positive PET scans, and a 26% relapse rate in patients with residual masses and negative PET scans.86 Where available, PET scanning may be routinely indicated to investigate abnormalities on other imaging studies. Staging laparotomy In the past, staging laparotomy was almost universally used in the staging of HL, including many patients who were already known to be stage IV. Staging laparotomy has

Comprehensive Geriatric Oncology

1082

been shown to upstage about 35% of patients and downstage about 15%.87 As the patterns of progression and treatment have become better understood, staging laparotomy has used less often. There are several advantages to staging laparotomy: accurate mapping of lymph node involvement can guide radiation fields, or convert recommended treatment to chemotherapy or combined modality; downstaging of patients with intraabdominal node enlargement can occur; the spleen is removed (which decreases side-effects of radiation to the left kidney and the bowel); and, for research protocols, it is assured that patients are assigned to the appropriate stage groups for more precise evaluation of treatment efficacy. However, morbidity and mortality are of significant concern, especially in debilitated patients. Recent improvements in risk assessment and treatment have obviated the need for laparotomy in many cases. The use of erythrocyte sedimentation rate and C-reactive protein (CRP) to estimate risk of abdominal disease is now widely used. Gallium-67 and PET scans provide staging information that in most cases eliminates the need for surgical staging. Treatment protocols with short-course chemotherapy, followed by consolidative radiation, can cure minimal disease in the abdomen. It should be noted that older age groups are at a higher risk of abdominal disease (see below). The Stanford study55 had 5 of 13 older patients with ‘early-stage’ HL, not staged by laparotomy, who died of progressive HL. Staging laparotomy has allowed the subclassification of stage III abdominal disease. Stage III 1A is disease limited to the upper abdomen, the spleen, as well as nodes in the celiac, splenic and hepatic portal areas, while stage III 2A is disease that has progressed to para-aortic, iliac, or mesenteric nodes. When radiation is used as the sole treat-ment, relapse-free survival is much better in patients with III 1A disease than III 2A disease, whereas this difference disappears when chemotherapy is used.88 Thus, to treat stage III disease with radiation only requires staging by laparotomy, unless more extensive radiation techniques, such as prophylactic hepatic irradiation, are used. Alterations in the elderly Older patients have a higher likelihood of more advanced HL. The Finsen Institute study70 had stage distributions as follows: for age less than 41: stage I, 19%; stage II, 35%; stage III, 28%; stage IV 17%; for age greater than 60: stage I, 22%; stage II, 28%; stage III, 29%, stage IV, 21%. While these differences certainly would not achieve statistical significance, these distributions were noted with 60% of younger patients being staged with laparotomy, while only 18% of older patients were staged with laparotomy. Also, B symptoms were found in 54% of older patients, and only 37% of younger patients. There was a trend towards more extensive peripheral nodal and intrathoracic tumor burdens in younger patients and more extensive abdominal tumor burdens in older patients. While this would be expected with the differences in histologic distribution and the predilection of nodular sclerosis HL for the mediastinum, this finding was actually independent of histologic subtype. Lokich et al89 found similar alterations in distribution, with more peripheral adenopathy in younger patients and more abdominal disease in older patients, as well as 25% B symptoms in older patients and only 2% in younger patients.

Hodgkin lymphoma in the elderly

1083

Treatment of HL Treatment based on stage The treatment of HL has become better defined by clinical trials. Early-stage disease (IA or IB, or IIA, especially when staged by laparotomy) is highly curable with appropriate fields of radiation. Experience with mantle and para-aortic field irradiation at the Harvard Joint Center90 and Stanford91 shows an 85–95% 5-year disease-free survival rate with radiation therapy alone, and no improvement with the addition of chemotherapy, in the absence of a large mediastinal mass. The number of involved sites does not appear to have a prognostic significance in stage II disease. For stage IA disease, surgically staged, mantle and para-aortic fields can be used. The mantle field includes cervical, supraclavicular, infraclavicular, axillary, mediastinal, and pulmonary hilar nodes. Some evidence suggests that, with adequate surgical staging and exceptionally good risk factors, a mantle field only can be used. Doses of radiation usually range form 3500 to 4400cGy. The risks of cardiac and pulmonary complications are small with adequate blocking techniques, if a large mediastinal mass is not present.92,93 There is a somewhat higher relapse rate in pelvic nodes with mixed cellularity histology (11%) than with nodular sclerosis or lymphocyte-predominant disease (5%).94,95 In clinically staged IA patients, the use of subtotal lymphoid irradiation is feasible; it must include the spleen. Older patients, with greater risk of intraabdominal disease, may be less desirable candidates for this approach, but it can be considered when the risks of laparotomy and of chemotherapy appear to be excessive. Combined-modality therapy reduces the risk of relapse, but has not been shown to improve survival in early-stage patients.96,97 Stage IB disease should be treated with radiation therapy as a single modality only if the patient has been surgically staged. Chemotherapy, either as a single modality or as a short course with radiation, should be used for clinically staged patients.98,99 Stage IIB disease is often treated with short-course chemotherapy and radiation. Surgically staged IIB patients are curable with radiation, and may be cured with salvage chemotherapy if relapse occurs. Stage I and IIA disease below the diaphragm is uncommon, and therefore more difficult to manage precisely. Stage IA disease appears to be reasonably managed by inverted Y treatment, while stage IIA probably requires total lymphoid irradiation (complete inverted Y and upper mantle radiation).100 Stage IIIA disease is usually treated with short-course chemotherapy and radiation. Surgically staged patients with stage IIIA 1 disease, especially with fewer than five splenic nodules, may be curable with total lymphoid irradiation. Low-dose radiation therapy to the liver is an option with this treatment. A retrospective study suggests improved survival with the addition of chemotherapy, but this has not been tested in randomized trials.101 Full-course chemotherapy is recommended for stage IIIA 2 disease or bulky abdominal disease. Stage IIIB and stage IV disease is treated with full-course chemotherapy. Stage II disease with bulky mediastinal disease does poorly with radiation alone, and should be treated with combined-modality therapy.102 Controversy exists as to what constitute a bulky mediastinal mass. The most common practice is to measure the maximum diameter of the mass and the maximum diameter of the pleural cavity, and calculate the ratio. Ratios greater than 1:3 are considered bulky mediastinal disease.2,71,103

Comprehensive Geriatric Oncology

1084

Some systems use the absolute diameter of the mass, placing the cutoff at 6cm,104 10cm,105 or 5cm from the midline.106 Others use the total tumor volume.107 These systems do not take into account the amount of lung field that may be subjected to radiation, and therefore may increase risk of serious side-effects. Multiple chemotherapy programs have been studied in HL. ABVD chemotherapy (Table 47.3) is as or more effective than the MOPP/ABV hybrid, which is more effective

Table 47.3 Chemotherapy for Hodgkin lymphoma MOPP •

Mechlorethamine 6mg/m2 i.v. days 1 and 8

•

Vincristine 1.4mg/m2 i.v. days 1 and 8a

•

Procarbazine 100mg/m2 p.o. day 1–14

•

Prednisone 40mg/m2 p.o. days 1–14b

Repeat every 28 days a

Vincristine is often limited to 2 mg maximum dose

b

Prednisone was originally given on cycles 1 and 4 only

ABVD •

Doxorubicin 25mg/m2 i.v. days 1 and 15

•

Bleomycin 10 units/m2 i.v. days 1 and 15

•

Vinblastine 6mg/m2 i.v. days 1 and 15

•

Dacarbazine 375mg/m2 i.v. days 1 and 15

Repeat every 28 days BCVPP •

Carmustine (BCNU) 100mg/m2 i.v. days 1

•

Cyclophosphamide 600mg/m2 i.v. days 1

•

Vinblastine 5mg/m2 i.v. days 1

•

Procarbazine 100mg/m2 p.o. days 1–10

•

Prednisone 60mg/m2 p.o. days 1–10

Repeat every 28 days

than MOPP alone. ABVD has some disadvantages in the elderly population. First, cardiac and pulmonary reserve must be acceptable because of the significant dosages of doxorubicin and bleomycin. Second, somewhat slower recovery of the marrow, which is more common in the elderly, makes treatment every 14 days difficult. BCVPP chemotherapy has a favorable acute toxicity profile, making it desirable in the debilitated or frail elderly. Here, the higher risk of acute leukemia may be less of an issue than in younger patients. There are less aggressive chemotherapy regimens, such as VBM.108

Hodgkin lymphoma in the elderly

1085

This had a 79% complete response rate with mild toxicity. Full-course chemotherapy is generally now given for a minimum of eight cycles or four cycles past complete remission, with a maximum of twelve cycles. Complications of therapy Long-term side-effects of treatment for HL are not uncommon. Acute myeloid leukemia (AML) may occur with combined-modality therapy or with combination chemotherapy, especially when alkylating agents are used. The risk is minimal but not non-existent with radiation therapy alone. MOPP chemotherapy results in about a 3% risk of AML in the first 10 years after therapy, with a peak at 5–9 years.109–111 ABVD chemotherapy appears to cause AML in somewhat less than 1% of patients.109 BCVPP chemotherapy has a reputation for excess cases of leukemia. At 15 years, the risk of second malignancies in total is about 13%.109,110 Common sites of increased cancer risk are lung and breast, especially in those individuals with substantial radiation exposure at a young age to these organs.112–114 These complications are less likely in older patients. The combination of bleomycin chemotherapy and mantle irradiation may result in severe pulmonary toxicity.115 Hypothyroidism is a common complication of radiation therapy to the upper mantle, even when the thyroid is blocked.116 Radiation pneumonitis, pericarditis, and coronary disease may occur as complications of radiation therapy. Increasing age and prior cardiac history were the only risk factors for coronary artery disease following mantle radiation.117 Fatigue remains a common and debilitating after-effect of both HL and its treatment.118 This fatigue may persist for years after curative therapy. Comorbid conditions, such as cardiovascular disease, chronic obstructive pulmonary disease (COPD), or diabetes (each with a greater than 10% incidence in older patients with HL) lead to reduced ability to give full-dose and full-course chemotherapy.119 Palliative measures should then be considered. Recurrent disease Recurrent HL remains a disease treatable for cure if radiation therapy was the only prior treatment, with 10-year survival rates in the range of 57–80%. 120–122 Relapse after chemotherapy is occasionally treatable for cure with chemotherapy. This is rarely successfiil if relapse has occurred within 1 year of completing chemotherapy, but is more likely in patients who relapse late.123,124 For eligible patients who have been shown to have chemotherapy-responsive disease, autologous hematopoietic stem cell transplantation probably offers the best chance of long-term survival.125,126 Since this is rarely applicable to the elderly population, the goals of therapy must be changed. Palliative care with radiation therapy to symptomatic sites, weekly injections of vinblastine, or daily oral alkylating agents may be well-tolerated therapies with effective palliation. More recently, fludarabine has demonstrated effective palliation with low risk of side-effects in elderly patients.127

Comprehensive Geriatric Oncology

1086

Prognosis of HL Several reports have outlined the prognosis of older patients with HL. Guinee et al128 compared the prognosis of HL in 136 patients aged 60–79 with that of 223 patients aged 40–59. The older group experienced twice the risk of dying from HL and four times the risk of dying from other causes. Stages were similar, although increased numbers had stage I disease in the older age group. Data on the frequency of staging procedures was not given. As expected, the histologies leaned toward nodular sclerosis in the younger versus older age groups (56% versus 39%) and away from mixed cellularity in younger versus older (32% versus 50%). Complete remission rates were similar in younger and older groups (88% for younger versus 84% for older), but patients aged 70–79 had a 41% relapse rate compared with less than 20% for younger patients. Looking only at deaths from HL, 50% of older patients had died at 5 years, while only 20% of younger patients had. Patients treated on CALGB protocols for advanced HL had a significantly poorer prognosis if aged 60 or older compared with those younger than 60.129 The 5-year survival rates were 79% for ages less than 40, 63% for ages 40–59, and 31% for ages 60 and older. The median survival was 1.5 years for ages 60 and over, and had not been reached for younger patients. Stage was similar, although disease in the abdomen was more frequent in older patients. The National Cancer Data Base report indicates an overall drop in disease-specific survival with each decade above age 30, up to age 60, and above.130 In the 60 and older group, there was a 75% survival rate for stage I, 63% for stage II, 56% for stage III, and 38% for stage IV. This is a retrospective study across many institutions, and does not control for staging procedures or therapy. Age is also an adverse factor after first relapse from HL.131 The 10-year rates of freedom from second relapse were 61% for ages less than 40 and 40% for ages 40 and over. The 10-year overall survival rates were 67% and 23%, respectively, reflecting deaths from other causes. A letter by Guinee132 (referencing his earlier work128) regarding this suggested that the adverse prognosis begins at about age 60. Patients aged 60 and older who progressed during first-line therapy had a 0% 2-year survival rate with salvage therapy in a report by the German Hodgkin Lymphoma Study Group.133 Poor prognosis is related (at least in part) to difficulty in delivering adequate therapy. Forsyth et al134 found that only 3 of 14 patients over the age of 70 were able to receive a planned dose intensity of chemotherapy. Montolo et al135 found that 40% of patients aged over 60 were unable to complete chemotherapy, compared with 3% under the age of 60. Zietman et al136 studied 29 early-stage HL patients over the age of 60. They found that if these patients were able to tolerate staging and radiation therapy as would be recommended for younger patients, then their prognosis was quite good (no relapses in 14 so-managed patients). Patients managed suboptimally had 5-year survival and 5-year disease-free survival rates of only 61% and 6% respectively. Many other studies relating to the prognosis of HL have shown advancing age to be a poor prognostic factor.70,137–141

Hodgkin lymphoma in the elderly

1087

Conclusions Hodgkin lymphoma presents in the elderly with a differing distribution of histologies, and probably with a different etiology. While a viral etiology seems likely in younger patients, it is probably not the cause of HL in a significant number of older patients. Older patients are more likely to present with intraabdominal disease, and more advanced stage, despite less aggressive staging studies. Tolerance to treatment is decreased in the elderly, but the principles of treatment are the same as for younger patients, with some adjustments being needed for the frail elderly and those with certain comorbid conditions. Prognosis is worse in the elderly, probably for several reasons, including higher-risk histologies, more advanced stage, poorer tolerance to treatment, comorbid conditions, and immune senescence. References 1. MacMahon B. Epidemiologic considerations in staging of Hodgkin’s disease. Cancer 1983; 31:1854–7. 2. Young J, Percy C, Asire A et al. Surveillance, Epidemiology and End Results: Inddence and Mortality. Bethesda, MD: National Cancer Institute, 1981. 3. Correa P, O’Conor GT, Berard CW et al. International comparability and reproducibility in histologic subclassification of Hodgkin’s disease. J Natl Cancer Inst 1973; 50:1429–35. 4. MacMahon B. Epidemiology of Hodgkin’s disease. Cancer Res 1966; 26:1189–200. 5. Rosdahl N, Larsen SO, Clemmensen J. Hodgkin’s disease in patients with previous mononucleosis, 30 years experience. BMJ 1974; ii: 253–256. 6. Munoz N, Davidson RJ, Withoff B et al. Infectious mononucleosis and Hodgkin’s disease. Int J Cancer 1978; 22:10–13. 7. Nonoyama M, Kawai Y, Huang CH et al. Epstein-Barr virus DNA in Hodgkin’s disease, American Burkitt’s lymphoma and other human tumors. Cancer Res 1974; 34:1228–31. 8. Flavell KJ, Biddulph JP, Coustandinou CM et al. Variation in the frequency of Epstein-Barr virus-associated Hodgkin’s disease with age. Leukemia 2000; 14:748–53 9. Mueller NE. Hodgkin’s disease. In: Cancer Epidemiology and Prevention, 2nd edn (Schottenfeld D, Fraumeni J, eds). New York: Oxford University Press, 1992. 10. Brinker MG, Poppema S, Buys CH et al. Clonal immunoglobulin gene rearrangements in tissues involved by Hodgkin’s disease. Blood 1987; 70:186–91. 11. Griesser H, Mak TW. Immunophenotyping in Hodgkin’s disease. Hematol Oncol 1988; 6:239– 45. 12. Knowles DM, Neri A, Pelicci PG et al. Immunoglobulin and T-cell receptor B-chain gene rearrangement analysis of Hodgkin’s disease: implications for lineage rearrangement analysis of Hodgkin’s disease: implications for lineage determination and differential diagnosis. Proc Natl Acad Sci USA 1986; 83:7942–6. 13. Raghavachar A, Binder T, Bartram CR. Immunoglobulin and T-cell receptor gene rearrangements in Hodgkin’s disease. Cancer Res 1988; 48:3591–4. 14. Weiss LM, Warnke RA, Sklar J. Clonal antigen receptor gene rearrangements and Epstein-Barr viral DNA in tissues of Hodgkin’s disease. Hematol Oncol 1988; 6:233–8. 15. Cossman J, Sundeen J, Uppenkamp M et al. Rearranging antigen-receptor genes in enriched Reed-Sternberg cell fractions of Hodgkin’s disease. Hematol Oncol 1988; 6:205–11. 16. Sundeen J, Lipford E, Uppenkamp M et al. Rearranged antigen receptor genes in Hodgkin’s disease. Blood 1987; 70:96–103.

Comprehensive Geriatric Oncology

1088

17. Kadin ME Muramoto L, Said J. Expression of T-cell antigens on Reed-Sternberg cells in a subset of patients with nodular sclerosing and mixed cellularity Hodgkin’s disease. Am J Pathol 1988; 130: 345–53. 18. Delabie J, Tierens A, Wu G et al. Lymphocyte predominance Hodgkin’s disease: lineage and clonality determination using a single-cell assay. Blood 1994; 84:3291–8. 19. Kuppers R, Rajewsky K, Zhao M et al. Hodgkin disease: Hodgkin and Reed-Sternberg cells picked from histological sections show clonal immunoglobulin gene rearrangements and appear to be derived from B cells at various stages of development. Proc Natl Acad Sci USA 1994; 91:10962–6. 20. Hummel M, Ziemann K, Lammert H et al. Hodgkin’s disease with monoclonal and polyclonal populations of Reed-Sternberg cells. N Engl J Med 1995; 333:901–6. 21. Stein H, Hansmann ML, Lennert K et al. Reed-Sternberg and Hodgkin’s cells in lymphocytepredominant Hodgkin’s disease of nodular subtype contain J chain. Am J Clin Pathol 1986; 86:292–7. 22. Pinkus, G, Said J. Hodgkin’s disease, lymphocyte predominance type, nodular—further evidence of a B-cell derivation. Am J Pathol 1988; 133:211. 23. Shibata D, Hu E, Weiss LM et al. Detection of specific t(14:18) chromosomal translocations in fixed tissues. Hum Pathol 1990; 21: 199–203. 24. Said H, Sassoon A, Sintaku I et al. Absence of bcl-2 major breakpoint region and JH gene rearrangement in lymphocyte predominance Hodgkin’s disease: results of Southern blot analysis and polymerase chain reaction. Am J Pathol 1991; 138:261–4. 25. Louie DC, Kant JA, Brooks JJ, Reed JC. Absence oft(14:18) major and minor breakpoints and of bcl-2 protein overproduction in Reed-Sternberg cells of Hodgkin’s disease. Am J Pathol 1991; 139: 1231–7. 26. Athan E, Chadburn A, Knowles DM. The bcl-2 gene translocation is undetectable in Hodgkin’s disease by Southern blot hybridization and polymerase chain reaction. Am J Pathol 1992; 141: 193–201. 27. Poppema S, Kaleta J, Hepperle B. Chromosomal abnormalities in patients with Hodgkin’s disease: evidence for frequent involvement of the 14q chromosomal region but infrequent bcl-2 gene rearrangement in Reed-Sternberg cells. J Natl Cancer Inst 1992; 84: 1789. 28. Mitani S, Sugawara I, Shiku H, Mori S. Expression of c-myc oncogene product and ras family oncogene products in various human malignant lymphomas defined by immunohistochemical techniques. Cancer 1988; 62:2085–93. 29. Steenvoorden A, Janssen J, Drexler H et al. Ras mutations in Hodgkin’s disease. Leukemia 1988; 2:325–6. 30. Gupta RK, Norton AJ, Thompson IW et al. p53 expression in Reed-Sternberg cells of Hodgkin’s disease. Br J Cancer 1992; 66: 649–52. 31. Gupta RK, Patel K, Bodmer WF, Bodmer JG. Mutation of p53 in primary biopsy material and cell lines from Hodgkin disease. Proc Natl Acad Sci USA 1993; 90:2817–21. 32. Watanabe K, Yamashita Y Nakayama A et al. Varied B-cell immunophenotype of Hodgkin/Reed-Sternberg cells in classic Hodgkin’s disease. Histopathology 2000; 36:353–61. 33. Pinkus G, Thomas P, Said JW. Leu-M1—a marker for Reed Sternberg cells in Hodgkin’s disease. Am J Pathol 1985; 119:244–52. 34. Hsu G, Jaffe E. Leu Ml and peanut agglutinin stain the neoplastic cells of Hodgkin’s disease. Am J Clin Pathol 1984; 82:29. 35. Strauchen J, Breakstone B. Leu-M1 antigen: comparative expression in Hodgkin’s disease and T-cell lymphoma. Hematol Oncol 1987; 5:107. 36. Wieczorek R, Burke J, Knowles D III. Leu-M1 antigen expression in T-cell neoplasia. Am J Pathol 1985; 212:374–80. 37. Sheibani K, Battifora H, Burke J, Rappaport H. Leu-M1 antigen in human neoplasms: an immunohistologic study of 400 cases. Am J Surg Pathol 1986; 10:227–36.

Hodgkin lymphoma in the elderly

1089

38. Schwab U, Stein H, Gerdes J et al. Production of a monoclonal antibody specific for Hodgkin and Reed-Sternberg cells in Hodgkin’s disease. Am J Pathol 1985; 118:209. 39. Stein H, Mason DY, Gerdes J et al. The expression of the Hodgkin’s disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood 1985; 66: 848–58. 40. Kadin M. Histogenesis of Hodgkin’s disease: possible insights from a comparison with lymphomatoid papulosis. Hum Pathol 1987; 18: 1085–8. 41. Davis TH, Morton CC, Miller-Cassman R et al. Hodgkin’s disease, lymphomatoid papulosis, and cutaneous T-cell lymphoma derived from a common T-cell clone. N Engl J Med 1992; 326:1115–22. 42. Kadin M, Sako D, Berliner N et al. Childhood Ki-1 lymphoma presenting with skin lesions and peripheral adenopathy. Blood 1986; 68:1042–9. 43. Kadin M. Ki-1 positive anaplastic large cell lymphoma: a clinicopathologic entity? J Clin Oncol 1991; 9:533–53. 44. Greer J, Kinney M, Collins R et al. Clinical features of 31 patients with Ki-1 anaplastic large cell lymphoma. J Clin Oncol 1991; 9: 533–6. 45. Andreesen R, Oslerholz J, Lohv GW et al. A Hodgkin cell-specific antigen is expressed on a subset of auto- and alloactivated T(helper) lymphoblasts. Blood 1984; 63:1299–302. 46. Hansmann ML, Kaiserling E. The lacunar cell and its relationship to interdigitating reticulum cells. Virchows Arch 1982; 39:323–32. 47. Fisher RI, Bates SE, Bostick-Bruton F et al. Neoplastic cells obtained from Hodgkin’s disease are potent stimulators of human primary mixed lymphocyte cultures. J Immunol 130:2666–70. 48. Cabanillas F, Pathak S, Trujillo J et al. Cytogenetic features of Hodgkin’s disease suggest a possible origin from a lymphocyte. Blood 1991; 71:1615–17. 49. Tilly H, Bastard C, Delastre T et al. Cytogenetic studies in untreated Hodgkin’s disease. Blood 1991; 77:1298–304. 50. Cabanillas F. A review and interpretation of cytogenetic abnormalities identified in Hodgkin’s disease. Hematol Oncol 1988; 6: 271–4. 51. Lee Y-TN, Terry R, Lukes. Lymph node biopsy for diagnosis: a statistical study. J Surg Oncol 1980; 14:53–60. 52. Sinclair S, Beckman E, Ellman S. Biopsy of enlarged, superficial lymph nodes. JAMA 1974; 228:602–3. 53. Greenfield S, Jordan C. The clinical investigation of lymphadenopathy in primary care practice. JAMA 1978; 240: 1388–93. 54. Saltzman SL. The fate of patients with nondiagnostic lymph node biopsies. Surgery 1965; 58:659. 55. Peterson B, Pajak T, Cooper MR et al. Effect of age on therapeutic response and survival in advanced Hodgkin’s disease. Cancer Treat Rep 1982; 66:889–98. 56. Strauchen JA, Dimitriu-Bona A. Immunopathology of Hodgkin’s disease: characterization of Reed-Sternberg cells with monoclonal antibodies. Am J Pathol 1986; 123:293–300. 57. Strauchen JA, Breakstone BA. IL-2 receptor expression in human lymphoid lesions. Immunohistochemical study of 166 cases. Am J Pathol 1987; 126:506–12. 58. Angel CA, Warford A, Campbell AC et al. The immunohistology of Hodgkin’s disease ReedSternberg cells and their variants. J Pathol 1987; 153:21–30. 59. Diehl V, Pfreundschul M, Fonatsch C et al. Phenotypic and genotypic analysis of Hodgkin’s disease derived cell lines: histopathological and clinical implications. Cancer Surv 1985; 4: 399–419. 60. Hansmann ML, Radzun HJ, Nebendahl C et al. Immunoelectron-microscopic investigation of Hodgkin’s disease with monoclonal antibodies against histiocytes. Eur J Haematol 1988; 40:25–30. 61. Lukes RJ. Criteria for involvement of lymph node, bone marrow, spleen and liver in Hodgkin’s disease. Cancer Res 1971; 31: 1755–67.

Comprehensive Geriatric Oncology

1090

62. Lukes RJ, Butler JJ. The pathology and nomenclature of Hodgkin’s disease. Cancer Res 1966; 26:1063–1081. 63. Lukes RJ, Craver LF, Hall TC et al. Report of the nomenclature committee. Cancer Res 1966; 26:1311. 64. Poppema S, Kaiserling E, Lennert K. Hodgkin’s disease with lymphocyte predominance, nodular type (nodular paragranuloma) and progressively transformed germinal centers—a cytohistological study. Histopathology 1979; 3:295–308. 65. Schnitzer B. Reed-Sternberg-like cells in lymphocytic lymphoma and chronic lymphocyte leukemia. Lancet 1970; i: 1399–400. 66. Bennett MH, MacLennan, Easterling MJ et al. Analysis of histological subtypes in Hodgkin’s disease in relation to prognosis and survival. In: The Cytology of Leukaemias and Lymphomas (Quaglino D, Hayhoe FGJ, eds). New York, Raven Press, 1985:15–32. 67. Keller AR, Kaplan HS, Lukes RJ et al. Correlation of histopathology with other prognostic indicators in Hodgkin’s disease. Cancer 1968; 22:487–99. 68. Hellman S, Jaffe E, DeVita V. Hodgkin’s disease. In: Cancer: Principles and Practice of Oncology (DeVita V, Hellman S, Rosenberg S, eds). Philadelphia: Lippincott, 1989:1698–740. 69. Newell Gr, Cole SR, Miettnen OS, MacMahon B. Age differences in the histology of Hodgkin’s disease. J Natl Cancer Inst 1970; 45:311. 70. Specht L, Nissen NI. Hodgkin’s disease and age. Eur J Haematol 1989; 43:127–35. 71. Austin-Seymour M, Hoppe R, Cox R et al. Hodgkin’s disease in patients over 60 years old. Ann Intern Med 1984; 100:13–6. 72. Twomey JJ, Rice L. Impact of Hodgkin’s disease upon the immune system. Semin Oncol 1980; 7:114–25. 73. Posner MR, Reinherz EL, Breard J et al. Lymphoid subpopulations of peripheral blood and spleen in untreated Hodgkin’s disease. Cancer 1981; 48:1170–6. 74. Fisher RI, Bates SE, Bostick-Bruton F et al. Neoplastic cells obtained from Hodgkin’s disease are potent stimulators of human primary mixed lymphocyte cultures. J Immunol 1983; 130: 2666–70. 75. Fisher RI, Vanhaelen CP, Bostick F. Increased sensitivity to normal adherent suppressor cells in untreated advanced Hodgkin’s disease. Blood 1981; 57:830–5. 76. Vanhaelen CP, Fisher RI. Increased sensitivity of lymphocytes from patients with Hodgkin’s disease to concanavalin A induced suppressor cells. J Immunol 1981; 127:1216–20. 77. Ford RJ, Tsao J, Kouttab NM et al. Association of an interleukin abnormality with the T cell defect in Hodgkin’s disease. Blood 1984; 64:386–92. 78. Slivnick DJ, Ellis TM, Nawrocki JF, Fisher RI. The impact of Hodgkin’s disease on the immune system. Semin Oncol 1996; 17: 673–82. 79. Carbone PP, Kaplan HS, Musshoff K et al. Report of the Committee on Hodgkin’s Disease Staging. Cancer Res 1971; 31:1860–1. 80. Kaplan HS. Hodgkin’s Disease, 2nd edn. Cambridge, MA, Harvard University Press, 1980. 81. Musshoff K. Prognostic and therapeutic implications of staging in extranodal Hodgkin’s disease. Cancer Res 1971; 31:1814–27. 82. Connors JM, Klimo P. Is it an E lesion or stage IV? An unsettled issue in Hodgkin’s disease staging. J Clin Oncol 1984; 2:1421–3. 83. Johnston GS, Go MF, Benua RS et al. Gallium-67 citrate imaging in Hodgkin’s disease. Final report of cooperative group. J Nucl Med 1977; 18:692–8. 84. Horn NL, Ray GR, Kriss JP. Gallium-67 citrate scanning in Hodgkin’s disease and nonHodgkin’s lymphoma. Cancer 1976; 37: 250–7. 85. Mikhael NG, Timothy AR, Hain SF, O’Doherty MJ. 18-FDG-PET for the assessment of residual masses on CT following treatment of lymphomas. Ann Oncol 2000; 11(Suppl 1): 147– 50. 86. Jerusalem G, Beguin Y, Fassotte MF et al. Whole-body positron emission tomography using 18 F-fluorodeoxyglucose for posttreatment evaluation in Hodgkin’s disease and non-Hodgkin’s

Hodgkin lymphoma in the elderly

1091

lymphoma has higher diagnostic and prognostic value than classical computed tomography scan imaging. Blood 1999; 94: 429–33. 87. Taylor MA, Kaplan HS, Nelson TS. Staging laparotomy with splenectomy for Hodgkin’s disease. The Stanford experience. World J Surg 1985; 9:449–60. 88. Stein RS, Golomb HM, Wiernik PH et al. Anatomic substages of stage IIIA Hodgkin’s disease. Followup of a collaborative study. Cancer Treat Rep 1982; 66:733–41. 89. Lokich JJ, Pinkus GS, Maloney WC. Hodgkin’s disease in the elderly. Oncology 1974; 29:484– 500. 90. Goodman RL, Piro AJ, Hellman S. Can pelvic irradiation be omitted in patients with pathologic stages IA and IIA Hodgkin’s disease? Cancer 1976; 37:2834–9. 91. Hoppe RT, Coleman CN, Cox RS et al. The management of stage I-II Hodgkin’s disease with radiation alone or combined modality therapy: the Stanford experience. Blood 1982; 59:455–65. 92. Tarbell NJ, Thompson L, Mauch P. Thoracic irradiation in Hodgkin’s disease. Disease control and long-term complications. Int J Radiat Oncol Biol Phys 1990; 18:275–81. 93. Marcus KC, Svensson G, Rhodes LP et al. Mantle irradiation in the upright position. A technique to reduce the volume of lung irradiated in patients with bulky mediastinal Hodgkin’s disease. Int J Radiat Oncol Biol Phys 1992; 23:443–7. 94. Mauch PM. Controversies in the management of early stage Hodgkin’s disease. Blood 1994; 83:318–29. 95. Zanni M, Viviani S, Santoro A et al. Extended-field radiotherapy in favorable stage IA-IIA Hodgkin’s disease (prognostic role of stage). Int J Radiat Oncol Biol Phys 1994; 30:813–19. 96. Koziner B, Myers J, Cirrincione C et al. Treatment of stages I and II Hodgkin’s disease with three different therapeutic modalities. Am J Med 1986; 80:1067–78. 97. Longo DL, Glatstein E, Duffy PL et al. Radiation therapy versus combination chemotherapy in the treatment of early stage Hodgkin’s disease: seven year results of a prospective clinical trial. J Clin Oncol 1991; 9:906–17. 98. Carde P, Hagenbeek A, Hayat M et al. Clinical staging versus laparotomy and combined modality with MOPP versus ABVD in early-stage Hodgkin’s disease: the H6 twin randomized trials from the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol 1993; 11:2258–72. 99. Crnkovich MJ, Leopold K, Hoppe RT et al. Stage I to IIB Hodgkin’s disease: the combined experience at Stanford University and the Joint Center for Radiation Therapy. J Clin Oncol 1987; 5:1041–9. 100. Krikorian JG, Portlock CS, Mauch PM. Hodgkin’s disease presenting below the diaphragm: a review. J Clin Oncol 1986; 4:1551–62. 101. Marcus KC, Kalish LA, Coleman CN et al. Improved survival in patients with limited stage IIIA Hodgkin’s disease treated with combined radiation therapy and chemotherapy. J Clin Oncol 1994; 12:2567–72. 102. Behar RA, Horning SJ, Hoppe RT. Hodgkin’s disease with bulky mediastinal involvement: effective management with combined modality therapy. Int J Radiat Oncol Biol Phys 1993; 25:771–6. 103. Rappaport H. Tumors of the hematopoietic system. In: Atlas of Tumor Pathology, Sect III, fasc 8. Washington, DC: Armed Forces Institute of Pathology, 1966. 104. Bonnadonna G, Valagussa P, Santoro A. Prognosis of bulky Hodgkin’s disease treated with chemotherapy alone or combined with radiotherapy. Cancer Surv 1985; 4:437–58. 105. Sutcliffe SB, Gospodarowicz MK, Bergsagel DE et al. Prognostic groups for management of localized Hodgkin’s disease. J Clin Oncol 1985; 3:393–401. 106. Mill WB, Lee FA. Prognostic parameters in early stage Hodgkin’s disease. Int J Radiat Oncol Biol Phys 1982; 8:837–41. 107. Willet CG, Linggod RM, Leong JC et al. Stage IA to IIB mediastinal Hodgkin’s disease: three-dimensional volumetric assessment of response to treatment. J Clin Oncol 1988; 6:819– 24.

Comprehensive Geriatric Oncology

1092

108. Zinzani PL, Magagnoli M, Bendandi M et al. Efficacy of the VBM regimen in the treatment of elderly patients with Hodgkin’s disease. Haematologica 2000; 85:729–32. 109. Valagussa P, Santoro A, Fossati-Bellani F et al. Second acute leukemia and other malignancies following treatment for Hodgkin’s disease. J Clin Oncol 1986; 4:830–7. 110. Tucker MA, Coleman CN, Cox RS et al. Risk of second cancers after treatment for Hodgkin’s disease. N Eng J Med 1988; 318: 76–81. 111. van Leeuwen FE, Chorus AM, van den Belt-Dusebout AW et al. Leukemia risk following Hodgkin’s disease: relation to cumulative dose of alkylating agents, treatment with teniposide combinations, number of episodes of chemotherapy and bone marrow damage. J Clin Oncol 1994; 12:1063–73. 112. Swerdlow AJ, Douglas AJ, Hudson GV et al. Risk of second primary cancers after Hodgkin’s disease by type of treatment: analysis of 2846 patients in the British National Lymphoma Investigation. BMJ 1992; 304:1137–43. 113. Yahalom J, Petrek JA, Biddinger PW et al. Breast cancer in patients irradiated for Hodgkin’s disease: a clinical and pathologic analysis of 45 events in 37 patients. J Clin Oncol 1994; 12:312–25. 114. Hancock SL, Tucker MA, Hoppe RT. Breast cancer after treatment of Hodgkin’s disease. J Natl Cancer Inst 1993; 85:25–31. 115. Bates NP, Williams MV, Bessel EM et al. Efficacy and toxicity of vinblastine, bleomycin and methotrexate with involved-field radiotherapy in clinical stage IA and IIA Hodgkin’s disease: a British National Lymphoma Investigation pilot study. J Clin Oncol 1994; 12:288–96. 116. Schimpff SC, Diggs CJ, Wiswell JG et al. Radiation-related thyroid dysfunction: implications for the treatment of Hodgkin’s disease. Ann Intern Med 1980; 92:91–8. 117. Reinders JG, Heijmen BJ, Olofsen-van Acht MJ et al. Ischemic heart disease after mantle field irradiation for Hodgkin’s disease in long term follow-up. Radiother Oncol 1999; 51:35–42. 118. Loge JH, Abrahamsen AF, Ekeberg O, Kaasa S. Hodgkin’s disease survivors more fatigued than the general population. J Clin Oncol 1999; 17:253–61. 119. Van Spronsen DJ, Jannssen-Heijnen ML, Breed WP, Coebergh JW. Prevalence of comorbidity and its relationship to treatment among unselected patients with Hodgkin’s disease and non-Hodgkin’s lymphoma, 1993–1996. Ann Hematol 1999; 78:315–19. 120. Roach M, Brophy N, Cox R et al. Prognostic factors for patients relapsing after radiotherapy for early stage Hodgkin’s disease. J Clin Oncol 1990; 8:623–9. 121. Specht L, Horwich A, Ashley S et al. Salvage of relapse of patients with Hodgkin’s disease in clinical stages I or II who were staged with laparotomy and initially treated with radiotherapy alone: a report from the International Database on Hodgkin’s Disease. Int J Radiat Oncol Biol Phys 1994; 30:805–11. 122. Healey EA, Tarbell NJ, Kalish LA et al. Prognostic factors for patients with Hodgkin’s disease in first relapse. Cancer 1993; 71: 2613–20. 123. Harker WG, Kushlan P, Rosenberg SA. Combination chemotherapy for advanced Hodgkin’s disease after failure of MOPP: ABVD and B-CAVe. Ann Intern Med 1984; 101:440–6. 124. Canellos GP, Petroni GR, Barcos M et al. Etoposide, vinblastine and doxorubicin: an active regimen for the treatment of Hodgkin’s disease in relapse following MOPP. J Clin Oncol 1995; 13:2005–11. 125. Bierman PJ, Bagin RG, Jagannath S et al. High dose chemotherapy followed by autologous hematopoietic rescue in Hodgkin’s disease: long term follow-up in 128 patients. Ann Oncol 1993; 4:767–73. 126. Reece DE Barnett MJ, Connors JM et al. Intensive chemotherapy with cyclophosphamide, carmustine, and etoposide followed by autologous bone marrow transplantation for relapsed Hodgkin’s disease. J Clin Oncol 1991; 9:1871–9. 127. Bordonaro R, Ferrau F Guiffrida et al. Fludarabine phosphate as an active and well tolerated salvage therapy in elderly heavily pretreated Hodgkin’s disease patient. Tumori 1999; 85:288–9.

Hodgkin lymphoma in the elderly

1093

128. Guinee VF, Giacco GG, Durand M et al. The prognosis of Hodgkin’s disease in older adults. J Clin Oncol 1991; 9:947–53. 129. Mir R, Anderson J, Strauchen J et al. Hodgkin disease in patients 60 years of age and older. Cancer 1993; 71:1857–66. 130. Kennedy BJ, Fremgen AM, Menck HR. The National Cancer Data Base report on Hodgkin’s disease for 1985–89 and 1990–94. Cancer 1998; 83:1041–7. 131. Healey EA, Tarbell NJ, Kalish LA et al. Prognostic factors for patients with Hodgkin’s disease in first relapse. Cancer 1993; 71: 2613–20. 132. Guinee VF. Prognostic factors for patients with Hodgkin disease in relapse. Cancer 1993; 72:2290. 133. Josting A, Rueffer U, Franklin J et al. Prognostic factors and treatment outcome in primary progressive Hodgkin lymphoma. A report from the German Hodgkin Lymphoma Study Group. Blood 2000; 96:1280–6. 134. Forsyth PD, Bessell EM, Moloney AJ et al. Hodgkin’s disease in patients older than 70 years of age: a registry-based study. Eur J Cancer 1997; 33:1638–42. 135. Montoto S, Camos M, Lopez-Guillermo A et al. Hybrid chemotherapy consisting of cyclophosphamide, vincristine, procarbazine, prednisone, Adriamycin, bleomycin and vinblastine (C-MOPP/ABV) as first line treatment for patients with advanced Hodgkin’s disease. Cancer 2000; 88:2142–8. 136. Zietman AL, Linggod RM, Brookes AR et al. Radiation therapy in the management of early stage Hodgkin’s disease presenting later in life. Cancer 1991; 68:1869–71. 137. Enblad G, Glimelius B, Sundstrom C. Treatment outcome in Hodgkin’s disease in patients above the age of 60: a population based study. Ann Oncol 1991; 2:297–302. 138. Haluska FG, Brufsky AM, Canellos GP. The cellular biology of the Reed-Sternberg cell. Blood 1994; 84:1005–19. 139. Terblanche AP, Falkson G, Matzner L. The prognostic significance of age in patients with advanced Hodgkin’s disease. Eur J Cancer Clin Oncol 1988; 24:1805–9. 140. Davis S, Dahlberg S, Myers MH et al. Hodgkin’s disease in the United States: a comparison of patients characteristics and survival in the Centralized Cancer Patient Data System and the Surveillance, Epidemiology, and End Results Program. J Natl Cancer Inst 1987; 78:471–8. 141. Walker A, Schoenfild ER, Lowman JT et al. Survival of the older patient compared with the younger patient with Hodgkin’s disease. Cancer 1990; 65:1635–40.

48 Non-Hodgkin lymphomas Stuart Bloom, Bruce Peterson Introduction The heterogeneous group of disorders known as the non-Hodgkin lymphomas (NHL) are predominantly diseases of older individuals. With the continued growth in the population over the age of 65 and the increasing incidence of NHL, this group of diseases will likely constitute a mounting clinical challenge. In recent years, much has been learned regarding the biology, clinical behavior, and therapy of these disorders. However, owing to the lack of clinical trial data in uniquely older populations, many questions remain concerning the management of the older lymphoma patient. Epidemiology According to the US National Cancer Data Base, the median age at diagnosis of NHL in aggregate is 65, with 61% of new cases occurring in patients over 60, and 37% in patients over the age of 70.1 From 1973 to 1996, the incidence has increased in patients over 65 by 79%, with a current annual rate of 75.5 per 100 000 people in this age group (Figure 48.1).2 The incidence increases as

Figure 48.1 Non-Hodgkin lymphoma: SEER incidence by age, 1973–1975

Non-Hodgkin lymphomas

1095

(triangles, dashed line) versus 1994– 1996 (circles, solid line); all races; males. people age, to a high of 100 per 100000 between the ages of 80 and 84.2 Given current population trends, it has been estimated that the number of patients with NHL over the age of 65 will double by the year 2025.3 Over the past two decades, there has been a parallel increase in lymphoma-related mortality in patients over the age of 65, with 43.6 deaths per 100000 reported in the US National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Cancer Statistics Review 1993–1997.2 Biology of NHL As a result of ongoing refmements in genetic, molecular, and immunologic techniques, there has been an explosion of new information regarding the pathophysiology of NHL. With this improved understanding and utilization of all relevant types of information have come more accurate definitions of distinct subtypes of NHL. The Revised European American Classification of Lymphoid Neoplasms (REAL) system4 and its subsequent revision by the World Health Organization (WHO)5–7 integrate multiple features of unique individual entities to provide more precise diagnoses. This new understanding of NHL biology has resulted not only in improved reliability of diagnosis and the elucidation of new clinical entities, but also in the creation and implementation of novel therapeutic strategies. These include monoclonal antibodies directed against unique malignant cell surface antigens,8,9 idiotype-specific lymphoma vaccines,10,11 and gene therapy,12 with numerous other new biologic agents in various states of research and development.13,14 Although primarily diseases of older patients, there are some obvious differences by age in histologic subtypes of NHL.15–17 For example, Burkitt lymphoma and precursor Blymphoblastic lymphoma are primarily diseases of children and young adults, whereas small lymphocytic and follicular lymphomas occur more frequently in elderly patients. Yet, despite the heterogeneity of NHL, there do not appear to be important age-related features in the biology of specific subtypes themselves.18 Unlike Hodgkin lymphoma, where elderly patients tend to

Table 48.1 Clinical characteristics of NHL patients aged 60 and younger and aged over 60, respectively21 <60 years (%)

>60 years (%)

Advanced stage (III/IV)

64

68

Elevated serum lactate dehydrogenase

41

39

Non-ambulatory performance status (2–4)

19

19

More than one extranodal disease site

30

30

Comprehensive Geriatric Oncology

1096

demonstrate more aggressive disease,19,20 the percentage of NHL patients who present with extensive disease (as measured by serum lactate dehydrogenase (LDH), performance status, advanced stage, or extranodal disease) is approximately the same in those both above and below the age of 6021 (Table 48.1). Etiology of NHL The strongest known risk factors for NHL are states associated with immunosuppression, which are thought to result in aberrant regulation of the immune system in combination with continuous stimulation from a variety of antigens.22,23 The incidence of NHL is increased in patients with a prior history of organ transplantation,22,24 human immunodeficiency virus (HIV) infection,25 and autoimmune disorders.26 Many lymphomas in these situations are associated with Epstein-Barr virus (EBV) infection,27 where it is postulated that the latent membrane protein 1 (LMP1) of EBV-infected cells results in prolonged cytokine stimulation and eventual malignant transformation.28 Similarly, in lymphomas of mucosaassociated lymphoid tissue (MALT), chronic antigenic stimulation by Helicobacter pylori infection, myoepithelial sialadenitis, and Hashimoto’s thyroiditis result in the genesis of malignant lymphoid tissue in, respectively, the stomach, salivary gland, and thyroid.29 Non-immunologic etiologies implicated in the pathogenesis of NHL include pesticides,30 chemical solvents,31 and radiation exposure.32 While it is known that immune function tends to decline as humans age,33 it is unsettled whether this association can account for the increased incidence of NHL in the elderly. Recent epidemiologic studies in persons over the age of 65 indicate that a diet high in meat and animal fat is associated with an increased risk of NHL, while fruit and vegetable consumption may decrease risk.34,35 Prior history of blood transfusion has also been reported as an association with NHL in the elderly.35 Although these studies are interesting, they await corroboration by other investigations, as well as further elucidation of the mechanism of pathogenesis. Classification of NHL The REAL classification was introduced to categorize lymphoma entities by utilizing all available pertinent morphologic, immunologic and genetic information.4,6 Prior to this, the standard classification in use was the Working Formulation, which divided lymphomas into subtypes based on their expected clinical behavior.36 At the time of its publication, the REAL classification was felt to be superior to previous classification systems because it combined the new understanding of the biology of lymphoma with the practical consideration of clinical behavior.37 Previously unclassified yet clinically relevant subtypes of NHL, such as mantle cell lymphoma and MALT lymphoma, were included. While there was early criticism that the REAL classification lacked clinical relevance,38 this new system has been widely accepted. It improves diagnostic accuracy and has clinical utility.39,40 A large international retrospective evaluation found the new

Non-Hodgkin lymphomas

1097

classification system to be reliable and valid, as well as providing valuable prognostic and clinical information.39 An updated version of the REAL classification was formulated by an international committee of hematolo- gists and pathologists on behalf of the WHO.5,7 The WHO

Table 48.2 Non-Hodgkin lymphomos most commonly presenting in older patients (WHO classification5,7) B-cell neoplasms Precursor B-cell neoplasm • Precursor B-lymphoblastic leukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia) Mature peripheral B-cell neoplasms • B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) • Lymphoplasmacytic lymphoma (LPL) • Splenic marginal zone B-cell lymphoma (with or without villous lymphocytes) • Extranodal marginal zone B-cell lymphoma of MALT type • Nodal marginal zone B-cell lymphoma (with or without monocytoid B cells) • Follicular lymphoma (FL) • Mantle cell lymphoma (MCL) • Diffuse large B-cell lymphoma (DLCL) • Burkitt lymphoma/Burkitt cell leukemia T-cell and NK-cell neoplasms Mature (peripheral) T-cell neoplasms • Anaplastic large cell lymphoma (ALCL), T/null cell, primary cutaneous type • Peripheral T-cell lymphoma, not otherwise characterized • Anaplastic large cell lymphomas (ALCL), T/null cell, primary systemic type

classification incorporates several changes to the REAL classification. These include changes in the division of disease categories as well as the nomenclature of some of the entities. An exhaustive review of all subtypes of NHL is beyond the scope of this chapter. What follows is a description of the clinical entities that make up the NHL that most commonly present in older patients (Table 48.2), with selected associated diagnostic criteria and clinical features.4,5,7 The WHO classification stratifies T- and B-cell malignancies into precursor neoplasms and mature T- and B-cell neoplasms. Mature T- and B-cell neoplasms have been informally grouped according to whether they are nodal, extranodal, or disseminated at presentation.5,7 For practical purposes, clinicians have divided these

Comprehensive Geriatric Oncology

1098

entities into indolent, aggressive, and highly aggressive NHL, based on their anticipated clinical behavior, and these clinical groupings will be used in the following discussion. Indolent lymphomas Indolent lymphomas are typically characterized by advanced disease stage at diagnosis and a slowly progressive clinical course. The life-expectancy for patients with indolent lymphoma is usually measured in years (sometimes in decades). While these diseases are sensitive to a variety of treatment modalities, there is little evidence that any therapy regularly results in cure. B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) • Working Formulation synonym: small lymphocytic, consistent with CLL. • Characteristic immunophenotype: faint surface immunoglobulin M (sIgM), CD19+, CD5+, CD23+, CD20+ (may be weak).4 • Selected clinical features: this is essentially a nodalpredominant version of CLL; patients often have associated hypogammaglobulinemia and autoimmune phenomena.41 Lymphoplasmacytic lymphoma (LPL) • Working Formulation synonym: small lymphocytic, plasmacytoid. • Characteristic immunophenotype: cytoplasmic IgM+ and sIgM+, CD19+, CD20+, CD22+, CD5−, CD23–. • Selected clinical features: patients often present with hyperviscosity due to monoclonal IgM serum paraprotein, and may have a more aggressive clinical course than CLL/SLL.42 Extranodal marginal zone B-cell lymphoma of MALT type Splenic marginal zone B-cell lymphoma (with or without villous lymphocytes) Nodal marginal zone B-cell lymphoma (with or without monocytoid B cells) • Working Formulation synonyms: none. • Characteristic immunophenotype: sIg+, CD19+, CD20+, CD22+, CD5−. • Selected clinical features:

Non-Hodgkin lymphomas

1099

– Extranodal: lymphomas of mucosa-associated lymphoid tissue most commonly present in the stomach, as well as the thyroid and salivary glands, and may have an associated nodal component.29 – Splenic: patients usually present with splenomegaly, but lymphadenopathy is uncommon. The WHO recognizes this disease as separate from both MALT lymphoma and extranodal marginal zone lymphoma.5,7 – Nodal: this rare entity often has a prominent monocytoid B-cell component.43,44 Follicular lymphoma (FL), grades I and II • Working Formulation synonyms: follicular, predominantly small cleaved, and follicular, mixed small cleaved and large cell. • Cytogenetics: t(14; 18) is present in 95% of cases. This cytogenetic rearrangement joins the BCL2 gene to a locus within the immunoglobulin heavy-chain gene. The BCL2 gene acts to prevent B-cell apoptosis.45 As a result of the t(14; 18) translocation, the BCL2 gene is overexpressed, thereby preventing programmed cell death in malignant lymphocytes.46 • Characteristic immunophenotype: sIg+, CD19+, CD20+, CD22+, CD5−. • Selected clinical features: FL comprise 67% of indolent lymphomas.1 Grading FL may be important to discriminate the more aggressive grade III from the more indolent grades I and II. There is a consensus that the difference in the natural history of grades I and II may not be significant enough to warrant continued separation of these entities.5,7 However, in an effort to avoid confusion, the three-tiered grading system was retained by the WHO.

Mantle cell lymphoma (MCL) Mantle cell lymphoma is listed as a separate category because its clinical behavior does not allow it to fit neatly into either the indolent or aggressive classification. The median survival is 3–4 years with conventional treatment modalities.47 • Working Formulation synonyms: small cleaved cell, diffuse or nodular; rarely diffuse mixed or large cleaved cell. • Cytogenetics: t(11; 14) in the majority of cases. This rearrangement juxtaposes the BCL1 gene within a locus of the immunoglobulin heavy-chain gene. This results in overexpression of cyclin D1, and subse- quent dysregulation of the cell cycle.48 • Characteristic immunophenotype: sIgM+, CD19+, CD20+, CD22+, CD5+, CD23−. • Selected clinical features: with a more aggressive clinical course than the indolent lymphomas, this has the poorest 5-year overall survival rate (27%) of all the lymphomas studied by the NHL Classification Project.39

Comprehensive Geriatric Oncology

1100

Aggressive lymphomas Aggressive lymphomas are characterized by a rapid clinical course that will usually result in death in a matter of months in the absence of therapy.37 Yet many of these entities are far more responsive to treatment than the indolent lymphomas, and a substantial proportion of patients are cured with standard chemotherapy. Diffuse large B-cell lymphoma (DLCL) • Working Formulation synonyms: large cell cleaved, non-cleaved, or immunoblastic. • Cytogenetics: t(14; 18) is present in 30% of cases. • Characteristic immunophenotype: CD19+, CD20+, CD22+, CD5/sIg/CD45/CD10 variable. • Selected clinical features: these entities constitute 30–40% of adult lymphomas.4 While several morphologic variants and subtypes are known in DLCL, the WHO did not recommend subclassification or separate categories for the clinical subtypes of DLCL. Anaplastic large cell lymphoma (ALCL) • Working Formulation synonym: not listed (diffuse large cell immunoblastic). • Cytogenetics: t(2; 5) is present in 50% of cases. This translocation fuses the nucleophosmin (NPM) gene on chromosome 5 to the anaplastic lymphoma kinase gene (ALK) on chromosome 2.49 • Characteristic immunophenotype: CD30+, others variable. • Selected clinical features: the clinical behavior and therapeutic response of ALCL are similar to those of the other aggressive lymphomas. Furthermore, the WHO felt that ALCL should be recognized as distinct from primary cutaneous ALCL, though a gold standard diagnostic test to discriminate between the two does not yet exist.5,7 Follicular lymphoma (FL), grade III • Working formulation synonym: follicular, predominantly large cell. • Cytogenetics: t(14; 18) is present in 70–95% of cases, which is slightly lower than in grade I and II FL. • Characteristic immunophenotype: sIg+, CD19+, CD20+, CD22+, CD5−. • Selected clinical features: more clinically aggressive than other follicular subtypes, these are treated as aggressive lymphomas (see the discussion of grades I and II FL above).

Non-Hodgkin lymphomas

1101

Peripheral T-cell lymphoma, not otherwise characterized Peripheral T-cell lymphoma • Working Formulation synonym: diffuse small cleaved cell, diffuse mixed small and large cell, large cell immunoblastic. • Genetics: human T-cell leukemia virus (human T-lymphotropic virus I, HTLV-I) genome may be present, and T-cell receptor (TCR) gene rearrangements are seen in most, although specific cytogenetic features are not defined.5 • Characteristic immunophenotype: T-cell antigens are variably expressed. • Selected clinical features: the WHO committee stated that the individual clinical syndromes associated with these disorders (e.g. mycosis fungoides and primary cutaneous T-cell lymphoma) are central to the definition of these neoplasms.5,7

Very aggressive lymphomas This group of lymphomas is defined as those that are fatal in a matter of weeks or months in the absence of therapy.21 In most series, they account for less than 10% of all nonindolent lymphomas in the elderly.50–56 Burkitt lymphoma • Working Formulation synonym: small non-cleaved cell, Burkitt type. • Cytogenetics: t(8;14) is present in most cases. This results in fusion of the c-MYC gene on chromosome 8 to the immunoglobulin heavy-chain region on chromosome 14, with subsequent malignant transformation.57 Less common variants include translocation of c-MYC to the light-chain loci on chromosome 2 (t(2; 8)) or chromosome 22 (t(8; 22)). • Characteristic immunophenotype: sIgM+, CD19+, CD20+, CD22+, CD10+, CD5−, CD23−. • Selected clinical features: although this is primarily seen in the pediatric population, it may also be seen in elderly patients. It can be associated with EBV infection. Burkittlike lymphoma, a provisional entity in the REAL classification, is included in the WHO classification as a variant of Burkitt lymphoma. Precursor B-lymphoblastic leukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia) • Working Formulation synonym: lymphoblastic. • Cytogenetics: variable. • Characteristic immunophenotype: terminal deoxynucleotidyl transferase (TdT)+, sIg−, CD10+ (most) CD19+, CD22+, CD34+ (most).

Comprehensive Geriatric Oncology

1102

• Selected clinical features: this is listed under the precursor B-cell neoplasms in the WHO classification; precursor B-cell lymphoblastic lymphoma is felt to be biologically indistinct from acute lymphoblastic leukemia.5,7

Evaluation of the patient with NHL The current classification by the WHO arose because prior classification systems that were based on histologic and cytologic characteristics were limited and often inaccurate.4 As the significance of immunologic, molecular, and cytogenetic mechanisms that underlie the pathogenesis of lymphoma became known, it was clear there was a correlation between this new information, standard morphology, and clinical behavior.37 The goal of the evaluation and staging of the elderly patient with NHL

Table 48.3 Ann Arbor staging system for NHL Stage

Description

Stage I Involvement of a single lymph node region (I) or a single extralymphatic organ or site (IE) Stage II

Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic organ or site (IIE)

Stage III

Involvement of lymph node regions on both sides of the diaphragm (III) or localized involvement of an extralymphatic organ or site (IIIE) or spleen (IIIS) or both (IIISE)

Stage IV

Diffuse or disseminated involvement of one or more extralymphatic organs, with or without associated lymph node involvement

Identification of the presence or absence of symptoms should be noted with each stage designation: A, asymptomatic; B, fever, sweats, weight loss >10% of body weight

should be to gather all relevant information so that appropriate decisions can be made regarding management.58 An excisional biopsy is the preferred technique for establishing the diagnosis, since this gives essential information regarding lymph node architecture—an important element in classification—and adequate tissue for all of the relevant ancillary studies. Needle core biopsy and fine-needle aspiration techniques are of limited benefit, and should be reserved for assessment of other sites once a diagnosis has already been made.59 The histologic grade of the tumor, related to the proportion of centroblasts or large cells in the biopsy, should be described, although this is an imprecise exercise. Material should also be available for morphologic, immunophenotypic (flow cytometry),60,61 molecular,46,61 and cytogenetic studies.58 Although patients with NHL are staged according to the Ann Arbor classification (Table 48.3), it is felt that this schema is less accurate in determining prognosis than it is for Hodgkin lymphoma, which more predictably spreads via contiguous lymph node groups. However, once the diagnosis has been made, standard staging and evaluation procedures include:62

Non-Hodgkin lymphomas

1103

• a careful history, with a focus on the presence or absence of B symptoms; • a detailed physical examination, with scrupulous attention being paid to masses and all node-bearing areas, as well as the liver and spleen; • a thorough past medical history, with assessment of all current comorbid conditions, as well as performance status—this is particularly important in the elderly patient, where the presence or absence of coincident illness may be predictive of subsequent therapeutic response (see the section below on prognostic factors);21 • laboratory analysis, including complete blood count, uric acid, and renal and liver function tests: LDH, serum protein electrophoresis (SPEP), and β2-microglobulin, if elevated at the time of diagnosis, provide valuable information, and can be used as markers of therapeutic response; • radiography, including compated tomography (CT) scans of the chest, abdomen, and pelvis, with a gallium scan reserved for questionable lesions; [19F]fluorodeoxyglucose positron emission tomography (FDG-PET) scanning has also been suggested as being useful in the staging and evaluation of residual disease;63,64 • bone marrow aspirate and bilateral biopsies.

Management of NHL As is true of many other malignancies, elderly patients with NHL have been historically underrepresented in clinical trials relative to the incidence in the general population.65–68 For example, only 14% of the 1380 patients enrolled on Southwest Oncology Group (SWOG) NHL protocols between 1993 and 1996 were over the age of 65,69 even though age 65 is the mean at diagnosis for NHL according to the National Cancer Data Base.1 Therefore, many current therapies are based upon data derived from studies that have either excluded geriatric patients or used limited numbers of them. Because of this bias excluding older patients, many of the conclusions or recommendations about managing NHL in the older population must be extrapolated from studies on younger patients. Management of indolent NHL Prognostic factors Although many patients with indolent NHL enjoy prolonged survival, there are clearly subsets of patients who do not. Prognostic factors can be used to identify which patients are at risk for a worse outcome. However, while they may give the patient and physician valuable information, their role in the decision to initiate therapy or in what treatment to use is limited. Age has long been acknowledged as an important prognostic factor.69–71 The International Non-Hodgkin’s Lymphoma Prognostic Factors Project identified five factors that correlated with worse outcome in diffuse aggressive NHL: age greater than 60, poor performance status, advanced disease stage, more than one site of extra-nodal involvement, and elevated LDH21 (for more details, see the discussion of prognostic factors in aggressive NHL below). The value of these five factors has also been assessed

Comprehensive Geriatric Oncology

1104

in indolent lymphomas. Lopez-Guillermo et al72 applied the International Prognostic Index (IPI; see below) to 125 patients with SLL or with grade I or II FL. The IPI significantly correlated with outcome, with 10-year survival rates of 73.6% for low-risk patients (0–1 risk factor), 50% for intermediate-risk patients (2–3 risk factors), and 0% for high-risk patients (4–5 risk factors). Despite this correlation, it has been suggested that the IPI has does not have good discriminating power, since the great majority of patients in this study were assigned to good-prognosis groups.73,74 A number of pathologic features have been reported to have prognostic significance in patients with indolent NHL. In an analysis of a large number of cases of FL, the presence of a diffuse element in the lymph node biopsy specimen was found to be associated with a worse overall survival.75 This has been corroborated by one study,76 but not by others.77,78 The proportion or numbers of centroblasts in the biopsy specimen enables the grade of FL to be assigned, although whether it is clinically relevant to distinguish between grade I and II FL is still unclear.5,7 Other pathologic features that have been associated with poorer prognosis include expression of Ki-67 and a high percentage of cells in S phase.79 Background Any discussion of the therapy for the indolent lymphomas must begin with a thorough understanding of their unique natural history. These neoplasms generally behave in a clinically indolent manner despite the frequent occurrence of disseminated disease at diagnosis.80,81 The majority of cases occur in patients aged over 65. However, since the median age of patients included in most clinical studies is considerably younger, determining the optimal management for the older patient can be problematic, and physicians must extrapolate from available data. While the indolent lymphomas are highly responsive to a variety of therapies, there is little convincing evidence that any is curative. Because of this, the management of patients is controversial. Initial options may range from highly aggressive combination chemotherapy regimens to no therapy at all. Most therapies can produce significant response rates, but the vast majority of patients will relapse. There is little evidence that any particular therapy, when compared with others, results in an improvement of overall survival. Given the indolent natural history of these neoplasms, as well as the assumption that early therapeutic intervention does not confer a survival advantage, ‘Watchful waiting’ or the deferral of therapy has emerged as a reasonable initial management option.80–82 In a retrospective study from Stanford University, 83 patients with advanced-stage FL or SLL (median age 57) were initially managed with observation alone.80 Indications for beginning therapy were progression of bulky disease, development of systemic symptoms, or laboratory evidence of bone marrow compromise. Treatment was eventually required at median intervals of 16.5 months for grade II FL, 48 months for grade I FL, and 72 months for SLL. When survival was compared with that of a similar group of patients who had received early chemotherapy, no difference was seen. This watch-and-wait strategy has been prospectively assessed.82,83 At the NCI, 99 patients (median age 51) with a variety of histologic subtypes of indolent NHL (mostly grade I and II FL) were randomized to receive either initial observation, or the aggressive

Non-Hodgkin lymphomas

1105

chemotherapy regimen ProMACE-MOPP (prednisone, methotrexate, leucovorin, doxorubicin, cyclophosphamide, etoposide, mechlorethamine, vincristine, and procarbazine) combined with radiotherapy.83 If those in the observation arm required therapy, they then received the same aggressive treatment as the study arm. While the disease-free survival (DFS) rate at 5 years was significantly better in those who received initial chemotherapy (51% versus 12%),83 there remains no difference in overall survival after more than 13 years of follow-up.84 Similarly, the Groupe D’Etude des Lymphomes Folliculaires (GELF) conducted a randomized phase III trial comparing initial observation, immediate treatment with oral prednimustine, and immediate treatment with interferon-α2b, all of which are substantially less toxic than ProMACE-MOPP.82 The trial included 195 patients aged less than 70 (median age 52) with FL and low tumor burden. Patients who deferred therapy until they were symptomatic had the same response rates as those given immediate treatment and there was no significant difference in 5-year survival rates (78% versus 70% versus 84%; p=0.24). Since none of the currently available therapies for indolent lymphoma result in cure, perhaps the most desirable therapeutic objective is to maximize quality of life (QoL). By reducing tumor mass, chemotherapy can lessen lymphoma-related symptoms and thus improve QoL. When treatment of symptomatic disease is initiated, it is done with the intention that short-term treatment-related toxicity is offset by symptom improvement.85 Yet, chemotherapy itself may be detrimental to short-term QoL.86 In 141 patients with low-grade NHL divided into two groups based on whether or not they were currently receiving chemotherapy, those on therapy reported significantly lower QoL scores. While the full impact of chemotherapy on QoL in low-grade NHL awaits more formal evaluation, it is nonetheless clear that (at least in the short term) chemotherapy can have an adverse effect on QoL. Taken together, these studies suggest that there is little advantage to treating asymptomatic patients with indolent NHL. Early initiation does not appear to confer a survival advantage, and the therapy may be associated with toxicity that can have a negative effect on QoL. Small lymphocytic lymphoma SLL is morphologically and immunophenotypically indistinct from chronic lymphocytic leukemia (CLL), and is essentially a nodal-predominant version of CLL. Since few studies have specifically investigated the therapy of SLL, most of the available information is derived from CLL data. Therapy of asymptomatic patients appears to offer no clinical benefit and may be associated with a poorer overall survival.87 When therapy is indicated, due to progressive systemic symptoms such as anemia, thrombocytopenia, infection, or splenomegaly, patients have historically been treated with oral alkylating agents such as chlorambucil or cyclophosphamide.88 More recently, the nucleoside analogue fludarabine has been shown to have special activity against CLL, and this has led to its adoption as first-line therapy.89 In a large intergroup trial, 544 patients with active CLL were randomized to receive fludarabine, chlorambucil, or a combination of the two agents.90 The median age was 63; 36% were aged between 60 and 70, and 25% were aged over 70. Fludarabine was found to be superior to chlorambucil in terms of complete response rate (20% versus 5%;

Comprehensive Geriatric Oncology

1106

p=0.0001), overall response rate (64% versus 39%; p=0.0001), and median response duration (28 months versus 19 months; p= 0.004). However, there has been no statistically significant difference in median overall survival (66 months versus 56 months; p=0.10). The combined-therapy arm showed equivalent responses to fludarabine alone, but was associated with a significantly higher rate of life-threatening toxicity and was abandoned. While fludarabine has demonstrated efficacy in the therapy of CLL (and, it is hoped, SLL by extension), it remains unsettled how long therapy should be administered. In addition, fludarabine has been associated with an increase in opportunistic infections.91 Patients older than 65 are at increased risk, and some physicians have recommended both antifungal and antibacterial prophylaxis for them.91 Lymphoplasmacytic lymphoma In LPL, the neoplastic cell shows plasmacytic differentiation and usually expresses and produces monoclonal IgM.42 When the circulating IgM attains high levels, this condition is referred to as Waldenstrom’s macroglobulinemia or macroglobulinemic lymphoma.4,92 The paraproteinemia can cause signs and symptoms attributable to hyperviscosity, such as fatigue, dizziness, and blurred vision, as well as easy bleeding of mucous membranes. Associated plasma volume expansion may result in high-output cardiac failure. Thus, therapy for symptomatic LPL may involve treating the paraproteinemia, in addition to the underlying malignancy. When symptoms attributable to hyperviscosity are present, plasmapharesis should be instituted, followed promptly by chemotherapy. Although no studies have specifically investigated LPL in elderly populations, standard treatment regimens usually include either a single oral alkylating agent (chlorambucil or cyclophosphamide) or a combination of an alkylating agent and a glucocorticoid (most commonly chlorambucil and prednisone). Response rates of 57–70% are routinely reported.42,93 Fludarabine has activity in previously treated disease (with a 30% partial response rate),92 and has led to response rates of 63–79% in untreated cases, as well.94 Another nucleoside analogue, 2-chlorodeoxyadenosine (cladribine) also has good activity in untreated disease, and may be appropriate if faster responses are needed.42,95 Owing to the relative rarity of LPL, there have been no randomized trials specifically comparing different therapies. Marginal zone lymphoma The different types of marginal zone lymphomas (MZL) each present unique treatment considerations. Patients with splenic MZL, with or without villous lymphocytes, often present with symptomatic splenomegaly, making a ‘watch-and-wait’ approach undesirable. In such cases, splenectomy is often performed, which not only corrects the hypersplenism, but can also improve lymphocytosis.96 Persistent problems may require the subsequent use of alkylating agents, such as in other indolent NHL. Nodal MZL probably represents a primary disease distinct from both MALT lymphomas and splenic MZL.5,7 Because it tends to have a more aggressive clinical course than MALT lymphomas,43,44 some recommend combination chemotherapy of the types used in aggressive NHL.97 However, the optimal therapy of nodal MZL remains to

Non-Hodgkin lymphomas

1107

be defined, and some patients can do well with either no initial therapy or single treatments of alkylating agents or modest combinations. Lymphomas of mucosa-associated lymphoid tissue (MALT) deserve special mention. The most common sites of involvement are the stomach, salivary gland, and thyroid, where it is thought that chronic antigenic stimulation by, respectively, Helicobacter pylori infection, myoepithelial sialadenitis, and Hashimoto’s thyroiditis play a role in the pathogenesis (see the section above on etiology of NHL).29 Other sites of involvement include the lung and skin. Since most gastric MALT lymphomas are stage I at diagnosis, local strategies such as gastrectomy and radiotherapy have been successfully employed in appropriate patients.98,99 However, several studies have now confirmed that regression of gastric MALT lymphoma often occurs following treatment to eradicate H. pylori.100–102 Roggero et al100 reported that in 25 out of 26 patients with gastric MALT lymphoma (median age 60) who were treated with antibiotics and cured of H. pylori infection, there was a 60% near or complete response rate. Furthermore, the MALT Lymphoma Study Group reported an 80% complete response rate at a follow-up of 19 months in 125 patients with gastric MALT lymphoma who experienced eradication of H. pylori infection.101 The remissions in this study appear to be durable, with no change in the complete response rate at a median follow-up of 32 months.102 Thus, appropriate antibiotic therapy is a reasonable first-line approach for patients with localized gastric MALT lymphoma and H. pylori infection. Alternatively, radiotherapy alone, which is reasonably well tolerated in young patients,98 or gastrectomy99 are options in patients with localized disease that is H. pylori-negative or persistent following eradication of H. pylori. Observation or simple chemotherapy can also be used for patients who do not respond to antibiotics, for those with advanced stage at diagnosis, and for those who present with MALT lymphoma of other extranodal sites. In these settings, chlorambucil or cyclophosphamide is associated with complete response rates of up to 75%.103 Follicular lymphomas Although three different subtypes or grades of FL are recognized, only grades I and II are included as indolent lymphomas. The more clinical aggressive grade III FL (follicular predominately large cell in the Working Formulation) is discussed later in this chapter. There is some controversy whether the differences in the natural histories of grade I and II FL are sufficient to warrant their continued distinction. Nonetheless, the three-tiered grading system has been retained for now.5,7 Localized disease Radiotherapy appears to have a useful role to play in the management of localized disease. The 15% of patients who present with clinical stage I or II disease are often treated with radiotherapy, with or without additional chemotherapy.104–106 The addition of chemotherapy to radiotherapy may slightly lengthen the time to treatment failure but has demonstrated no significant effect on overall survival. This is true of the addition both of aggressive combination chemotherapy regimens107,108 and of less aggressive approaches

Comprehensive Geriatric Oncology

1108

such as CVP (cyclophosphamide, vincristine, and prednisone)109,110 and oral chlorambucil.111 Whether radiation alone is curative in this setting is unknown. However, a retrospective study from Stanford University suggests that cure may have been achieved.106 In this study, 177 patients with localized FL (median age 52) were treated with involved-field radiotherapy, extended-field radiotherapy, or total lymphoid irradiation. Actuarial survival rates and relapse-free survival rates were, respectively, 82% and 55% at 5 years, 64% and 44% at 10 years, 44% and 40% at 15 years, and 35% and 37% at 20 years. In a subset analysis, patients older than 60 had a shorter time to relapse than younger patients (median 4.3 years versus 9.0 years; p=0.038). The 10-year survival rate was also worse for the elderly (30% versus 70%; p= 0.0001), which in part reflected deaths due to causes other than lymphoma. Chemotherapy A variety of single-agent and combination chemotherapy regimens have been evaluated in the treatment of disseminated FL over the past three decades, most of which appear to have equivalent efficacy. In the 1970s, three small randomized studies in patients with disseminated indolent lymphoma compared either oral cyclophosphamide or chlorambucil as single agents or CVP combination chemotherapy.81,112,113 The complete response rates varied substantially, depending on how long patients were treated, but there was no difference in overall survival by treatment in any of the studies. Subsequent studies explored the potential benefit of more intensive combinations. Lepage et al114 randomized 113 patients, most of whom had FL (median age 51), to cyclophosphamide, vincristine, procarbazine, and prednisone, with or without doxorubicin. The time to disease progression was similar (39 months) and there was no difference in survival. In a retrospective analysis of 415 patients with SLL, or with grade I or II FL, treated on three Southwestern Oncology Group (SWOG) protocols, no difference in survival was seen between patients who received CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and those who received less intensive regimens.115 These studies included 123 patients over the age of 60, and age greater than 59 was associated with inferior survival. However, the adverse impact of age did not vary according to treatment. A single oral alkylating agent has also been compared with CHOP-B (cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin), and the overall results in FL are identical.116 These studies suggest that the more aggressive regimens, which include doxorubicin, are of no greater clinical benefit than less toxic therapies as the initial treatment of patients with advanced FL. However, there may be a role for combination chemotherapy regimens in the treatment of grade II FL. In a study from the NCI, 79 patients with grade II FL (median age 49) who were treated with C-MOPP (cyclophosphamide, vincristine, procarbazine, and prednisone) experienced a 76% complete response rate, with 52% of patients remaining in remission at a median follow-up of 7 years.117 This was much longer than expected for patients with FL. There is similar evidence from a randomized trial conducted by the Cancer and Leukemia Group B (CALGB) comparing cyclophosphamide with CHOP-B.116 The failure-free and overall survival rates at 10

Non-Hodgkin lymphomas

1109

years are significantly better in grade II FL for those treated with CHOP-B (48% and 61%). However, the administration of aggressive chemotherapy may be difficult in elderly patients with multiple comobidities, in whom toxicity would be presumably increased. Interferons Recombinant interferons have been used successfully in the elderly for a variety of malignant and non-malignant conditions.118–121 Although there have been no published clinical trials specifically investigating interferons in elderly patients with FL, a number of phase I and II studies have demonstrated that recombinant interferon-α (IFN-α) has significant activity both alone and in conjunction with chemotherapy.122,123 As a single agent in patients with asymptomatic grade I or II FL, IFN-α yields a 42% CR rate,82 an antitumor effect approaching that of many standard chemotherapy regimens. Combinations of IFN-α with chemotherapy have been explored in over 2000 adults with NHL.124–134 The great majority of those included had FL but most of these studies contain only small numbers of elderly patients. Taken as a group, these studies indicate that the addition of IFN-α during induction does not greatly improve the response rate or survival. One exceptional study132 enrolled 273 patients younger than 70 with advanced FL and large tumor burden, and randomized them to receive either CHVP (cyclophosphamide, doxorubicin, teniposide, and prednisone) or CHVP with IFN-α for a total of 18 months. At a median follow-up of 6 years, survival was significantly improved in the combined therapy arm versus CHVP alone (overall survival rate 70%, median not reached versus 56% and 5.6 years median survival; p= 0.0084 and 0.016, respectively). While encouraging, this result has yet to be confirmed in other studies. The use of IFN-α as maintenance therapy may slightly prolong time to treatment failure, but has a limited effect on survival. Only one study of FL has specifically involved older patients. The GELA randomized 131 patients over the age of 60 with FL (all grades) to either 12 courses of CHVP followed by 18 months of IFN-α or to 12 monthly courses of fludarabine without IFNα.135 All of the patients had high tumor burden and 12% of the patients had grade III FL. CHVP plus IFN-α resulted in a better 2-year survival rate compared with fludarabine (81% versus 59%; p= 0.04). However, toxicity was significantly increased in those receiving CHVP/IFN-α, and 43% of the patients receiving IFN-α stopped therapy prematurely. This study suggests that while the CHVP/IFN-α regimen may result in improved survival in elderly patients with high-risk disease, it does so at the cost of significant toxicity, and the contribution of the individual agents in the combination, including IFN-α, is unknown. Because the putative benefits of IFN-α therapy in younger patients are unclear, its role in the treatment of elderly patients with low-grade FL remains suspect. Given that this treatment is not without considerable side-effects and cost, it is unlikely that it will be widely accepted into clinical practice in the absence of definitive studies proving a significant impact on outcome.

Comprehensive Geriatric Oncology

1110

Other therapies Purine analogs such as fludarabine and cladribine show activity in both relapsed and de novo FL. However, the response rates seen with these agents are similar to those of other chemotherapy drugs and are no more durable.84 Two randomized trials have compared fludarabine versus CVP in previously untreated patients with indolent NHL, with no difference in overall survival reported.136,137 While nucleoside analogs clearly are active, their therapeutic role remains unclear. The chimeric anti-CD20 antibody rituximab is available for the treatment of relapsed FL. One study that included patients up to the age of 81 (median age 58), showed a 46% response rate in patients with relapsed FL, with the median time to disease progression not reached at 9 months of follow-up.138 Other phase II studies have reported similar response rates.139,140 Building on its success in relapsed disease, a phase II study has been published testing the efficacy of rituximab as initial systemic therapy in patients with indolent NHL, reporting a 54% objective response rate.141 Side-effects such as fever and chills can be seen in up to 70% of patients during the initial infusion, but occur less often during subsequent administration. Given its overall favorable toxicity profile, rituximab may be uniquely suited for use in elderly patients with relapsed indolent NHL. Current clinical trials are evaluating this agent in combination with a variety of chemotherapy regimens. In addition, conjugating an anti-CD20 antibody to either iodine-131 or yttrium90 is postulated to enhance its cytotoxicity.142 Early trials of tositumomab, a 131I-labeled anti-CD20 antibody, have been associated with response rates of 57–71% in patients with relapsed or refractory low-grade and transformed B-cell lymphomas.143,144 Both autologous and allogeneic transplantation with either bone marrow or peripheral blood stem cells are being studied in the setting of low-grade FL.145–147 Given the significant morbidity and questionable clinical benefit associated with these procedures, they are generally thought to be inappropriate for elderly patients.148 Management of mantle cell lymphoma Originally included in the category of indolent lymphomas, it has become increasingly clear that MCL is a unique clinical entity that combines the worst features of both indolent and aggressive NHL. Its clinical behavior is far from indolent, with median overall survival times of 3–4, yet therapy is rarely curative.47,149–152 Like indolent NHL, it is a disease of elderly patients, with a median age at diagnosis of 68 in one populationbased study.151 There are consistent data suggesting that aggressive combination chemotherapy does not confer a survival advantage when compared with lower-intensity regimens.151–154 Meusers et al153 randomized 63 patients to receive either CVP or the same regimen with the addition of doxorubicin (CHOP). There were no statistical differences in complete response rate (41% versus 58%; p=NS) or median overall survival (32 months versus 37 months; p=NS) between the two treatment groups. Similarly, in two retrospective analyses of patients with MCL, there was no difference in median overall survival between aggressive combination chemotherapy and less toxic regimens.152,154 In fact, one cohort of 16 patients aged under 60 who were selected as being able to tolerate very

Non-Hodgkin lymphomas

1111

intensive chemotherapy plus radiotherapy had overall survival comparable to that of those who received less aggressive therapy.154 Thus, the bulk of evidence would indicate that modest therapies, such as CVP, while not adequate, are as effective as more potentially toxic approaches. There is limited experience with newer agents in the therapy of MCL.94,155,156 Fludarabine yields an approximately 40–50% response rate, 20–30% of which are complete responses, in previously untreated patients.94,156 The median time to disease progression is brief—about 1 year. The anti-CD20 monoclonal antibody rituximab may also be of limited therapeutic benefit. Phase II studies report response rates of 34–38%, with a median response duration of approximately 1 year.139,157 Finally, hematopoietic stem cell transplantation has been reported to be of benefit in patients with MCL,158–161 although other studies dispute this.162 However, few elderly patients have been included in these trials, and the role of transplantation in the treatment of elderly patients with MCL, if any, must be considered limited. Management of aggressive NHL Clinical prognostic factors Numerous studies have been published in an attempt to identify prognostic subgroups of patients with aggressive

Table 48.4 Development of a prognostic factor model: the International Prognostic Index (IPI) and the age-adjusted IPIa No. of risk factors

Distribution of cases (%)

Risk group

CR rate (%)

RFS rate of CRs (%) 2-yr

5-yr

Survival rate (%) 2-yr

5-yr

IPI (patients of all ages) Low (L)

0–1

35

87

79

70

84

73

Low2 intermediate (LI)

27

67

66

50

66

51

Highintermediate (HI)

3

22

55

59

49

54

43

High (H)

4–5

16

44

58

40

34

26

0

22

92

88

86

90

83

Low1 intermediate (LI)

32

78

74

66

79

69

Age-adjusted IPI (applied to patients aged ≤60) Low (L)

Comprehensive Geriatric Oncology

1112

Highintermediate (HI)

2

32

57

62

53

59

46

High (H)

3

14

46

61

58

37

32

0

18

91

75

46

80

56

Low1 intermediate (LI)

31

71

64

45

68

44

Highintermediate (HI)

2

35

56

60

41

48

37

High (H)

3

16

36

47

37

31

21

Age-adjusted IPI (applied to patients aged >60) Low (L)

a

Data from reference 21. CR, complete response; RFS, relapse-free survival

NHL whose pretreatment clinical characteristics predict therapeutic response.21,65,66,163–174 Characteristics that were generally shown to predict survival among these early studies were B symptoms, serum LDH, nodal and extra-nodal sites of disease, disease stage, performance status, and, most importantly, age at diagnosis. Prior to the mid-1990s, the analysis of age as a prognostic factor had yielded equivocal findings. While numerous single-institution studies found that age did predict response to therapy,65,66,163,165 others found no such association.166–173 Subset analyses of older patients enrolled in large clinical trials open to all age groups also produced ambiguous findings.175,176 Given the diversity of the elderly patient population, perhaps this is not surprising. However, the majority of the patients in these trials were highly selected. Moreover, these studies represented a variety of therapeutic modalities and inclusion criteria that further limit the generalizability of their conclusions. However, in an analysis of an international population of 2031 patients (1340 aged 60 and older) with aggressive NHL treated with doxorubicin-containing chemotherapy regimens between 1982 and 1987, age was found to be an important independent prognostic factor.21,177 Patients younger than 60 had higher complete response rate (68% versus 62%; p<0.001), relapse-free survival rate (67% versus 49%; p<0.01), and overall survival rate (60% versus 41%; p<0.01) than patients older than 60. Four other adverse risk factors (advanced disease stage, elevated serum LDH, poor performance status, and presence of more than one site of extranodal disease) were also individually associated with a similar degree of increased risk. Since the additive risk for each factor was comparable, the International Prognostic Index (IPI) was defined. This assigned people to four risk groups on the basis of how many of these five risk factors were present. The 5year survival rate was 73% for low risk (0–1 risk factor), 51% for low-intermediate risk (2 risk factors), 43% for high-intermediate risk (3 risk factors), and 26% for high risk (4– 5 risk factors). To evaluate the difference in outcome between younger and older patients, the IPI was further modified to adjust for age (Table 48.4). The age-adjusted index was defined on the basis of stage, performance status, and LDH, features independently associated with

Non-Hodgkin lymphomas

1113

survival in those younger than 60. While patients older than 60 had similar complete response rates to younger patients, the durability of these remissions was significantly worse. Clearly, this diminished disease-free survival in the elderly was the major contributing factor to their worse overall survival, and this difference in outcome is not due to differences in tumor burden at diagnosis. Despite similar disease at presentation, the elderly fare worse, suggesting that any clinical factor with an adverse impact has an effect of greater magnitude in older patients. The higher incidence of comorbidities in elderly patients clearly plays a role in their poorer overall survival, even when complete response rates are similar to those of younger patients. In a study from the University of Nebraska, there was no significant difference in complete response rate or treatment-related toxicity between older and younger patients who received anthracycline-based chemotherapy for aggressive NHL.172 However, the 5-year survival rate in those under the age of 60 was better (61% versus 38%; p=0.01). This was largely attributed to the high frequency of death not related to lymphoma in older as compared with younger patients. In summary, while complete response rates appear to be similar for patients both over and under 60 who have similar disease features and are selected to receive the same treatment, the durability of these remissions may be shorter in elderly patients. Overall survival is clearly less in elderly patients, in part owing to shorter times to failure and an increase in death from causes other than lymphoma. Advanced disease (stages III and IV) Efficacy of polychemotherapy The development of combination chemotherapy for the treatment of advanced-stage aggressive lymphoma over the past three decades is a major success in cancer therapy.67 Prior to the mid 1970s, the use of single-agent chemotherapy and combination regimens (typically CVP) resulted in median survivals of less than 1 year.178 Because of the impressive success of polychemotherapy in Hodgkin lymphoma reported by DeVita et al179 in 1970, a similar approach was tried in patients with diffuse histiocytic lymphoma (large B-cell lymphoma).180 Employing a regimen of cyclophosphamide, vincristine, procarbazine, and prednisone (C-MOPP), a complete response rate of 41% was reported. Most impressively, 10 out of 11 patients with a complete response experienced long-term disease-free survival. Approximately 37% were apparent cures in a disease that had been invariably fatal. In a subsequent study, the SWOG introduced doxorubicin, an anthracycline antibiotic that had shown anti-lymphoma activity as a single agent, into combination therapy.181 This regimen—cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)—improved the complete response rate for patients with diffuse lymphomas. Later trials showed complete response rates of 53% and a consistent longterm disease-free survival rate of 30%.182 In an attempt to improve on the outcome of CHOP, subsequent second- and thirdgeneration combination chemotherapy regimens were developed183–187 featuring the addition of other agents to the core CHOP regimen, as well as varying the doses and schedules of administration. Initial pilot studies of these regimens were very promismg. To make a valid comparison between these regimens, a large prospective randomized

Comprehensive Geriatric Oncology

1114

cooperative group trial, entitled the National High Priority Lymphoma Study, was conducted.67 In this study, 899 patients with intermediate- or high-grade NHL were randomized to receive CHOP or one of three other regimens. This study included 360 patients over age 60 evenly distributed among the treatment arms. There were no significant differences in response, time to failure, or survival between the treatment arms. However, the newer combinations were associated with a higher incidence of fatal toxic death. Because of these and other results, CHOP has remained standard therapy for advanced-stage aggressive NHL.188 Evolution of polychemotherapy in the elderly With the successful development of polychemotherapy came concern that elderly patients would not be able to share in its benefit, because of an expectation of increased treatment-related toxicity. Indeed, early studies appeared to corroborate this view, with toxic death rates of up to 30% being reported.189 Most toxic deaths in elderly patients were due to sepsis and occurred during the first two cycles of therapy. While the number of patients in these studies was small, the outcome seemed to substantiate fears that elderly patients experience higher morbidity from therapy than do younger patients. This in turn led to trials employing automatic dose reduction in elderly patierits.172,175,176 In 1986, Dixon et al175 published a retrospective analysis of two SWOG trials comprising 307 patients with diffuse large cell lymphoma (81 patients aged 65 and older) treated with CHOP with or without bleomycin, and treated with CHOP with or without immunotherapy. As part of the study design, there was an automatic 50% dose reduction for patients aged 65 or older. The complete response rate and median survival dropped significantly with increasing age: 65% and 101 months in those aged under 40, 60% and 52 months in those aged, 41–54, 55% and 34 months in those aged 55–64, and 37% and 16 months for those 65 and older. However, in 23 of 81 non-randomized patients aged 65 or older who inadvertently received full-dose chemotherapy, there was no difference in complete response rate, duration of response, or frequency of treatment complications, compared with younger study patients. While this does not explain the inferior outcome in those patients with advancing age under age 65 (who presumably received full-dose chemotherapy), it does illustrate that there was a subset of elderly patients in the SWOG trials who appeared to derive the same benefit as younger patients from aggressive chemotherapy. It also suggests that dose reduction in elderly patients may be a contributing factor to their poorer result. Likewise, in CALGB 7851, dose reduction in older patients was associated with inferior outcome.176 In this study, patients with DLCL were treated with three courses of CHOP with or without bleomycin, and the responders then received either high-dose or standard-dose methotrexate prior to three more courses of CHOP. In the 44 patients older than 70, the proportion who received less than 80% of the specified doses of doxorubicin and cyclophosphamide was significantly greater than that of younger patients (48% and 40%, versus 19% and 15%, respectively). These were not automatic dose reductions, but were done in response to treatment-related toxicity, especially myelosuppression. The complete response rate was 53% in patients younger than 70 and 27% in those older than 70 (p=0.01). The 5-year failure-free survival rate was also less in elderly patients (38% for those younger than 50 versus 22% for those older than 60), although this did not reach

Non-Hodgkin lymphomas

1115

statistical significance. The presence of poor performance status and B symptoms were found to be significant prognostic factors in this study. After adjusting for these, age was found not to be an independent risk factor, perhaps suggesting a benefit for at least one cycle of full-dose therapy prior to subsequent dose reductions. Because of concerns over excessive toxicity, other combination regimens have been proposed for elderly patients with aggressive NHL. These regimens utilize a variety of substitutes for anthracyclines, and often feature novel schedules of administration or utilization of oral agents. Dozens of single-institution studies in older patients have been published, representing almost 30 different treatment regimens.53,190–218 All of these studies report active programs with ‘acceptable’ toxicity. However, because small uncontrolled studies are notoriously unreliable, it is difficult to draw conclusions about the utility of these regimens in the absence of randomized clinical trials. Prospective randomized trials in the elderly Since 1994, a number of prospective randomized clinical trials have been published that contain important data regarding the therapy of elderly patients with aggressive NHL. They include both subset analyses of older patients included in trials open to all age groups treated with full-dose chemotherapy174 and prospective randomized clinical trials specifically designed for elderly patients.51,56,219–223 Taken as a whole, they clarify some of the issues concerning preferred treatments for elderly patients with aggressive NHL (Table 48.5). An analysis of the older patients in the National High Priority Lymphoma Study provides evidence that selected patients 60 and older who are treated with full-dose CHOP can have survival comparable to that of their younger counterparts, as well as similar toxicity.67,174 A significant decrease in survival for patients older than 60 was seen between the treatment arms, primarily due to increased toxicity with MACOP-B (methotrexate, leucovorin, doxorubicin, vincristine, bleomycin, prednisone, and trimethoprim-sulfamethoxazole). When patients treated with MACOP-B were excluded from analysis, there was no statistically significant difference in 5-year overall survival rates between those under 60 and over 60 (49% versus 41%; p=0.22). The elderly patients who received CHOP experienced the same frequency of fatal toxicities (all due to infection during neutropenia) and were just as likely to complete the planned course of chemotherapy as younger patients. While this analysis provided support for the role of CHOP as first-line therapy for patients over the age of 60 with aggressive NHL, important questions such as the incidence of non-fatal toxicities and outcome among subgroups remained. Intensive polychemotherapy regimens were of undeniable benefit in younger patients, yet studies remained to be done on specifically older patient populations, where the issue of attenuating toxicity while optimizing efficacy is considered of central importance. A study conducted by the Groupe d’Etudes des Lymphomes de l’Adulte (GELA) provides evidence of the importance of including an anthracycline as part of therapy.220 In this trial, 453 high-risk patients aged 70 and older (median age 75) were randomly assigned to a regimen of cyclophosphamide, teniposide, and prednisone or the same regimen plus pirarubicin, an anthracycline with lower reported risk of cardiac toxicity than doxorubicin. The complete response and 5-year survival rates were improved by the

Comprehensive Geriatric Oncology

1116

addition of pirarubicin: 47% versus 32%; (p=0.0.0001) and 26% versus 19%. (p<0.05), respectively. Neutropenia and infection were slightly more frequent and severe in the pirarubicin arm. However, cardiac problems were actually less frequent in patients who received the anthracycline (2.6% versus 4.6%). Progressive disease was the major cause of death in these patients, and was equally distributed between the treatment arms. The GELA study highlights the need for the inclusion of an anthracycline in the chemotherapy regimen of elderly patients with aggressive NHL; others have assessed drug substitution, schedules, and dose as means of reducing toxicity. A small Canadian study randomized 38 elderly patients (median age 71) with advanced-stage intermediategrade NHL to receive either standard full-dose CHOP given every 3 weeks or CHOP at one-third dose given weekly.219 The objective was to determine whether elderly patients could receive increased dose intensity if smaller drug doses of CHOP were given more frequently. Standard CHOP at 3-week intervals often requires substantial dose reduction due to myelosup-

Table 48.5 Randomized clinical trials in elderly patients with aggressive NHL220 Ref

Regimen

No. of Median CR rate patients age (%) (years)

OS rate Comments (%)

67

CHOP

90

NA

NA

45

174

m-BACOD

90

NA

NA

39

ProMACE-CytaBOM

90

NA

NA

41

MACOP-B

90

NA

NA

23

CHOP (full dose, every 3 weeks)

19

70.5

68

74

CHOP (⅓ dose, weekly)

19

71.8

74

51

(p=0.9)

(p=0.05)

219

56

220

CHOP

72

70

49

42

CNOP

76

71

31

26

(p=0.03)

(p=0.029)

Cyclophosphamide/teniposide/prednisone 220

75

32

19

Cyclophosphamide/teniposide/prednisone 233 +pirarubicin

75

47

26

222,223 CHOP VMP

(p=0.0001) (p<0.05)

60

75

45

65

60

75

27

30

No difference in toxicity

53% of study population had 2–3 adverse prognostic factors No difference in toxicity

Non-Hodgkin lymphomas

51

1117

(p=0.06)

(p=0.004)

CEOP-Bleo

86

69

71

72

CIOP-Bleo

83

69

48 (p<0.01)

34 (p<0.01)

No difference in toxicity

CR, complete response; OS, overall survival; NA, not available. CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; m-BACOD, methotrexate, leucovorin, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone; ProMACE-CytaBOM, cyclophosphamide, doxorubicin, etoposide, cytarabine, bleomycin, vincristine, methotrexate, leucovorin, prednisone, and trimethoprim-sulfamethoxazole; MACOP-B, methotrexate, leucovorin, doxorubicin, vincristine, bleomycin, prednisone, and trimethoprim-sulfamethoxazole; CNOP, cyclophosphamide, mitoxantrone, vincristine, and prednisone; VMP, etoposide, mitoxantrone, and prednimustine; CEOP-Bleo, cyclophosphamide, epirubicin, vincristine, and bleomycin; CIOP-Bleo, cyclophosphamide, idarubicin, vincristine, and bleomycin.

pression. There was no difference in dose intensity (amount of drug given per unit time) received between the treatment groups. Despite the small sample size, a statistically significant difference in survival was observed, with full-dose CHOP showing better results than weekly CHOP (2-year overall survival rate 74% versus 51%; p=0.05). There was an increase in myelotoxicity in the full-dose arm, but no cardiac toxicity was observed in either group. Not all anthracyclines have equivalent efficacy. The National Medical Center of Mexico tried to determine if other anthracyclines could be successfully substituted for the doxorubicin in CHOP. In this study, 169 elderly patients (median age 69) were randomized to receive either cyclophosphamide, epirubicin, vincristine, prednisone, and bleomycin (CEOP-Bleo), or the same regimen but substituting for epirubicin a different anthracycline, idarubicin (CIOP-Bleo).51 Both epirubicin and idarubicin apparently have less cardiac toxicity than doxorubicin.224,225 The complete response and 3-year survival rates were higher in those who received CEOP-Bleo: 71% versus 48% (p<0.01) and 72% versus 34% (p <0.01), respectively. Toxicity, including cardiac toxicity, was similar in the two groups. Declines in left ventricular ejection fraction (LVEF) were seen in 8% receiving CEOP-Bleo and 5% receiving CIOP-Bleo. However, there were no reports of clinical congestive heart failure in either arm. Thus, epirubicin is better than idarubicin in these specific combinations. Unfortunately, neither was directly compared with doxorubicin, and the results cannot be used to justify the replacement of doxorubicin routinely by epirubicin. Since age over 70 is a known risk factor for doxorubicin-induced cardiomyopathy,226 many trials have examined other substitutes for doxorubicin in an attempt to avoid this side effect.51,56,220,227 Mitoxantrone, an anthra-cendione derivative that is similar in structure to anthra-cycline drugs except that it lacks a sugar moiety, has been proposed as an alternative in elderly patients.230 The mechanism of its action is similar to that of the anthra-cyclines, but the free radicals that are thought to contribute to anthracyclineassociated cardiotoxicity are not produced.229 A multicenter randomized phase III trial was published comparing the efficacy and toxicity of CHOP and CNOP (mitoxantrone substituted for doxorubicin) in 148 patients aged over 60 (median age 70–71) with advanced-stage intermediate- and high-grade NHL.56 The use of CHOP resulted in higher complete response and 3-year survival rates: 49% versus 31% (p=0.03) and 42% versus

Comprehensive Geriatric Oncology

1118

26% (p=0.029), respectively. Neutropenia and infection were the most common reported side-effects and did not differ between the groups. Serial measurements of LVEF were performed in a subgroup of 45 patients; an absolute reduction in LVEF of greater than 15% was seen in 9 of 23 CNOP and 10 of 22 CHOP patients. Toxic death due to cardiac causes (mostly congestive heart failure), was seen in 2 of 76 (2.6%) of CNOP patients and 4 of 72 (5.6%) CHOP patients. Thus, the substitution of mitoxantrone did not result in significantly less cardiotoxicity. A study conducted by The European Organization for Research and Treatment of Cancer (EORTC) compared VMP (etoposide, mitoxantrone, and prednimustine)—a regimen specifically designed for elderly patients—with CHOP.201 The EORTC Lymphoma Group randomized 120 patients older than 70.222 Patients with poor performance status received reduced doses, which were subsequently increased if tolerated. Those treated with CHOP had a borderline significantly better complete response rate (45% versus 27%; p=0.06) and significantly better 2-year progression-free survival rate (55% versus 25%; p =0.002) and survival rate (65% versus 30%; p=0.004). Hematologic toxicity and infection were similar, but gastrointestinal toxicity was more common in those receiving CHOP. Cardiotoxicity was evaluated clinically, and was found in 11% of all patients in the study, without significant difference between therapies. Cardiovascular deaths occurred in three patients with VMP and four patients with CHOP. Considerable attention has been focused on the cardiotoxic effects of chemotherapy in the elderly. However, in the studies reviewed above, symptomatic cardiomyopathy has been infrequently reported. Severe neutropenia, on the other hand, occurs in up to 50% of treated patients. While the most common cause of death in these studies is progressive lymphoma, complications from neutropenia are the most common cause of treatmentrelated death, occurring in up to 15% of patients.220 In a retrospective study from the Instituto de Enfermedades (Spain), 269 older patients (median age 70) who had received CHOP were analyzed to determine which clinical parameters predicted the occurrence of treatment-related death.230 There were 35 toxic deaths (13% of patients): 19 due to neutropenic sepsis, 10 due to infection without evident myelotoxicity, and 6 due to other causes, only one of which was cardiac (myocardial infarction). In a multivariate analysis, poor performance status, rather than increasing age, was the most important factor associated with treatment-related death in patients aged 60–69, 70–79, and 80–94 (with toxic death rates of 12%, 13%, and 19%, respectively; p=NS). Chemotherapy-induced myelosuppression often leads to unwanted dose reduction of otherwise-effective agents, which in turn impairs outcome.231 The use of granulocyte colony-stimulating factor (G-CSF) can mitigate the myelosuppressive effects of chemotherapy,221,223 and reduce neutropenia and infections.232,233 Growth factors have also recently been shown to allow the administration of chemotherapy in full doses to older patients.55,221,234,235 Investigators at the Instituto di Ematologia (Bologna) investigated the potential of GCSF to decrease myelosuppression during treatment in 149 patients (median age 69.5) who were randomized to a regimen of cyclophosphamide, mitoxantrone, vincristine, etoposide, bleomycin and prednisone (VNCOP-B) with or without concurrent G-CSF.221 The use of G-CSF did not influence the complete response rate or survival, but severe neutropenia was less frequent (23% versus 55.5%; p=0.00005) and there were fewer

Non-Hodgkin lymphomas

1119

clinically relevant infections (5% versus 21%; p=0.004). Since the only effect of G-CSF was on mitigating the consequences of myelotoxicity, it is unclear whether it should be used routinely in older patients or only in those demonstrating serious neutropenia. Summarizing the available data, when treated with curative intent, selected elderly patients with advanced-stage aggressive NHL can expect to have complete response rates that rival those in younger patients and with acceptable toxicity. Overall survival is decreased in elderly patients, probably owing to causes of death unrelated to lymphoma and the higher likelihood of earlier relapse. It is important to note that because of the considerable selection that occurred in most studies of treatment in older patients, it is unclear whether the results are generalizable to the overall population of older patients with NHL. Individuals with seriously impaired performance status or significant comorbidity were usually not included. Therefore, in the absence of an available clinical trial, patients with significant cardiac disease or other functional compromise may be reasonably treated with one of the many single-institution regimens specifically designed for older patients, although criteria with which to distinguish between them are obviously vague. However, for those judged suitable for treatment, CHOP remains the standard against which future therapy will be measured. Strategies to avoid anthracyclines, either by elimination or by replacement with mitoxantrone, result in inferior outcome. Growth factor support likely reduces neutropenia and infections associated with the myelosuppressive effects of chemotherapy, but thus far has had no significant impact on either response or survival. Immunotherapy Since the majority of DLCL are CD20+, the chimeric anti-CD20 antibody rituximab has been used to treat a growing number of patients with these and other aggressive lymphomas. Coiffier et al236 randomized 54 patients with relapsed or refractory aggressive NHL (mostly DLCL) to one of two doses of rituximab as a single agent. The median age of the study patients was approximately 63, and the overall response rate was 31%, with no difference between the treatment arms. Building on these data, GELA has completed a randomized phase III trial comparing rituximab plus CHOP (r-CHOP) versus CHOP alone in 400 patients aged 60–80.237 An interim analysis of this study, specifically designed for older patients, shows that the addition of rituximab results in improved complete response rate (76% versus 60%; p= 0.004), 12-month event-free survival rate (69% versus 49%; p<0.0005), and 12-month overall survival rate (83% versus 68%; p<0.01) compared with CHOP alone. No differences in toxicity were noted between treatment arms. While a final analysis of the completed trial awaits formal publication, this combination therapy may be on its way to becoming a new standard in the treatment of older patients with advanced aggressive NHL. Localized disease (stages I and II) Prior to the introduction of effective combination chemotherapy, radiotherapy was the primary treatment for patients with localized aggressive lymphoma.105,178,238–240 However, CHOP was also quite effective, especially in clinically staged patients in whom the

Comprehensive Geriatric Oncology

1120

relapse rate following irradiation was high.241 The results of large prospective trials have now confirmed the benefits of combined modality treatment. The Eastern Cooperative Oncology Group (ECOG) studied 345 patients (median age 59) with stage II and bulky/extranodal stage I aggressive NHL who received eight cycles of CHOP alone or followed by radiotherapy. The results were improved with combined therapy. Both the 6year failure-free survival rate (73% versus 58%; p<0.04) and the overall survival rate (84% versus 70%; p=0.06) were better.242 The preliminary report did not give an analysis by age. Subsequently, the strategy of brief chemotherapy followed by irradiation was studied by the SWOG. In this study, 401 patients with stage I and II aggressive NHL received either three cycles of CHOP followed by involved-field radiotherapy or eight cycles of CHOP alone.243 Of the study patients, 49% were over the age of 60, and 33% had stage II disease. Even in this setting, the addition of radiotherapy was beneficial. Patients treated with combined-modality therapy had a better 5-year overall survival rate (82% versus 72%; p=0.02). Toxicity was also higher in the CHOP-only arm. When it has been specifically studied, elderly patients with early-stage disease appear to have the same outcome as younger patients, whether they are treated with initial radiotherapy, initial chemotherapy, or a combination of the modalities. In a multivariate analysis of 148 consecutive patients with stage I and II aggressive NHL treated with either primary radiation or combined chemoradiotherapy,240 age greater than 60 did not predict treatment response, but was associated with a decrease in overall survival. Disease stage, rather than age, is the predominant predictor of outcome.244 Although these studies were not primarily conducted in elderly patients, it is reasonable to offer elderly patients the same therapy as younger patients. While the best treatment remains under study, particularly for elderly patients, the combination of involved-field radiotherapy with three cycles of CHOP limits exposure to the potential cardiotoxicity of the doxorubicin, while maximizing tumor response. Conclusions We are on the verge of a new era in the therapy of NHL. Our new understanding of the unique biology of these diseases has facilitated the design and implementation of rationally designed therapies that will hopefully result in improved efficacy and decreased toxicity. Phase III studies specifically designed for older patients are ongoing, and their results are anxiously anticipated. References 1. Glass AG, Karnell LH, Menck HR. The National Cancer Data Base Report on non-Hodgkin’s lymphoma. Cancer 1997; 80:2311–20. 2. Surveillance, Epidemiology and End Results (SEER) Review 1973–1997. Bethesda, MD: National Cancer Institute, 2000. 3. McNeil C. Non-Hodgkin’s lymphoma trials in elderly look beyond CHOP. J Natl Cancer Inst 1998; 90:266–7.

Non-Hodgkin lymphomas

1121

4. Harris NL, Jaffee ES, Stein H et al. A revised European-American Classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84:1361– 92. 5. Harris NL, Jaffe ES, Diebold J et al. World Health Organization Classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee Meeting—Airlie House, Virginia, November 1997. J Clin Oncol 1999; 17:3835–49. 6. Harris NL, Jaffe ES, Diebold J et al. Lymphoma classification—from controversy to consensus; the R.E. A.L. and WHO Classification of lymphoid neoplasms. Ann Oncol 2000; 11(Suppl 1): 3–10. 7. Jaffe ES, Harris NL, Stein H, Vardiman JW (eds). World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press, 2001. 8. Press OW. Prospects for the management of non-Hodgkin’s lymphomas with monoclonal antibodies and immunoconjugates. Cancer J Sci Am 1998; 4(Suppl 2): S19–26. 9. Johnson TA, Press OW. Therapy of B-cell lymphomas with monoclonal antibodies and radioimmunoconjugates: the Seattle experience. Ann Hematol 2000; 79:175–82. 10. Schultze JL. Vaccination as immunotherapy for B cell lymphoma. Hematol Oncol 1997; 15:129–39. 11. Bendandi M. Anti-idiotype vaccines for human follicular lymphoma. Leukemia 2000; 14:1333– 39. 12. Fielding AK, Russell SJ. Gene therapy for B cell lymphomas. Cancer Surv 1997; 30:327–42. 13. Dutcher JP, Wiernik PH. Novel biologic approaches to hematologic malignancies. Cancer Treat Res 1999; 99:275–306. 14. Waldmann TA. T-cell receptors for cytokines: targets for immunotherapy of leukemia/lymphoma. Ann Oncol 2000; 11(Suppl 1): 101–6. 15. Maartense E, Hermans J, Kluin-Nelemans JC et al. Elderly patients with non-Hodgkin’s lymphoma: population-based results in The Netherlands. Ann Oncol 1998; 9:1219–27. 16. Carbone A, Franceschi S, Gloghini A et al. Pathological and immunophenotypic features of adult non-Hodgkin’s lymphoma by age group. Hum Pathol 1997; 28:580–7. 17. Groves FD, Linet MS, Travis LB et al. Cancer surveillance series: non-Hodgkin’s lymphoma incidence by histologic subtype in the United States from 1978 through 1995. J Natl Cancer Inst 2000; 92: 1240–51. 18. Carbone A, Volpe R, Gloghini A et al. Non-Hodgkin’s lymphoma in the elderly. I. Pathologic features at presentation. Cancer 1990; 66:1991–4. 19. Peterson BA, Pajak TF, Cooper MR et al. Effect of age on therapeutic response and survival in advanced Hodgkin’s disease. Cancer Treat Rep 1982; 66:889–98. 20. Greil R: Prognosis and management strategies of lymphatic neoplasias in the elderly. II. Hodgkin’s disease. Oncology 1998; 55: 265–75. 21. Shipp MA, Harrington DP, Anderson JR et al. A predictive model for aggressive lymphoma: the International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 1993; 329: 987–94. 22. Levine AM. Lymphoma complicating immunodeficiency disorders. Ann Oncol 1994; 5(Suppl 2): 29–35. 23. Gaidano G, Capello D, Carbone A. The molecular basis of acquired immunodeficiency syndrome-related lymphomagenesis. Semin Oncol 2000; 27:431–41. 24. Swinnen LJ. Overview of posttransplant B-cell lymphoproliferative disorders. Semin Oncol 1999; 26(Suppl 14): 21–5. 25. Biggar RJ, Rabkin CS. The epidemiology of acquired immunodeficiency syndrome-related lymphomas. Curr Opin Oncol 1992; 4: 883–93. 26. Kamel OW, Van De Rijn M, Hanasono M et al. Immunosuppression-associated lymphoproliferative disorders in rheumatic patients. Leuk Lymphoma 1995; 16:363–8.

Comprehensive Geriatric Oncology

1122

27. Nalesnik MA. Clinicopathologic features of posttransplant lymphoproliferative disorders. Ann Transplant 1997; 2:33–40. 28. Liebowitz D. Epstein-Barr virus and a cellular signaling pathway in lymphomas from immunosuppressed patients. N Engl J Med 1998; 338:1413–21. 29. Isaacson PG. Mucosa-associated lymphoid tissue lymphoma. Semin Hematol 1999; 36:139–47. 30. Zahm SH, Weisenburger DD, Babbitt PA et al. A case-control study of non-Hodgkin’s lymphoma and the herbicide 2, 4-dichlorophenoxyacetic acid (2, 4-D) in eastern Nebraska. Epidemiology 1990; 1:349–56. 31. Brandt L, Kristoffersson U, Olsson H et al. Relation between occupational exposure to organic solvents and chromosome aberrations in non-Hodgkin’s lymphoma. Eur J Haematol 1989; 42: 298–302. 32. Bebbe GW, Kato G, Land CE. Studies of the mortality of A-bomb survivors: 6. mortality and radiation dose, 1950–1974. Radiat Res 1978; 75:138–201. 33. Wick G, Grubeck-Loebenstein B. The aging immune system: primary and secondary alterations of immune reactivity in the elderly. Exp Gerontol 1997; 32:401–13. 34. Chiu BC-H, Cerhan JR, Folsom AR et al. Diet and risk of non-Hodgkin lymphoma in older women. JAMA 1996; 275:1315–21. 35. Cerhan JR. New epidemiologic leads in the etiology of non-Hodgkin lymphoma in the elderly: the role of blood transfusion and diet. Biomed Pharmacother 1997; 51:200–7. 36. National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin’s Lymphoma Pathologic Classification Project. Cancer 1982; 49:2112–35. 37. Hiddemann W, Longo DL, Coiffier B et al. Lymphoma classification—the gap between biology and clinical management is closing. Blood 1996; 88:4085–9. 38. Rosenberg SA. Classification of lymphoid neoplasms. Blood 1994; 84:1359–60. 39. Non-Hodgkin’s Lymphoma Classification Project. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s Lymphoma. Blood 1997; 89:3909–18. 40. Melnyk A, Rodriguez A, Pugh WC et al. Evaluation of the Revised European-American Lymphoma Classification confirms the clinical relevance of immunophenotype in 560 cases of aggressive non-Hodgkin’s lymphoma. Blood 1997; 89:4514–20. 41. Pangalis GA, Angelopoulou MK, Vassilakopoulos TP et al. B-chronic lymphocytic leukemia, small lymphocytic lymphoma, and lymphoplasmacytic lymphoma, including Waldenstrom’s macroglobulinemia: a clinical, morphologic, and biologic spectrum of similar disorders. Semin Hematol 1999; 36:104–14. 42. Dimopoulos MA, Alexanian R. Waldenstrom’s macroglobulineia. Blood 1994; 83:1452–9. 43. Nathwani BN, Drachenberg MR, Hernandez AM et al. Nodal monocytoid B-cell lymphoma (nodal marginal-zone B-cell lymphoma). Semin Hematol 1999; 36:128–38. 44. Nathwani BN, Anderson JR, Armitage JO et al. Marginal zone B-cell lymphoma: a clinical comparison of nodal and mucosa-associated lymphoid tissue types. J Clin Oncol 1999; 17:2486–92. 45. Vaux DL, Cory S, Adams JM. bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 1988; 335:440–2. 46. Dalla-Favera R, Gaidano G. Molecular biology of lymphomas. In: Cancer: Principles and Practice of Oncology, 6th edn (DeVita VT Jr, Hellman S, Rosenberg SA, eds). Philadelphia: Lippincott-Raven, 2001:2215–35. 47. Campo E, Raffeld M, Jaffe ES. Mantle-cell lymphoma. Semin Hematol 1999; 36:115–27. 48. Motokura T, Bloom T, Kim HG et al. A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature 1991; 350:512–15. 49. Mason DY, Bastard C, Rimokh R et al. CD30-positive large cell lymphomas (‘Ki-1 lymphoma’) are associated with a chromosomal translocation involving 5q35. Br J Haematol 1990; 74:161–8.

Non-Hodgkin lymphomas

1123

50. d’Amore F, Brincker H, Christensen BE et al. Non-Hodgkin’s lymphoma in the elderly. A study of 602 patients aged 70 or older from a Danish population-based registry. Ann Oncol 1992; 3: 379–386. 51. Aviles A, Nambo MJ, Talavera A et al. Epirubicin (CEOP-Bleo) versus idaurubicin (CIOPBleo) in the treatment of elderly patients with aggressive non-Hodgkin’s lymphoma: dose escalation studies. Anticancer Drugs 1997; 8:937–42. 52. Caracciolo F, Capochiani E, Papineschi F et al. Consolidation therapy with idarubicin, cisplatin and prednisone (CIP) after P-VABEC regimen in the treatment of intermediate and high grade non-Hodgkin’s lymphoma of the elderly. Leuk Lymphoma 1997; 24:335–61. 53. Bellesi G, Rigacci L, Alternini R et al. A new protocol (MiCEP) for the treatment of intermediate or high-grade non-Hodgkin’s lymphoma in the elderly. Leuk Lymphoma 1996; 20:475–80. 54. Freilone R, Botto B, Vitolo U et al. Combined modality treatment with a weekly brief chemotherapy (ACOP-B) followed by locoregional radiotherapy in localized-stage intermediate- to high-grade non-Hodgkin’s lymphoma. Ann Oncol 1996; 7:919–24. 55. Guerci A, Lederlin P, Reyes F et al. Effect of granulocyte colony-stimulating factor administration in elderly patients with aggressive non-Hodgkin’s lymphoma treated with a pirarubicin-combination chemotherapy regimen. Ann Oncol 1996; 7:966–9. 56. Sonneveld P, de Ridder M, van der Lelie H et al. Comparison of doxorubicin and mitoxantrone in the treatment of elderly patients with advanced diffuse non-Hodgkin’s lymphoma using CHOP versus CNOP chemotherapy. J Clin Oncol 1995; 13:2530–9. 57. Cory S, Vaux DL, Strasser A et al. Insights from Bcl-2 and Myc: malignancy involves abrogation or apoptosis as well as sustained proliferation. Cancer Res 1999; 59(Suppl 7): 1685s92s. 58. Gascoyne RD. Establishing the diagnosis of lymphoma: from initial biopsy to clinical staging. Oncology 1998; 12(Suppl 8): 11–16. 59. Pontifex AH, Klimo P. Application of aspiration biopsy cytology to lymphoma. Cancer 1984; 53:553–6. 60. Jennings CD, Foon KA. Recent advances in flow cytometry: application to the diagnosis of hematologic malignancy. Blood 1997; 90: 2863–92. 61. Gascoyne RD. Pathologic prognostic factors in diffuse aggressive non-Hodgkin’s lymphoma. Hematol Oncol Clin North Am 1997; 11:847–62. 62. Armitage JO, Mauch PH, Harris, NL, Bierman P. Non-Hodgkin’s lymphomas. In: Cancer: Principles and Practice of Oncology, 6th edn (DeVita VT Jr, Hellman S, Rosenberg SA, eds). Philadelphia: Lippincott-Raven, 2001:2256–316. 63. Zinzani PL, Magagnoli M, Chierichetti F et al. The role of positron emission tomography (PET) in the management of lymphoma patients. Ann Oncol 1999; 10:1181–4. 64. Buchmann I, Moog F, Schirrmeister H et al. Positron emission tomography for detection and staging of malignant lymphoma. Rec Res Cancer Res 2000; 156:78–89. 65. Hoskins PJ, Ng V, Spinelli JJ et al. Prognostic variables in patients with diffuse large-cell lymphoma treated with MACOP-B. J Clin Oncol 1991; 9:220–6. 66. Danieu L, Wong G, Koziner B et al. Predictive model for prognosis in advanced diffuse histiocytic lymphoma. Cancer Res 1986; 46: 5372–9. 67. Fisher RI, Gaynor ER, Dahlberg S et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 1993; 328:1002–6. 68. Hutchins LF, Unger JM, Crowley JJ et al. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 1999; 341:2061–7. 69. Leonard RCF, Hayward RL, Prescott RJ et al. The identification of discrete prognostic groups in low grade non-Hodgkin’s lymphoma. Ann Oncol 1991; 2:655–62. 70. Soubeyran P, Eghbali H, Bonichon F et al. Low-grade follicular lymphomas: analysis of prognosis in a series of 281 patients. Eur J Cancer 1991; 27:1606–13.

Comprehensive Geriatric Oncology

1124

71. Seng JE, Petroni GR, Oken MM et al. A prognostic model for low grade follicular nonHodgkin’s lymphoma. Proc Am Soc Clin Oncol 1998; 17:10a (Abst 35). 72. Lopez-Guillermo A, Montserrat E, Bosch F et al. Applicability of the International Index for aggressive lymphomas to patients with low-grade lymphoma. J Clin Oncol 1994; 12:1343–8. 73. Bastion Y, Coiffier B. Is the International Prognostic Index for aggressive lymphoma patients useful for follicular lymphoma patients. J Clin Oncol 1995; 12:1340–2. 74. Moore DF, Cabanillas F. Overview of prognostic factors in non-Hodgkin’s lymphoma. Oncology 1998; 12(Suppl 8): 17–24. 75. Ezdinli EZ, Costello WG, Kucuk O et al. Effect of the degree of nodularity on the survival of patients with nodular lymphomas. J Clin Oncol 1987; 5:413–18. 76. Hu E, Weiss LM, Hoppe RT et al. Follicular and diffuse mixed small-cleaved and large-cell lymphoma—a clinicopathologic study. J Clin Oncol 1985; 3:1183–7. 77. Bastion Y, Berger F, Bryon P-A et al. Follicular lymphoma: assessment of prognostic factors in 127 patients followed for 10 years. Ann Oncol 1991; 2(Suppl 2): 123–9. 78. Nathwani BN, Metter GE, Miller TP et al. What should be the morphologic criteria for the subdivision of follicular lymphomas? Blood 1986; 69:837–45. 79. Macartney JC, Camplejohn RS, Morris R et al. DNA flow cytometry of follicular nonHodgkin’s lymphoma. J Clin Pathol 1991; 44: 215–18. 80. Horning SJ, Rosenberg SA. The natural history of initially untreated low-grade non-Hodgkin’s lymphomas. N Engl J Med 1984; 311:1471–5. 81. Rosenberg SA. The low-grade non-Hodgkin’s lymphomas: challenges and opportunities. J Clin Oncol 1985; 3:299–310. 82. Brice P, Bastion Y, Lepage E et al. Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Group D’Etude des Lymphomes Folliculaires. J Clin Oncol 1997; 15:1110–17. 83. Young RC, Longo DL, Glatstein E et al. The treatment of indolent lymphomas. Watchful waiting v aggressive combined modality treatment. Semin Hematol 1988; 25:11–26. 84. Cheson BD. Current approaches to therapy for indolent non-Hodgkin’s lymphoma. Oncology 1998; 12(Suppl 8): 25–34. 85. Cella D, Webster KA. Quality of life and treatment value in the management of hematologic malignancies. Semin Oncol 1999; 26(Suppl 14): 34–42. 86. Webster KL, Cella D. Quality of life in patients with low-grade non-Hodgkin’s lymphoma. Oncology 1998; 12:697–717. 87. French Cooperative Group on Chronic Lymphocytic Leukemia. Effects of chlorambucil and therapeutic decision in initial forms of chronic lymphocytic leukemia (stage A): results of a randomized clinical trial on 612 patients. Blood 1990; 75:1414–21. 88. Rai KR, Patel DV. Chronic lymphocytic leukemia In: Hematology. Basic Principles and Practice, 3rd edn (Hoffman R, Benz EJJ, Shattil SJ et al, eds). New York: Churchill Livingstone, 1999:1350–63. 89. Tallman MS, Hakimian D. Purine nucleoside analogs: emerging roles in indolent lymphoproliferative disorders. Blood 1995; 86: 2463–74. 90. Rai KR, Peterson BL, Appelbaum FR et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukaemia. N Engl J Med 2000; 343:1750–7. 91. Anaissie EJ, Kontoyiannis D, O’Brien S et al. Infections in patients with chronic lymphocytic leukemia treated with fludarabine. Ann Intern Med 1998; 129:559–66. 92. Leblond V, Ben-Othman T, Deconinck E et al. Activity of fludarabine in previously treated Waldenstrom’s macroglobulinemia: a report of 71 cases. J Clin Oncol 1998; 16:2060–4. 93. Papamichael D, Norton AJ, Foran JM et al. Immunocytoma: a retrospectve analysis from St. Bartholomew’s Hospital—1972 to 1996. J Clin Oncol 1999; 17:2847–53. 94. Foran JM, Rohatiner AZS, Coiffier B et al. Multicenter phase II study of fludarabine phosphate for patients with newly diagnosed lymphoplasmacytoid lymphoma, Waldenstrom’s macroglobulinemia, and mantle-cell lymphoma. J Clin Oncol 1999; 17:546–53.

Non-Hodgkin lymphomas

1125

95. Dimopoulos MA, Kantarjian H, Estey E et al. Treatment of Waldenstrom macroglobulinemia with 2-chlorodeoxyadenosine. Ann Intern Med 1993; 118:195–8. 96. Catovsky D, Matutes E. Splenic lymphoma with circulating villous lymphocytes/splenic marginal-zone lymphoma. Semin Hematol 1999; 36:148–54. 97. Coiffier B, Thieblemont C, Felman P et al. Indolent nonfollicular lymphomas: characteristics, treatment, and outcome. Semin Hematol 1999; 36:198–208. 98. Schechter NR, Yahalom J. Low-grade MALT lymphoma of the stomach: a review of treatment options. Int J Radiat Oncol Biol Phys 2000; 46:1093–103. 99. Fung CY, Grossbard ML, Linggood RM et al. Mucossa-associated lymphoid tissue lymphoma of the stomach: long term outcome after local treatment. Cancer 1999; 85:9–17. 100. Roggero E, Zucca E, Pinotti G et al. Eradication of helicobacter pylori infection in primary low-grade gastric lymphoma of mucosa-associated lymphoid tissue. Ann Intern Med 1995; 122: 767–9. 101. Morgner A, Bayerdorffer E, Neubauer A et al. Cure of Helicobacter pylori infection in 125 patients with primary gastric low-grade MALT lymphoma. Gut 1998; 43(2S): 64A. 102. Bayerdbrffer E, Morgner A, Thiede C et al. Cure of Helicobacter pylori infection is associated with long-term remission in limited stages of low-grade gastric MALT lymphoma. Gut 1999; 45(Suppl III): A68. 103. Hammel P, Haioun C, Chaumette MT et al. Efficacy of single-agent chemotherapy in lowgrade B-cell mucosa-associated lymphoid tissue lymphoma with prominent gastric expression. J Clin Oncol 1995; 13:2524–9. 104. Chen MG, Prosnitz LR, Gonzalez-Serva A et al. Results of radiotherapy in control of stage I and II non-Hodgkin’s lymphoma. Cancer 1979; 43:1245–54. 105. Hoppe RT: The role of radiation therapy in the management of the non-Hodgkin’s lymphomas. Cancer 1985; 55:2176–83. 106. MacManus M, Hoppe R. Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University. J Clin Oncol 1996; 14:1282–90. 107. McLaughlin P, Fuller L, Redman J et al. Stage I-II low-grade lymphomas: a prospective trial of combination chemotherapy and radiotherapy. Ann Oncol 1991; 2(Suppl 2): 137–40. 108. Yahalom J, Varsos G, Fuks Z et al. Adjuvant cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy after radiation therapy in stage I low-grade and intermediate-grade non-Hodgkin’s lymphoma. Results of a prospective randomized study. Cancer 1993; 71:2342– 50. 109. Landberg TG, Hakansson LG, Moller TR et al. CVP-remission-maintenance in stage I or II non-Hodgkin’s lymphomas. Preliminary results of a randomized study. Cancer 1979; 44:831–8. 110. Monfardini S, Banfi A, Bonadonna G et al. Improved five year survival after combined radiotherapy-chemotherapy for stage I-II non-Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys 1980; 6: 125–34. 111. Kelsey S, Newland A, Vaughan-Hudson G et al. A British National Lymphoma Investigation randomised trial of single agent chlorambucil plus radiotherapy versus radiotherapy alone in low grade localised non-Hodgkin’s lymphoma. Med Oncol 1994; 11:19–25. 112. Kennedy BJ, Bloomfield CD, Kiang DT et al. Combination versus successive single agent chemotherapy in lymphocytic lymphoma. Cancer 1978; 41:23–8. 113. Lister TA, Cullen MH, Beard MEJ et al. Comparison of combined and single-agent chemotherapy in non-Hodgkin’s lymphomas of favourable histologic type. BMJ 1978; i: 533–7. 114. Lepage E, Sebban C, Gisselbreche C et al. Treatment of low grade non-Hodgkins lymphomas: assessment of doxorubicin in a controlled trial. Hematol Oncol 1990; 8:31–9. 115. Dana B, Dahlberg S, Bharat N et al. Long term follow up of patients with low grade malignant lymphomas treated with doxorubicin-based chemotherapy or chemoimmunity. J Clin Oncol 1993; 11:644–51.

Comprehensive Geriatric Oncology

1126

116. Peterson B, Anderson J, Frizzera G et al. Combination chemotherapy prolongs survival in follicular mixed lymphoma. Proc Am Soc Clin Oncol 1990; 9:259. 117. Longo DL, Young RC, Hubbard SM et al. Prolonged initial remission in patients with nodular mixed lymphoma. Ann Intern Med 1984; 100:651–6. 118. Hilbe W, Apfelbeck U, Fridrik M et al. Interferon-a for the treatment of elderly patients with chronic myeloid leukaemia. Leuk Res 1998; 22:881–6. 119. Eyigun CP, Van Thiel DH, De Maria N. Use of interferon for the treatment of chronic hepatitis C in the elderly. Hepato-Gastroenterology 1998; 45:325–7. 120. Delannoy A, Sebban C, Cony-Makhoul P et al. Age-adapted induction treatment of acute lymphoblastic leukemia in the elderly and assessment of maintenance with interferon combined with chemotherapy. A multicentric prospective study in forty patients. French Group for Treatment of Adult Acute Lymphoblastic Leukemia. Leukemia 1997; 11:1429–34. 121. Oken MM, Leong R, Lenhard RE Ir et al. The addition of interferon or high dose cyclophosphamide to standard chemotherapy in the treatment of patients with multiple myeloma: phase III Eastern Cooperative Oncology Group clinical trial EST 9486. Cancer 1999; 86:957–68. 122. Foon KA, Sherwin SA, Abrams PG et al. Treatment of advanced non-Hodgkin’s lymphomas with recombinant leukocyte A interferon. N Engl J Med 1984; 311:1148–52. 123. Ozer H, Wiernik PH, Giles F et al. Recombinant interferon-α therapy in patients with follicular lymphoma. Cancer 1998; 82:1821–30. 124. Arranz R, Garcia-Alfonso P, Sobrino P et al. Role of α-2b interferon in the induction and maintenance treatment of low-grade non-Hodgkin’s lymphoma: results from a prospective, multicenter trial with double randomization. J Clin Oncol 1998; 16:1538–46. 125. Aviles A, Duque G, Talavera A et al. Interferon α2b as maintenance therapy in low grade malignant lymphoma improves duration of remission and survival. Leuk Lymphoma 1996; 20:495–9. 126. Dana BW, Unger J, Fisher RI: A randomized study of oc-interferon consolidation in patients with low-grade lymphoma who have responded to Pro-MACE-MOPP (day 1–8) (SWOG 8809). Proc Am Soc Clin Oncol 1998, 17:3a. 127. Hagenbeek A, Carde P, Meerwaldt JH et al. Maintenance of remission with human recombinant interferon alfa-2a in patients with stages III and IV low grade malignant nonHodgkin’s lymphoma. J Clin Oncol 1998; 16:41–7. 128. Peterson BA, Petroni GR, Oken MM et al. Cyclophosphamide versus cyclophosphamide plus interferon alfa-2b in follicular low grade lymphomas: an intergroup phase III trial (CALGB 8691 and EST 7486). Proc Am Soc Clin Oncol 1997; 16:14a (Abst 48). 129. Rohatiner A, Crowther D, Radford J et al. The role of interferon in follicular lymphoma. Proc Am Soc Clin Oncol 1996; 15:418. 130. Smalley R, Andersen J, Hawkins M et al. Interferon alfa combined with cytotoxic chemotherapy for patients with non-Hodgkin’s lymphoma. N Engl J Med 1992; 327:1336–41. 131. Unterhalt M, Herrmann R, Nahler M et al. Significant prolongation of disease free survival in advanced low grade non-Hodgkin lymphomas (NHL) by interferon α maintenance. Blood 1995; 86: 439a. 132. Solal-Celigny P, Lepage E, Brousse N et al. A doxorubicin containing regimen with or without interferon α2b (IFNab) in advanced follicular lymphomas. Final analysis of survival, toxicity and quality of life of the GELF86 trial. Blood 1996; 88:453a. 133. Anderson JW, Smalley RV. Interferon alfa plus chemotherapy for non-Hodgkin’s lymphoma: five year follow-up. N Engl J Med 1993; 329:1821–2. 134. Fisher RI, Dana BW, LeBlanc M et al. Interferon oc consolidation after intensive chemotherapy does not prolong the progression-free survival of patients with low-grade nonHodgkin’s lymphoma: results of the Southwest Oncology Group randomized phase III study 8890. J Clin Oncol 2000; 18:2010–16.

Non-Hodgkin lymphomas

1127

135. Coiffier B, Neidhardt-Berard EM, Tilly H et al. Fludarabine alone compared to CHVP plus interferon in elderly patients with follicular lymphoma and adverse prognostic parameters: a GELA study. Groupe d’Etudes des Lymphomes de l’Adulte. Ann Oncol 1999; 10: 1191–7. 136. Hagenbeek A, Eghbali H, Monfardini S et al. Fludarabine versus conventional CVP chemotherapy in newly diagnosed patients with stages III and IV low grade malignant nonHodgkin’s lymphoma. Preliminary results from a prospective, randomized phase III clinical trial in 381 patients. Blood 1998; 92(Suppl 10): 315e. 137. Klasa R, Meyer R, Shustik C et al. Fludarabine versus CVP in previously treated patients with progressive low grade non-Hodgkin’s lymphomas (lg-NHL). Proc Am Soc Clin Oncol 1999; 18:9a. 138. Maloney DG, Grillo-Lopez AJ, White CA et al. IDEC-C2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood 1997; 90: 2188–91. 139. Foran JM, Gupta RK, Cunningham D et al. A UK multicentre phase II study of rituximab (chimaeric anti-CD20 monoclonal antibody) in patients with follicular lymphoma, with PCR monitoring of molecular response. Br J Haematol 2000; 109:81–8. 140. McLaughlin P, Grillo-Lopez AJ, Link BK et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998; 16:2825–33. 141. Hainsworth JD, Burris HA 3rd, Morrissey LH et al. Rituximab monoclonal antibody as initial systemic therapy for patients with low-grade non-Hodgkins lymphoma. Blood 2000; 95:3052– 56. 142. Press OW. Innovative new therapies for non-Hodgkin’s lymphomas: monoclonal antibodies and immunoconjugates. In: American Society of Clinical Oncology Educational Book (Perry MC, ed). American Society of Clinical Oncology, 2000:328–37. 143. Kaminski MS, Estes J, Zasadny KR et al. Radioimmunotherapy with idodine 131I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term followup of the University of Michigan experience. Blood 2000; 96:1259–66. 144. Vose JM, Wahl RL, Saleh M et al. Multicenter phase II study of iodine-131 tositumomab for chemotherapy-relapsed/refractory low-grade and transformed low-grade B-cell non-Hodgkin’s lymphomas. J Clin Oncol 2000; 18:1316–23. 145. Gribben JG. Bone marrow transplantation for low-grade B-cell malignancies. Curr Opin Oncol 1997; 9:117–21. 146. Stiff PJ. Blood and marrow transplantation in relapsed or refractory non-Hodgkin’s lymphoma. Oncology 1998; 12(Suppl 8): 56–62. 147. Freedman AS, Ritz J, Neuberg D et al. Autologous bone marrow transplantation in 69 patients with a history of low-grade B-cell non-Hodgkin’s lymphoma. Blood 1991; 77:2524–9. 148. Roitman D, Abraham R, Tripp K et al. High treatment-related mortality in elderly patients undergoing autotransplants for non-Hodgkin’s lymphoma (NHL). Proc Am Soc Clin Oncol 1998; 17: 86a. 149. Fisher RI, Dahlberg S, Nathwani BN et al. A clinical analysis of two indolent lymphoma entities: mantle cell lymphoma and marginal zone lymphoma (including the mucosa-associated lymphoid tissue and monocytoid B-cell subcategories): A Southwest Oncology Group study. Blood 1995; 85:1075–82. 150. Weisenburger DD, Armitage JO. Mantle cell lymphoma—an entity comes of age. Blood 1996; 87:4483–94. 151. Velders GA, Kluin-Nelemans JC, De Boer CJ et al. Mantle-cell lymphoma: a populationbased clinical study. J Clin Oncol 1996; 14:1269–74. 152. Teodorovic I, Pittaluga S, Kluin-Nelemans JC et al. Efficacy of four different regimens in 64 mantle-cell lymphoma cases: clinicopathologic comparison with 498 other non-Hodgkin’s lymphoma subtypes. J Clin Oncol 1995; 13:2819–26.

Comprehensive Geriatric Oncology

1128

153. Meusers P, Englehard M, Bartels H et al. Multicentre randomized therapeutic trial for advanced centrocytic lymphoma: anthracycline does not improve the prognosis. Hematol Oncol 1989; 7:365–80. 154. Argatoff LH, Connors JM, Klasa RI et al. Mantle cell lymphoma: a clinicopathologic study of 80 cases. Blood 1997; 89:2067–78. 155. Decaudin D, Bosq J, Tertian G et al. Phase II trial of fludarabine monophosphate in patients with mantle-cell lymphomas. J Clin Oncol 1998; 16:579–83. 156. Kaufmann T, Coleman M, Pasmantier M. Purine analogue therapy for untreated mantle cell and monocytoid lymphomas: immunophenotype does not predict response to fludarabine and cladribine—CdA). Proc Am Soc Clin Oncol 1996; 15:1320. 157. Foran JM, Rohatiner AZ, Cunningham D et al. European phase II study of rituximab (chimeric anti-CD20 monoclonal antibody) for patients with newly diagnosed mantle-cell lymphoma and previously treated mantle-cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma. J Clin Oncol 2000; 18:317–24. 158. Stewart DA, Vose JM, Weisenburger DD et al. The role of high-dose therapy and autologous hematopoietic stem cell transplantation for mantle cell lymphoma. Ann Oncol 1995; 6:263–6. 159. Nademanee A, Molina A, Smith E et al. High-dose therapy and autologous peripheral blood stem transplantation (ABSCT) during first remission in patients with advanced stages and poor prognosis mantle cell lymphoma. Blood 1996; 88(Suppl 1): 474. 160. Blay JY, Sebban C, Surbiguet C et al. High-dose chemotherapy with hematopoietic stem cell transplantation in patients with mantle cell or diffuse centrocytic non-Hodgkin’s lymphomas: a single center experience on 18 patients. Bone Marrow Transplant 1998; 21:51–4. 161. Armitage JO. Management of mantle cell lymphoma. Oncology 1998; 12(Suppl 8): 49–55. 162. Freedman AS, Neuberg D, Gribben JG et al. High-dose chemoradiotherapy and anti-B-cell monoclonal antibody-purged autologus bone marrow transplantation in mantle-cell lymphoma: no evidence for long-term remission. J Clin Oncol 1998; 16:13–18. 163. Jagannath S, Velasquez WS, Tucker SL et al. Stage IV diffuse large-cell lymphoma: a longterm analysis. J Clin Oncol 1985; 3:39–47. 164. Cowan RA, Jones M, Harris M et al. Prognostic factors in high and intermediate grade nonHodgkin’s lymphoma. Br J Cancer 1989; 59:276–82. 165. Velasquez WS, Jagannath S, Tucker SL et al. Risk classification as the basis for clinical staging of diffuse large-cell lymphoma derived from 10-year survival data. Blood 1989; 74:551– 7. 166. Bloomfield CD, Goldman A, Dick F et al. Multivariate analysis of prognostic factors in the non-Hodgkin’s malignant lymphomas. Cancer 1974; 33:870–9. 167. Cabanillas F, Burke JS, Smith RL et al. Factors predicting for response and survival in adults with advanced non-Hodgkin’s lymphoma. Arch Intern Med 1978; 138. 168. Fisher RI, Hubbard SM, DeVita VT et al. Factors predicting long-term survival in diffuse mixed, histiocytic, or undifferentiated lymphoma. Blood 1981; 58:45–51. 169. Armitage JO, Dick FR, Corder MP et al. Predicting therapeutic outcome in patients with diffuse histiocytic lymphoma treated with cyclophosphamide, Adriamycin, vincristine and prednisone (CHOP). Cancer 1982; 50:1695–702. 170. Koziner B, Little C, Passe S et al. Treatment of advanced diffuse histiocytic lymphoma: an anlysis of prognostic variables. Cancer 1982; 49:1571–9. 171. Shipp MA, Harrington DP, Klatt MM et al. Identification of major prognostic subgroups of patients with large-cell lymphoma treated with m-BACOD or M-BACOD. Ann Intern Med 1986; 104: 757–65. 172. Vose JM, Armitage JO, Weisenburger DD et al. The importance of age in survival of patients treated with chemotherapy for aggressive non-Hodgkin’s lymphoma. J Clin Oncol 1988; 6:1838–44.

Non-Hodgkin lymphomas

1129

173. Grogan L, Corbally N, Dervan PA et al. Comparable prognostic factors and survival in elderly patients with aggressive non-Hodgkin’s lymphoma treated with standard-dose Adriamycinbased regimens. Ann Oncol 1994; 5(Suppl 2): S47–51. 174. Gaynor EB, Dahlberg S, Fisher RI. Factors affecting reduced survival of the elderly with intermediate and high grade lymphoma: an analysis of SWOG-8516 (INT 0067)—the National High Priority Lymphoma Study—a randomized comparison of CHOP vs m-BACOD vs ProMACE-CytaBOM vs MACOP-B. Proc Am Soc Clin Oncol 1994; 13:370. 175. Dixon DO, Neilan B, Jones SE et al. Effect of age on therapeutic outcome in advanced diffuse histiocytic lymphoma: the Southwest Oncology Group experience. J Clin Oncol 1986; 4:295– 305. 176. Gottlieb AJ, Anderson JR, Ginsberg SJ et al. A randomized comparison of methotrexate dose and the addition of bleomycin to CHOP therapy for diffuse large cell lymphoma and other nonHodgkin’s lymphomas: Cancer and Leukemia Group B study 7851. Cancer 1990; 66:1888–96. 177. International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 1993; 329:987–94. 178. Sweet DL, Golomb HM. The treatment of histiocytic lymphoma. Semin Oncol 1980; 7:302–9. 179. DeVita VT Jr, Serpick AA, Carbone PP. Combination chemotherapy in the treatment of advanced Hodgkin’s disease. Ann Intern Med 1970; 73:881–95. 180. DeVita VT, Canellos GP, Chabner B et al. Advanced diffuse histiocytic lymphoma: a potentially curable disease. Lancet 1975; i: 248–50. 181. McKelvey EM, Gottlieb JA, Wilson HE et al. Hydroxydaunomycin (Adriamycin) combination chemotherapy in malignant lymphoma. Cancer 1976; 38:1484–93. 182. Fisher RI, Miller TP, Dana BW et al. Southwest Oncology Group clinical trials for intermediate- and high-grade non-Hodgkin’s lymphomas. Semin Hematol 1987; 24(Suppl 1): 21–5. 183. Longo DL, DeVita VT, Duffey PL et al. Superiority of ProMACE-CytaBOM over ProMACEMOPP in the treatment of advanced diffuse aggressive lymphoma: results of a prospective randomized trial. J Clin Oncol 1991; 9:25–38. 184. Klimo P, Connors JM. MACOP-B chemotherapy for the treatment of diffuse large-cell lymphoma. Ann Intern Med 1985; 102:596–602. 185. Shipp MA, Yeap BY, Harrington DP et al. The m-BACOD combination chemotherapy regimen in large-cell lymphoma: analysis of the completed trial and comparison with the MBACOD regimen. J Clin Oncol 1990; 8:84–93. 186. Skarin AT, Canellos GP, Rosenthal DS et al. Improved prognosis of diffuse histiocytic and undifferentiated lymphoma by use of high dose methotrexate alternating with standard agents (M-BACOD). J Clin Oncol 1983; 1:91–8. 187. Connors JM, Klimo P. MACOP-B chemotherapy for malignant lymphomas and related conditions: 1987 update and additional observations. Semin Hematol 1988; 25(Suppl 2): 41–6. 188. Fisher RI, Gaynor ER, Dahlberg S et al. A phase III comparison of CHOP vs. m-BACOD vs. Pro-MACE-CytaBOM vs. MACOP-B in patients with intermediate- or high-grade nonHodgkin’s lymphoma: results of SWOG-8516 (Intergroup 0067), the National High-Priority Lymphoma Study. Ann Oncol 1994; 5:91–5. 189. Armitage JO, Potter JF. Aggressive chemotherapy for diffuse histiocytic lymphoma in the elderly: increased complications with advancing age. J Am Geriatr Soc 1984; 32:269–73. 190. Tirelli U, Carbone A, Crivellari D et al. A phase II trial of teniposide (VM 26) in advanced non-Hodgkin’s lymphoma, with emphasis on the treatment of elderly patients. Cancer 1984; 54:393–6. 191. Tirelli U, Carbone A, Zagonel V et al. Non-Hodgkin’s lymphomas in the elderly: prospective studies with specifically devised chemotherapy regimens in 66 patients. Eur J Cancer Clin Oncol 1987; 23:535–40. 192. Watkin SW, Green JA. Non-Hodgkin’s lymphoma. A four-drug regimen suitable for elderly patients with advanced disease. Acta Oncol 1990; 29:733–7.

Comprehensive Geriatric Oncology

1130

193. Zagonel V, Tirelli U, Carbone A et al. Combination chemotherapy specifically devised for elderly patients with unfavorable non-Hodgkin’s lymphoma. Cancer Invest 1990; 8:577–82. 194. Sonneveld P, Michiels JJ. Full dose chemotherapy in elderly patients with non-Hodgkin’s lymphoma: a feasibility study using a mitoxantrone containing regimen. Br J Cancer 1990; 62:105–8. 195. McMaster ML, Johnson DH, Greer JP et al. A brief-duration combination chemotherapy for elderly patients with poor-prognosis non-Hodgkin’s lymphoma. Cancer 1991; 67:1487–92. 196. McMaster ML, Greer JP, Greco A et al. Effective treatment of small non-cleaved cell lymphoma with high-intensity, brief duration chemotherapy. J Clin Oncol 1991; 9:941–6. 197. Kitamura K, Takaku F. Pirarubicin: a novel derivative of doxorubicin. THP-COP therapy for non-Hodgkin’s lymphoma in the elderly. Am J Clin Oncol 1990; 13(Suppl 1): 815–19. 198. Tigaud J-D, Demolombe S, Bastion Y et al. Ifosfamide continuous infusion plus etoposide in the treatment of elderly patients with aggressive lymphoma: a phase II study. Hematol Oncol 1991; 9: 225–33. 199. Salvagno L, Contu A, Bianco A et al. A combination of mitoxantrone, etoposide and prednisone in elderly patients with non-Hodgkin’s lymphoma. Ann Oncol 1992; 3:833–7. 200. O’Reilly SE, Klimo P, Connors JM. Low-dose ACOP-B and VABE: weekly chemotherapy for elderly patients with advanced-stage diffuse large-cell lymphoma. J Clin Oncol 1991; 9:741–7. 201. Tirelli U, Zagonel V, Errante D et al. A prospective study of a new combination chemotherapy regimen in patients older that 70 years with unfavorable non-Hodgkin’s lymphoma. J Clin Oncol 1992; 10: 228–36. 202. Ansell SM, Falkson G. A phase II trial of a chemotherapy combination in elderly patients with aggressive lymphoma. Ann Oncol 1993; 4:172–5. 203. Martelli M, Guglielmi C, Coluzzi S et al. P-VABEC: A prospective study of a new weekly chemotherapy regimen for elderly aggressive non-Hodgkin’s lymphoma. J Clin Oncol 1993; 11:2362–9. 204. O’Reilly SE, Connors JM, Howdle S et al. In search of an optimal regimen for elderly patients with advanced-stage diffuse large-cell lymphoma: results of a phase II study of P/DOCE chemotherapy. J Clin Oncol 1993; 11:2250–7. 205. Bertini M, Freilone R, Vitolo U et al. P-VEBEC: a new 8-weekly schedule with or without rGCSF for elderly patients with aggressive non-Hodgkin’s lymphoma (NHL). Ann Oncol 1994; 5: 895–900. 206. Young WA, Greco FA, Greer JP et al. Aggressive non-Hodgkin’s lymphoma in the elderly: an effective, well-tolerated treatment regimen containing extended-schedule etoposide. J Natl Cancer Inst 1994; 86:1346–7. 207. Bessell EM, Coutts A, Fletcher J et al. Non-Hodgkin’s lymphoma in elderly patients: a phase II study of MCOP chemotherapy in patients aged 70 years or over with intermediate- or highgrade histology. Eur J Cancer 1994; 30A: 1337–41. 208. Goss P, Burkes R, Rudinskas L et al. A phase II trial of prednisone, oral etoposide, and novantrone (PEN) as initial treatment of non-Hodgkin’s lymphoma in elderly patients. Leuk Lymphoma 1995; 18: 145–52. 209. Novitzky N, King HS, Johnson C et al. Treatment of aggressive non-Hodgkin’s lymphoma in the elderly. Am J Hematol 1995; 49: 103–8. 210. Bertini M, Freilone R, Vitolo U et al. The treatment of elderly patients with aggressive nonHodgkin’s lymphomas: feasibility and efficacy of an intensive multidrug regimen. Leuk Lymphoma 1996; 22:483–93. 211. Niitsu N, Umeda M. THP-COPBLM (pirarubicin, cyclophosphamide, vincristine, prednisone, bleomycin and procarbazine) regimen combined with granulocyte colony-stimulating factor (GCSF) for non-Hodgkin’s lymphoma in elderly patients: a prospective study. Leukemia 1997; 11:1817–20.

Non-Hodgkin lymphomas

1131

212. Niitsu N. Prognostic factors in elderly patients with non-Hodgkin’s lymphoma treated with cyclophosphamide, vincristine, prednisone, bleomycin, Adriamycin, procarbazine (COPBLAM) therapy. Acta Haematol 1997; 98:130–5. 213. Merli F, Federico M, Avanzini P et al. Weekly administration of vincristine, cyclophosphamide, mitoxantrone and bleomycin (VEMB) in the treatment of elderly aggressive non Hodgkin’s lymphoma. Haematologica 1998; 83:217–21. 214. Yau JC, Germond C, Gluck S et al. Mitoxantrone, prednimustine, and vincristine for elderly patients with aggressive non-Hodgkin’s lymphoma. Am J Hematol 1998; 59:156–60. 215. Wiedemann GJ, Zchaber R, Hegewisch-Becker S et al. Efficacy and safety of two oral trofosfamide schedules in elderly patients (>65 yrs) with refractory non-Hodgkin’s lymphoma (NHL). Proc Am Soc Clin Oncol 1998; 17:13a. 216. Sherwood GK, Fredette R, Roberson JM. N-COPE. A potentially curative regimen for the treatment of aggressive non-Hodgkin’s lymphoma (NHL) in frail elderly patients. Proc Am Soc Clin Oncol 1998; 17:38a. 217. Soubeyran P, Eghbali H, Ceccaldi J et al. Randomized phase II trial of two schedules including cyclophosphamide (C), epirubicin (E), etoposide (V), vincristine (O) and prednisone (P) in intermediate and high grade non-Hodgkin’s lymphoma (HG NHL) in the elderly. Proc Am Soc Clin Oncol 1998; 17:38a. 218. Salvagno L, Bianco A, Contu A et al. Feasibility of 2 regimens with mitoxantrone (MX) and VP-16 (VP) in elderly patients (pts) with non-Hodgkin’s lymphoma (NHL). Proc Am Soc Clin Oncol 1998; 17:36a. 219. Meyer RM, Browman GP, Samosh ML et al. Randomized phase II comparison of standard CHOP with weekly CHOP in elderly patients with non-Hodgkin’s lymphoma. J Clin Oncol 1995; 13: 2386–93. 220. Bastion Y, Blay J-Y, Divine M et al. Elderly patients with aggressive non-Hodgkin’s lymphoma: disease presentation, response to treatment and survival—a Groupe d’Etude des Lymphomes de FAdulte study on 453 patients older than 69 years. J Clin Oncol 1997; 15:2945– 53. 221. Zinzani PL, Pavone E, Storti S et al. Randomized trial with or without granulocyte colonystimulating factor as adjunct to induction VNCOP-B treatment of elderly high-grade nonHodgkin’s lymphoma. Blood 1997; 89:3974–9. 222. Tirelli U, Errante D, Van Glabbeke M et al. CHOP is the standard regimen in patients ≥70 years of age with intermediate-grade and high-grade non-Hodgkin’s lymphoma: results of a randomized study of the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Study Group. J CHn Oncol 1998; 16:27–34. 223. Tirelli U, Zagonel V, Errante D et al. Treatment of non-Hodgkin’s lymphoma in the elderly: an update. Hematol Oncol 1998; 16:1–13. 224. Anderlinii P, Benjamin Rs, Wong FC et al. Idarubicin cardiotoxicity: a retrospective study in acute myeloid leukemia and myelodysplasia. J Clin Oncol 1995; 13:2827–34. 225. Cottin Y, Touzery C, Dalloz F et al. Comparison of epirubicin and doxorubicin cardiotoxicity induced by low doses: evolution of the diastolic and systolic parameters studied by radionucide angiography. Clin Cardiol 1988; 21:665–70. 226. Singal PK, Illiskovic N. Current concepts: Doxorubicin-induced cardiomyopathy. N Engl J Med 1998; 339:900–5. 227. Bezwoda W, Rastogi RB, Valla AE et al. Long-term results of a multicentre randomised, comparative phase III trial of CHOP versus CNOP regimens in patients with intermediate- and high-grade non-Hodgkin’s lymphomas. Eur J Cancer 1995; 31A: 903–11. 228. Bennett JM, Muss HB, Doroshow JH et al. A randomized multi-center trial comparing mitoxantrone, cyclophosphamide, and flurorouracil in the therapy of metastatic breast carcinoma. J Clin Oncol 1988; 6:1611–20.

Comprehensive Geriatric Oncology

1132

229. Faulds D, Blafour JA, Chrisp P et al. Mitoxantrone. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the chemotherapy of cancer. Drugs 1991; 41: 400–49. 230. Gomez H, Hidalgo M, Casanova L et al. Risk factors for treatment-related death in elderly patients with aggressive non-Hodgkin’s lymphoma: results of a multivariate analysis. J Clin Oncol 1998; 16: 2065–9. 231. Talcott JA, Finberg R, Mayer RJ et al. The medical course of cancer patients with fever and neutropenia. Clinical identification of a low-risk subgroup at presentation. Arch Intern Med 1988; 148: 2561–8. 232. Pettengell R, Gurney H, Radford JA et al. Granulocyte colony-stimulating factor to prevent dose-limiting neutropenia in non-Hodgkin’s lymphoma: a randomized controlled trial. Blood 1992; 80:1430–6. 233. Gerhartz HH, Engelhard M, Meusers P et al. Randomized, double-blind, placebo-controlled, phase III study of recombinant human granulocyte-macrophage colony-stimulating factor as adjunct to induction treatment of high-grade malignant non-Hodgkin’s lymphomas. Blood 1993; 82:2329–39. 234. Jacobson JO, Grossbard M, Shulman LN et al. CHOP chemotherapy with G-CSF in elderly patients with intermediate grade lymphoma (IGL): full dose intensity is possible. Proc Am Soc Clin Oncol 1998; 17:11a. 235. Meyer RM, Gyger M, Langley R et al. A phase I trial of standard and cyclophosphamide doseescalated CHOP with granulocyte colony stimulating factor in elderly patients with nonHodgkin’s lymphoma. Leuk Lymphoma 1998; 30:591–600. 236. Coiffier B, Haioun C, Ketterer N et al. Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood 1998; 92:1927–32. 237. Coiffier B, Lepage E, Herbrecht R et al. Mabthera (rituximab) plus CHOP is superior to CHOP alone in elderly patients with diffuse large B-cell lymphoma (DLCL): interim results of a randomzied GELA trial. Blood 2000; 96:2239. 238. Jones SE, Fuks Z, Kaplan HS et al. Non-Hodgkin’s lymphomas. V. Results of radiotherapy. Cancer 1973; 32:682–91. 239. Levitt SH, Bloomfield CD, Frizzera G et al. Curative radiotherapy for localized diffuse histiocytic lymphoma. Cancer Treat Rep 1980; 64:175–7. 240. Kaminski MS, Coleman CN, Colby TV et al. Factors predicting survival in adults with stage I and II large-cell lymphoma treated with primary radiation therapy. Ann Intern Med 1986; 104:747–56. 241. Miller TP, Jones SE. Initial chemotherapy for clinically localized lymphomas of unfavorable histology. Blood 1983; 62:413–18. 242. Glick JH, Kim K, Earle J et al. An ECOG randomized phase III trial of CHOP vs. CHOP+radiotherapy (XRT) for intermediate grade early stage non-Hodgkin’s lymphoma (NHL). Proc Am Soc Clin Oncol 1995; 14:391. 243. Miller TP, Dahlberg S, Cassady JR et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin’s lymphoma. N Engl J Med 1998; 339:21–6. 244. Jones SE, Miller TP, Connors JM. Long-term follow-up and analysis for prognostic factors for patients with limited-stage diffuse large-cell lymphoma treated with initial chemotherapy with or without adjuvant radiotherapy. J Clin Oncol 1989; 7: 1186–91.

49 Advances in the treatment of multiple myeloma in the elderly patient Gabriela Ballester, Oscar Ballester, Claudia Corrado, David Vesole Introduction This chapter will review the treatment options available today for the elderly patient with mutliple myeloma. Nearly three decades of clinical trials exploring conventional-dose chemotherapy have resulted in no appreciable improvement in the outcomes of patients with myeloma. The past 10 years, however, have seen the development of new strategies and early confirmation of their benefits. These will be the primary focus of this chapter and include (i) the role of high-dose therapy with autologous hematopoietic stem cell transplantation (HSCT), (ii) demonstration of a graft-versus-myeloma effect, (iii) adjuvant therapy of bone disease, and (iv) activity of thalidomide. Each of these developments represents substantial improvements in survival, disease control, and/or quality of life of patients with myeloma. In the last section, we shall briefly discuss how recent knowledge gained in our understanding of the biology of the disease is shaping the development of new therapies. An extensive discussion on the biology, clinical features of the disease, and conventional therapy of this disease is outside the scope of this chapter. The reader is referred to several excellent recent reviews on the subject.1–3 Multiple myeloma in the elderly does not appear to have distinct biological or clinical characteristics compared with those of younger patients. Several studies (reviewed by Ballaster et al4) have indicated that the outcomes of elderly patients with myeloma are similar to those of younger individuals, provided they receive comparable therapy. The very old myeloma patient, however, may be at higher risk primarily from the occurrence of comorbid conditions. In a recent review of 130 patients over the age of 75, only patients over 85 were found to have a poor prognosis. The diagnosis of myeloma is more often delayed in older patients. This appears to be related to the fact that bone pain is initially neglected or misinterpreted in older patients, since this is a common complaint. The study also found that infections are more common at presentation in the elderly population.5

Table 49.1 Prognostic factors in multiple myeloma • Durie-Salmon clinical stage III • Elevated serum β2-microglobulin levels • Cytogenetic abnormalities, particularly involving chromosome 13 • Plasmablastic morphology • Elevated serum C-reactive protein • Elevated serum interleukin-6 receptor levels

Comprehensive Geriatric Oncology

1134

• Decreased serum albumin levels

The decision to treat a newly diagnosed patient is based on the presence of significant symptoms (bone pain, hypercalcemia, hyperviscosity, renal failure, or anemia) or by a profile of known prognostic factors (Table 49.1) that will predict that the development of symptomatic disease is imminent. It is important to stress that some patients with asymptomatic stage I disease can be followed with observation, without active therapy, for extended periods of time. Patients fulfilling the criteria for stage I multiple myeloma but with relatively small monoclonal protein peaks and no evidence of osteolytic bone lesions could remain stable for several years before therapy is required. This is particularly relevant for the older population, whose quality of life is more likely to be compromised by unnecessary toxicity. Outside clinical trials, these patients, as well as those with monoclonal gammopathies of undetermined significance (MGUS) or with indolent/ smoldering myeloma, should not be treated until the development of progressive disease. Chemotherapy has been the primary form of therapy for patients with multiple myeloma. Single alkylating agents in combination with pulsed steroids or multiagent combination chemotherapy including anthracyclines and vinca alkaloids have been the standards. No single regimen has been shown to produce superior results, although some combination chemotherapy programs (such as VAD: vincristine, doxorubicin, and dexamethasone) may result in higher remission rates and more profound cytoreductions. If the patient is a potential candidate for autologous HSCT, it is advisable to avoid extensive use of alkylators, such as melphalan. VAD or similar regimens are preferred in these cases. High-dose therapy with autologous hematopoietic stem cell transplantation The landmark French trial published in 1996 defined the role of high-dose therapy with autologous stem cell rescue in multiple myeloma.6 In this phase III study, 200 patients with symptomatic multiple myeloma were prospectively randomized to receive conventional-dose chemotherapy with multiple alkylating agents or high-dose therapy with autologous HSCT. High-dose therapy consisted of melphalan 140mg/m2 plus total body irradiation (TBI). Transplanted patients received bone marrow grafts. At the time of the original report, with a median follow-up of 37–41 months, there was a significant improvement in disease-free survival (DFS) and overall survival (OS) for patients assigned to the high-dose therapy arm compared with those in the conventional chemotherapy arm. The OS rate at 5 years was slightly over 50% in the high-dose group, compared with 12% in the conventional-dose chemotherapy arm. In this trial, the control group behaved as expected from similarly treated patients in numerous other trials of conventional-dose chemotherapy. This study has recently been updated, now with up to 8 years of follow-up, and continues to show a benefit for the high-dose therapy group. While the trial included only patients with age up to 65, numerous other reports have demonstrated that older patients are able to tolerate and benefit from high-dose therapy with autologous transplants. Table 49.2 summarizes some of these reports.7–11 No

Advances in the treatment of multiple myeloma in the elderly patient

1135

differences in hematological recovery or toxicity were observed when myeloma patients older than 60 were compared with younger age groups. In only one of these studies, which included 20 patients older than 60, was the outcome of older patients inferior to that of the younger population.8 The largest reported series, which included 70 myeloma patients older than 70, suggested that melphalan 140mg/m2 with autol- ogous stem cell support was well tolerated in this population, some of whom were able to receive tandem transplants. The transplant-related mortality rate was 2% for the first transplant and 10% after the second. Patients who received tandem transplants (n=31) had a median eventfree survival (EFS) of 4 years. While it is clear that high-dose therapy can improve the response rate (including complete clinical remissions), DFS and OS, the issue is now whether any proportion of patients are cured with this approach. Documentation that some patients can live for long periods of time (>10 years) in complete remission has lead to the concept of ‘functional cures’. This concept may be more relevant to the elderly patient. Since their lifeexpectancy is limited, many years of disease control could be considered more equivalent to a ‘functional cure’. High-dose therapy upfront versus at time of relapse Since many patients do respond to conventional therapy and may enjoy a period of disease control without further therapy (plateau phase), the issue has been raised as whether high-dose therapy should be used as part of the initial treatment or should be reserved for the time of relapse. A prospective randomized study has compared these two approaches.12 The reported OS from the time of entry into the study was similar in the two groups. However, the study found a difference in the group’s TwiSTT scores (time without symptoms, therapy, or therapy-related toxicity)—a measure of quality of life— favoring the patients transplanted ‘upfront’.

Table 49.2 High-dose therapy with autologous transplants for multiple myeloma in elderly patients Authors

Inclusion agea

No. of cases

TRM rate (%)

CR rate (%)

Median EFS (months)

Palumbo et al7

>55 (64)

71

0

47

34

Dumontet et al8

>60 (63)

20

NA

NA

12

Siegel et al9

>65 (67)

49

8

20

18

>65 (67)

17

17

35

24

>70 (72)

70

2–16

20–28

34–36

Sirohi et al

10 11

Badros et al

TRM, transplant-related mortality; CR, complete remission; EFS, event-free survival; NA, not available. a Median in parentheses.

Comprehensive Geriatric Oncology

1136

How do we improve the outcome of autologous transplants? While autologous transplants improve the survival and disease-free survival of patients with symptomatic myeloma, less than 50% of patients achieve a complete remission and nearly 50% will relapse and die in the first 5 years. The success of autologous transplants depends primarily on the efficacy of the high-dose regimen in eliminating tumor cells and on the ability of the graft to reconstitute hematopoiesis without reseeding tumor cells (autologous grafts are nearly always contaminated by tumor cells). Therefore (at least theoretically), the outcomes of autologous transplants could be improved by enhancing the tumor kill efficacy of the high-dose regimen and by means of creating a tumor-free graft. The University of Arkansas has explored tandem transplants (two sequential transplants 3–6 months apart), utilizing melphalan 200mg/m2 as the high-dose regimen and autologous bone marrow or peripheral blood stem cells. An analysis of their newly diagnosed patients revealed a 58% OS rate at 5 years, with a proportion of patients remaining progression-free at this time point.13 As with all other series, there is a continuous relapse rate and no apparent plateau in the progression-free survival curve, suggesting that a proportion of patients may be cured. Tandem transplants can be done with a relatively low transplant-related mortality rate of about 2–5%. A recent preliminary report has suggested that tandem transplants are superior to single transplants, particularly when peripheral blood stem cells are utilized. Some 400 patients were randomized to single or double transplant using either bone marrow or peripheral blood grafts. The proportion of patients in complete remission or very good partial remission, EFS, and OS appear to indicate a benefit for the use of peripheral stem cells over bone marrow grafts, and for tandem compared with single transplants. The full report of this trial is awaited.14 A comparison of the original regimen used by the French randomized study (melphalan 140mg/m2 plus TBI) with single-agent melphalan at 200mg/m2 showed basically that there is no DFS benefit for one regimen over the other. OS was better with melphalan 200mg/m2—a difference attributed to the better salvage of patients after relapse. Melphalan 200mg/m2 was also better tolerated. Therefore, melphalan 200mg/m2 is currently considered the standard program against which newer regimens should be compared.15 Another approach explored the issue of tumor cell contamination of autologous grafts. All bone marrow grafts and a large percentage of peripheral blood stem cell grafts are contaminated with tumor cells. Various approaches have been explored to purge grafts of tumor cells. Positive selection of stem cells based on an anti-CD34 monoclonal antibody resulted in a several-log reduction in the number of contaminating tumor cells.16,17 A prospective randomized trial compared CD34-selected peripheral blood grafts with unselected (standard-arm) grafts. While the study demonstrated that engraftment and toxicity were not different with the use of grafts selected for CD34+ cells, there was no OS or DFS advantage for the study population.16 The complete remission rate in this trial was very low: only 15–16%. The CD34 selection yielded a tumor-negative graft by polymerase chain reaction (PCR) analysis in only half of the patients in the selected arm. Since most patients did have clinically evident residual disease after high-dose therapy, there was no demonstrable benefit to receiving a purged graft.

Advances in the treatment of multiple myeloma in the elderly patient

1137

Graft-versus-myeloma effect The existence of a graft-versus-myeloma (GVM) effect was first suggested by the outcomes of patients in the rather limited experience with allogeneic transplants. While allogeneic transplants have been associated with a high transplant-related mortality rate, the risk of relapse decreases significantly after 2–3 years, suggesting that a proportion of survivors may in fact be cured.18 Following an allogeneic transplant, a significant proportion of patients achieve clinical and molecular complete remissions, including individuals who have remained free of disease for more than 10 years.19 In comparison, after autologous transplants, the majority of the patients have evidence of molecular residual disease—even among those who achieve clinical complete remissions. This difference is attributed to the potential GVM effect of the transplanted donor immune cells. This notion has been further confirmed by the ability of donor lymphocyte infusions (DLI) to achieve long-lasting complete remissions in patients who have relapsed after allogeneic transplants.20,21 The risk involved with the use of DLI is the development of graft-versus-host disease (GVHD) and bone marrow aplasia. Some patients can achieve a response to DLI without development of GVHD or marrow aplasia, suggesting that the GVM effect and GVHD are parallel phenomena—but not necessarily the same. An approach explored to balance both effects is the use of T-cell-depleted allogeneic transplants (to decrease the risk of GVHD), followed by DLI (to gain a GVM effect).22 Patients with multiple myeloma tend to be older and tend to have a higher mortality rate with allogeneic transplants (as compared with allogeneic transplants for other diagnoses). An attractive approach to decrease the early mortality rate of allogeneic transplants is the use of non-myeloablative conditioning regimens. A recent report compared the mortality rates for standard allogeneic transplants with those of nonmyeloablative regimens in multiple myeloma. When patients who have had only one previous autologous transplant are analyzed, a very low mortality rate is observed as compared with the standard allogeneic transplant.23 Investigators in Seattle are using a tandem approach: an initial autologous transplant with high-dose melphalan to debulk the disease, followed in 3–6 months by an allogeneic transplant utilizing a non-myeoablative conditioning to gain the GVM effect. Preliminary reports are encouraging.24 Is it possible to generate an ‘autologous’ graft-versus-myeloma effect? Spontaneously occurring clones of T cells capable of lysing autologous myeloma cells have been identified in some patients with multiple myeloma. This is a specific phenomenon, since these T cells were not cytotoxic to other cells, including autologous B cells or T cells, virally transformed cells, or a panel of myeloma cell lines. While the antigen triggering this response was not identified in the study, it was demonstrated that lysis was major histocompatibility complex (MHC) class I-dependent.25 It is possible, then, that individual patients can induce cytotoxic T-cell responses to their own tumor cells, and justifies the intense efforts by many institutions in developing approaches to generate such responses. These include vaccination trials utilizing the

Comprehensive Geriatric Oncology

1138

idiotypic protein, antigen-pulsed presenting cells, or whole tumor cells.26–29 The idiotypic protein produced and present only in the tumor cells of each patient is the obvious tumorspecific antigen to be targeted. While several groups have demonstrated that patients can build cellular and humoral responses (although not consistently) to idiotypic determinants in the monoclonal protein, a clear clinical benefit to these responses is yet to be shown. Patients have been vaccinated following autologous transplants (the time of minimal residual disease) using the idiotypic proteins conjugated with keyhole limpet hemocyaain (KLH) as immuno-adjuvants.27 In an animal model, vaccination with a whole tumor cell transfected with the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene resulted in a T-celldependent rejection of a tumor challenge (Figure 49.1). This T-cell-mediated antitumor activity was effective in drug-sensitive as well as in refractory tumors.28 Dendritic cells, as antigen-presenting cells, pulsed with idiotypic protein have been used at several institutions. Again, this approach has been generally used to vaccinate patients after transplantation. Specific antitumor responses were demonstrated in vitro.29

Advances in the treatment of multiple myeloma in the elderly patient

Figure 49.1 (a) T-cell-mediated rejection of myeloma growth in animals previously inoculated with a GM-CSF-transfected inactivated tumor cell vaccine. (b) Tumor cell growth in a control (not vaccinated) animal.

1139

Comprehensive Geriatric Oncology

1140

Courtesy of Y Hu, PhD, H Lee Moffitt Cancer Center. Japanese investigators have produced a monoclonal antibody that recognizes myeloma cells and normal plasma cells. This antibody is responsible for cell-mediated cytotoxicity. Even patients who have been heavily treated can generate responses (in vitro).30 No clinical data are available on the clinical effectiveness of this antibody. Adjuvant therapy of bone disease Bone disease is one of the most important causes of morbidity and impaired quality of life in myeloma patients.31 In a study published by Berenson et al32,33 in 1996 and 1998, the administration of pamidronate (monthly for 9 months), along with standard chemotherapy, resulted in a significant decrease in the incidence of skeletal-related events as compared with patients receiving placebo.32,33 Interestingly, bone pain scores decreased below baseline levels within weeks among patients who received paminodrate, while this took up to 6 months in patients receiving placebo. This study demonstrated for the first time that adjuvant therapy of bone disease in myeloma patients, receiving standard chemotherapy, is of significant benefit to their quality of life. The administration of paminodrate was well tolerated and did not affect the overall survival of this cohort. Zoledronic acid, a more powerful bisphosphonate than pamidronate, has recently completed a phase III trial. The trial compared the standard dose of pamidronate (90mg) versus 4mg of zoledronate. The study, which was designed to demonstrate equivalency, revealed similar toxicity profiles and similar therapeutic effects for both drugs.34 Extensive lytic bone disease in multiple myeloma results from enhanced osteoclast activation. The mechanism(s) of this enhanced osteoclast activity are beginning to be unveiled (Figure 49.2). Stromal cells in the bone marrow produce and secrete RANK (‘receptor activator of NF-κB’) ligand (RANKL) in the bone marrow microenvironment. This is the result of direct cell-to-cell interactions mediated by α4β1 integrin on the myeloma cell and vascular adhesion molecule 1 (VCAM1) on stromal cells. Osteoclast

Advances in the treatment of multiple myeloma in the elderly patient

1141

Figure 49.2 Biology of bone disease in multiple myeloma. MIP-1α, macrophage inflammatory protein 1α; VCAM1, vascular cell adhesion molecule 1; RANKL, RANK (‘receptor activator of NF-κB’) ligand; IL-6, interleukin-6. precursors express RANK and are stimulated by RANKL to mature and proliferate. High levels of RANKL are expressed in bone marrow stromal cells of patients with myeloma, as compared with normal controls. A soluble form of RANK named osteoprotegerin (OPG) may serve as a decoy soluble receptor blocking the activity of RANKL. OPG is downregulated in osteoblasts from myeloma patients as compared with normal controls.35 In an animal model, the administration of OPG was shown to inhibit the development of osteolytic bone disease from myeloma. While OPG had only a minor impact on the development of the disease, extensive osteolytic bone disease was completely prevented.36 Myeloma cells have been shown to produce macrophage inflammatory protein 1α (MIP-1α), which stimulates osteoclastogenesis through a mechanism independent of RANKL and interleukin-6 (IL-6). MIP-1α is found at high levels in the marrow microenvironment of patients with advanced and active multiple myeloma, at concentrations higher than those known to produce maximal stimulation of osteoclastogenesis. MIP-loc works independently and synergistically with IL-6, as shown by in vitro osteoclastogenesis experiments.37,38

Comprehensive Geriatric Oncology

1142

It is hoped that these molecules could be targets for new drugs in an attempt to further improve the recovery of bone structure in myeloma patients. OPG may enter clinical trials soon. Thalidomide and angiogenesis The demonstration of the significant clinical activity of single-agent thalidomide in patients with refractory multiple myeloma represents one of the major clinical advances in the therapy of the disease over the last decade. In the initial report from the University of Arkansas, and its most recent update, thalidomide shows a 37% response rate in patients who have failed extensive previous chemotherapy, including autologous transplants.39,40 Currently, thalidomide is being explored in combination with steroids and/or chemotherapy in the upfront treatment of the disease. Thalidomide is administered daily by mouth in doses ranging from 50 to 800mg. The optimal dose has not yet been defined. Some investigators have suggested a doseresponse relationship, and propose dose escalation to maximal tolerated doses. Others have described clinical activity with relatively small doses (50–150mg/day). While thalidomide is an ideal drug for the elderly patient, the issue of the dose is important, since some patients cannot tolerate it, particularly at higher doses. The administration of thalidomide is associated with sedation, constipation, neuropathy, and an increased risk for deep venous thrombosis. However, there is no significant myelosuppression.41 Thalidomide was initially explored in multiple myeloma because of its antiangiogenesis properties. Increased neovascularization was demonstrated in the bone marrow of patients with myeloma.42 Further, the microvessel density level appears to correlate with prognosis.43 Microvessel density decreases towards normal levels after effective therapy. Myeloma cells secrete vascular endothelial growth factor (VEGF), which stimulates angiogenesis. VEGF also stimulates myeloma cell growth and migration.44 Anti-VEGF approaches are currently being explored in phase I–II clinical trials. Besides inhibiting angiogenesis, a number of other mechanisms of action have been described for thalidomide. These include blockade of the activity of VEGF and basic fibroblast growth factor (bFGF) on the growth and migration activity of myeloma cells, blockade of cytokine production by stromal cells in the marrow microenvironment (including tumor necrosis factor α (TNF-α) and IL-6), blockade of plasma cell-stromal cell interactions, and immunomodulatory effects with increased IL-2 and interferon-γ (IFN-γ) secretion and induction of CD8+ T cells and natural killer (NK) cells. At present, it is difficult to assess which of these multiple mechanisms of action are more relevant in relationship to the observed anti-myeloma activity. Recently, thalidomide and its analogs (ImiDs) have been shown to directly induce apoptosis and growth arrest of myeloma cells resistant to steroids and chemotherapy drugs. Thalidomide and ImiDs may enhance the proapoptotic activity of chemotherapy drugs and other signals.45,46

Advances in the treatment of multiple myeloma in the elderly patient

1143

Molecular biology and targeted therapies The last decade has seen a rapid growth in our understanding of the biology of multiple myeloma, which was facilitated by technological advances and by a renewed interest in this disease. Unveiling the pathways and molecules involved in tumor cell growth and survival should provide the basis for more rational and selective treatment approaches. Less toxic and more effective therapies could be developed by targeting specific molecules, particularly when these molecules are differentially expressed in tumor cells.47 DNA microarray analysis revealed a marked heterogeneity and complexity in the patterns of gene expression when normal plasma cells are compared with malignant plasma cells. Even more interesting is the diversity among myeloma tumor cells from various groups of patients. In a recent study, DNA microarray techniques were utilized to look at the patterns of expression of more than 6000 genes in myeloma cells and normal plasma cells.48 Normal and malignant plasma cells could be differentiated by the patterns of expression of some 120 genes (some upregulated, others downregulated). Four distinct patterns of gene expression were observed among myeloma cells, correlating with differences in the clinical aggressiveness of the disease. Interestingly, there were differences in the expression of more than 200 genes among some of these groups. These studies, along with previous reports analyzing cytogenetic abnormalities and patterns of oncogene expression, point again to the complexity and heterogeneity of molecular abnormalities in myeloma cells. While only a few of these genes may be relevant for therapy-targeting purposes, it is unlikely that a ‘single-drug targeted to a single molecule’ model will be successful in the treatment of multiple myeloma. Historically, IL-6 was the first targeted molecule in myeloma. The role of this cytokine in myeloma has been defined over the past decade (and work continues today). IL-6 was described as a cytokine with a very important role in the biology of multiple myeloma. Systemic blockade of IL-6 with neutralizing monoclonal antibodies, however, did not result in significant tumor responses in patients with advanced disease. The initial work of Japanese and French investigators proposed that the growth of myeloma cells was primarily driven by IL-6. While some myeloma cells can produce IL6 (autocrine loop), the marrow environment (stromal cells, endothelial cells, and others) secretes high levels of IL-6 (paracrine loop). Here again, numerous studies have demonstrated that myeloma cell lines as well as fresh samples explanted from patients are quite heterogeneous in their responses and dependence on IL-6. Some myeloma cells are dependent on IL-6 for in vitro growth, while others are not. An interesting experiment provides some perspective on this issue.49 An IL-6independent myeloma cell line (from its ability to produce IL-6 via an autocrine loop) carrying a mutated p53 gene was transfected with a wild-type p53 gene. This single manipulation resulted in loss of the IL-6 autocrine loop, with the cell line becoming IL-6dependent. In the absence of IL-6, the cell became resistant to chemotherapy drugs. In relation to the role played by IL-6, this experiment may describe what happens to the biology of myeloma during the course of disease progression. Clinically, mutations in p53 frequently occur in the later stages of the disease. In the absence of wild-type p53, triggering of CD40 on the surface of myeloma cells by CD40 ligand (CD40L, CD154) on stromal cells induces tumor cell proliferation. In the presence of wild-type p53, however, CD40L induced growth arrest and apoptosis.50 During the initial stages of the disease,

Comprehensive Geriatric Oncology

1144

myeloma cells, which are dependent on IL-6 produced primarily by stromal cells in the marrow microenvironment, grow primarily in the bone marrow. As the disease progresses and acquires further genetic mutations (including p53

Figure 49.3 Typical morphological changes of apoptosis in myeloma cells explanted from a patient’s bone marrow. Courtesy of Dr LC Moscinski, H Lee Moffitt Cancer Center. mutations or deletions), myeloma cells may develop the ability to produce their own IL-6 and/or to respond to other signals, facilitating their growth outside the marrow environment. IL-6 is perhaps more relevant for its role as an anti-apoptotic factor. Myeloma could be viewed as a disease of arrested apoptosis, resulting in the accumulation of tumor cells in the bone marrow. The myeloma cell growth fraction is usually very low (<1%) at presentation. Removing myeloma cells from their marrow microenvironment induces apoptosis (Figure 49.3). This phenomenon occurs within minutes and does not require protein synthesis or gene expression. Soon after either a ‘death’ signal is given or a ‘survival’ signal is withdrawn from specific receptors, myeloma cells can rapidly and efficiently undergo apoptosis. These findings will have profound implications for the development of targeted therapies. There are basically two pathways to signal cells to undergo apoptosis. Apoptosis is mediated, downstream, by the activation of caspases. Activation of caspases can be initiated (i) by an external signal, namely interaction of ligands with specific ‘death

Advances in the treatment of multiple myeloma in the elderly patient

1145

receptors’ on the cell membrane, or (ii) by induction of the release of mitochondrial mediators (cytochrome c, Smac, and Apaf-1). The family of Bcl-2 proteins (with more than 20 members) includes proteins with proand anti-apoptotic functions. Bcl-2, for example, is located in the mitochondrial membrane and prevents the release of cytochrome c, thus inhibiting apoptosis. Bax, on the other hand, mediates p53 signals by activating the release of apoptotic mediators from the mitochondria. As compared with normal plasma cells, plasma cells from MGUS or myeloma patients express higher levels of Bcl-2 and Bax.51 The balance in the expression of pro- and antiapoptotic proteins appears to be a crucial factor determining the fate of these cells. Drugs that may affect this balance could be of therapeutic benefit. A Bcl-2 antisense molecule is currently undergoing phase I–II clinical trials. Dexamethasone is known to induce apoptosis of myeloma cells. Enforced expression of Bcl-2 by gene transfection blocks the ability of dexamethasone to induce apoptosis.52 Dexamethasone induces apoptosis by the release from the mitochondria of Smac, an inhibitor of caspase inhibitors. IL-6 prevents dexamethasone-induced apoptosis by inhibiting the dexamethasone-induced release of Smac from the mitochondria.53,54 Myeloma cells adherent to stromal cells in the bone marrow become resistant to chemotherapy drugs. Investigators have attempted to explain this phenomenon on the basis of induction of differential expression of pro-and anti-apoptotic proteins. However, studies have failed to reveal any significant differences of expression of these proteins upon cell adhesion.55 Adhesion-related resistance to apoptosis in tumor cells must be related to some other, as yet unknown, mechanisms. As we begin to understand how clinically effective drugs work and how tumor cells became resistant to them, the potential for more rational approaches to myeloma therapy seems to be within reach. This is illustrated by preclinical and clinical data from two different approaches: (i) triggering death receptor signals and (ii) proteasome inhibitors. Triggering death receptor signals An obvious potential therapeutic approach is to trigger ‘death receptors’ with their ligands. Currently two types of ‘death receptors’ with clinical relevance have been described: (i) Fas (CD95) and (ii) the Apo2L/TRAIL receptor. Fas ligand is toxic to normal cells, which hinders its clinical use. Apo2L/TRAIL (‘TNF-related apoptosisinducing ligand’) seems to have some selectivity for tumor cells, since normal bone marrow and peripheral blood cells show no significant induction of apoptosis. Apo2L/TRAIL induces apoptosis of myeloma cells in a dose-dependent manner.56 In animal models, Apo2L/TRAIL administered for 14 days was safe and actually prevented the growth of inoculated myeloma cells. Apo2L/TRAIL is currently in the process of entering clinical trials.

Comprehensive Geriatric Oncology

1146

Proteasome inhibitors Proteasomes are proteins that degrade activated proteins in the cell. In vitro, PS321, a proteasome inhibitor currently in clinical trials, inhibits the growth and induces apoptosis of myeloma cells.57 It also inhibits the binding of myeloma cells to bone marrow stromal cells, and the secondary upregulation of IL-6. PS321 inhibits the activation of NF-κB, an important regulatory element of survival/apoptosis signals. NF-κB mediates the transcription of over a hundred different genes that are connected with survival and apoptosis. Induction of apoptosis and growth inhibition of myeloma cells was also observed in cells that were dexamethasone- and chemotherapy-resistant. Addition of PS321 further increased the growth inhibition induced by dexamethasone. This synergistic inhibition was not blocked by IL-6. Early reports from phase I-II trials indicate that this drug is indeed clinically active as a single agent in previously treated patients. Several experiments have demonstrated the potential for combining drugs that trigger apoptotic signals at multiple levels. Combining Apo2L/TRAIL (signalling the cell to undergo apoptosis) with a proteasome inhibitor (blocking mechanisms that may prevent apoptosis) results in a synergistic effect. Experiments conducted with a doxorubicinsensitive myeloma cell line showed that a subtoxic concentration of doxorubicin combined with a suboptimal dose of Apo2L/TRAIL resulted in induction of massive apoptosis. Marked induction of apoptosis was also observed under the same experimental conditions with a doxorubicin-resistant cell line. Doxorubicin was able to sensitize doxorubicin-resistant cells to the apoptosis induced by Apo2L/TRAIL.58 Conclusions Based on the achievements of the last several years and the new treatment modalities currently under development, it is hoped that the next decade will provide continuous improvement in the survival and quality of life of myeloma patients. It would appear that modulators of apoptotic signaling could become particularly useful in view of the preliminary data reviewed above. The use of these agents combined with standard chemotherapy drugs (in standard high-dose regimens) could result in more efficacious and less toxic regimens. Continued progress in the treatment of bone disease is expected with the availability of more powerful bisphosphonates, as well as with the development of new agents such as OPG. Immunotherapy approaches aimed at generating an antimyeloma immune response (in either the autologous or the allogeneic setting) could become an essential part of treatment regimens, particularly in the context of minimal residual disease. While the immediate goal is better control of the disease for longer periods of time, the rational and combined use of new treatment strategies could begin to bring us closer to the elusive cure.

Advances in the treatment of multiple myeloma in the elderly patient

1147

References 1. Hallek M, Bergsagel PL, Anderson KC. Multiple myeloma: increasing evidence for a multi-step transformation process. Blood 1998; 91: 3–21. 2. Kuehl WM, Bergsagel PL. Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer 2002; 2:175–87. 3. Bataille R, Harousseau JL. Multiple myeloma. N Engl J Med 1997; 336:1657–64. 4. Ballester OF, Corrado C, Vesole D. Multiple myeloma. In: Comprehensive Geriatic Oncology, 1st edn (Balducci L, Lyman GH, Ershler WB, eds). Amsterdam. Hardwood Academic Publishers, 1998: 595–609. 5. Rodon P, Linassier C, Gauvain JB et al. Multiple myeloma in elderly patients: presenting features and outcome. Eur J Haematol 2001; 66: 11–17. 6. Attal M, Harousseau JL, Stoppa AM et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med 1996; 335:91–7. 7. Palumbo A, Triolo S, Argentino C et al. Dose-intensive melphalan with stem cell support (MEL 100) is superior to standard treatment in elderly myeloma patients. Blood 1999; 94:1248–53. 8. Dumontet C, Ketterer N, Espinouse D et al. Reduced progression-free survival in elderly patients receiving intensification with autologous peripheral blood stem cell reinfusion for multiple myeloma. Bone Marrow Transplant 1998; 21:1037–41. 9. Siegel D, Desikan K, Metha J et al. Age is not a prognostic variable with autotransplant for myeloma multiple. Blood 1999; 93:51–4. 10. Sirohi B, Powles R, Treleaven J et al. The role of autologous transplantation in patients with myeloma multiple aged 65 and over. Bone Marrow Transplant 2000; 25:533–9. 11. Badros A, Barlogie B, Siegel E et al. Autologous stem cell transplantation in elderly myeloma patients over the age of 70 years. Br J Haematol 2001; 114:600–7. 12. Fernand JP, Ravaud P, Chevret S et al. High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: up front or rescue treatment? Result of a multicenter sequential randomized clinical trial. Blood 1998; 9:3131–6. 13. Barlogie B, Jagannath S, Desikan KR et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood 1999; 93: 55–65. 14. Attal M, Harousseau JP. Randomized trial experience of the Intergroupe-Francophone du Myelome. Semin Hematol 2001; 38:226–30. 15. Moreau P, Facon T, Attal M et al. Comparison of 200mg/m2 melphalan and 8 Gy total body irradiation plus 140mg/m2 melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myelome 9502 randomized trial. Blood 2002; 99:731–5. 16. Stewart K, Vescio R, Schiller G et al. Purging of autologous peripheral-blood stem cells using CD34 selection does not improve overall or progression-free survival after high-dose chemotherapy for multiple myeloma: results of a multicenter randomized controlled trial. J Clin Oncol 2001; 19:3771–9. 17. Lemoli R, Martinelli G, Zamagni E et al. Engraftment, clinical, and molecular follow-up of patients with multiple myeloma who were reinfused with highly purified CD34+ cells to support single or tandem high-dose chemotherapy. Blood 2000; 95:2234–9. 18. Bensinger WI, Maloney D, Storb R. Allogeneic hematopoietic cell transplantation for multiple myeloma. Semin Hematol 2001; 38: 243–9. 19. Cavo M, Terranga C, Martinelli G et al. Molecular monitoring of minimal residual disease in patients in long-term complete remission after allogeneic stem cell transplantation for multiple myeloma. Blood 2000; 96:355–7. 20. Lokhorst H, Schattenberg A, Cornelissen J et al. Donor lymphocyte infusions for relapsed multiple myeloma after allogeneic stem-cell transplantation: predictive factors for response and long-term outcome. J Clin Oncol 2000; 18:3031–7.

Comprehensive Geriatric Oncology

1148

21. Alyea E, Soiffer R, Canning C et al. Toxicity and efficacy of defined doses of CD4+ donor lymphocytes for treatment of relapse after allogeneic bone marrow transplant. Blood 1998; 91:3671–80. 22. Alydea E, Weller E, Schlossman R et al. T-cell-depleted allogeneic bone marrow transplantation followed by donor lymphocyteinfusion in patients with multiple myeloma: induction of graft-versus-myeloma effect. Blood 2001; 98:934–9. 23. Badros A, Barlogie B, Morris C et al. High response rate in refractory and poor-risk multiple myeloma after allotransplantation using a nonmyeloablative conditioning regimen and donor lymphocyte infusions. Blood 2001; 97:2574–9. 24. Maloney DG, Sahebi F, Stockerl-Goldstein KE et al. Combining an allogeneic graft-versusmyeloma effect with high-dose autologous stem cell rescue in the treatment of multiple myeloma. Blood 2001; 98: a1822. 25. Pellat-Deceunynck C, Jego G, Harousseau JL et al. Isolation of human lymphocyte antigens class I-restricted cytotoxic T lymphocytes against autologous myeloma cells. Clin Cancer Res 1999; 5: 705–9. 26. Steinman R, Dhodapkar M. Active immunization against cancer with dendritic cells: the near future. Int J Cancer 2001; 94:459–73. 27. Massala M, Borrione P, Battaglio S et al. Idiotype vaccination in human myeloma: generation of tumor-specific immune responses after high-dose chemotherapy. Blood 1999; 94:673–83. 28. Shtil A, Turner J, Durfee J et al. Cytokine-based tumor cell vaccine is equally effective against parental and isogenic multidrug-resistant myeloma cell: the role of cytotoxic T-lymphocytes. Blood 1999; 93: 1831–7. 29. Reichardt V, Okada C, Liso A et al. Idiotype vaccination using dendritic cells after autologous peripheral blood stem cell transplantation for multiple myeloma—a feasibility study. Blood 1999; 93: 2411–19. 30. Ozaki S, Kosaka M, Wakahara Y et al. Humanized anti-HM 1.24 antibody mediates myeloma cell cytotoxicity that is enhanced by cytokine stimulation of effector cells. Blood 1999; 93:3922–30. 31. Callander NS, Roodman GD. Myeloma bone disease. Semin Hematol 2001:38:276–85. 32. Berenson J, Lightenstein A, Porter L et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. N Engl J Med 1996; 334:488–93. 33. Berenson JR, Lichtenstein A, Porter L et al. Long term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. J Clin Oncol 1998; 16:593–602. 34. Berenson JR, Rosen LS, Howell A et al. Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases. Cancer 2001; 91:1191–200. 35. Giulliani N, Bataille R, Mancini C et al. Myeloma cells induce imbalance in the osteoprotegerin/osteoprotegerin ligand system in the human bone marrow environment. Blood 2001; 98:3527–33. 36. Croucher P, Shipman C, Lippitt J et al. Osteoprotegerin inhibits the development of osteolytic bone disease in multiple myeloma. Blood 2001; 98:3534–40. 37. Choi S, Cruz J, Craig F et al. Macrophage inflammatory protein-la is a potential osteoclast stimulatory factor in multiple myeloma. Blood 2000; 96:671–5. 38. Han J-H, Choi S, Kurihara N et al. Macrophage inflammatory protein-loc is an osteoclastogenic factor in myeloma that is independent of receptor activator of nuclear factor KB ligand. Blood 2001; 97:3349–53. 39. Singhal S, Metha J, Desikan R et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341: 1565–71. 40. Barlogie B, Desikan R, Eddlemon P et al. Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients. Blood 2001; 98:492–4. 41. Richardson P, Hideshima T, Anderson KC. Thalidomide in multiple myeloma. Biomed Pharmacother 2002; 56:115–28.

Advances in the treatment of multiple myeloma in the elderly patient

1149

42. Vacca A, Ribatti D, Presta M et al. Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase-2 secretion parallel progression of human multiple myeloma. Blood 1999; 93:3064–73. 43. Rajkumar V, Leong T, Roce P et al. Prognostic value of bone marrow angiogenesis in multiple myeloma. Clin Cancer Res 2000; 6:3111–16. 44. Podar K, Tai Y, Davies F. Vascular endothelial growth factor triggers signaling cascades mediating multiple myeloma cell growth and migration. Blood 2001; 98:428–35. 45. Hideshima T, Chauhan D, Shima Y et al. Thalidomide and its analogs overcome drugs resistance of human multiple myeloma cells to conventional therapy. Blood 2000; 96:2943–50. 46. Mitsiades N, Mitsiades C, Poulaki V et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma: therapeutic implications. Blood 2002; 99:4525–30. 47. Anderson KC. Targeted therapy for multiple myeloma. Semin Hematol 2001; 38:286–94. 48. Zhan F, Hardin J, Kordsmeier B et al. Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cell. Blood 2002; 99: 1745–57. 49. Rowley M, Liu P, Van Ness B. Heterogeneity in therapeutic response of genetically altered myeloma cell lines to interleukin 6, dexamethasone, doxorubicin, and melphalan. Blood 2000; 96:3175–80. 50. Teoh G, Tai T, Urashima M et al. CD40 activation mediates p53-dependent cell cycle regulation in human multiple myeloma cell lines. Blood 2000; 95:1039–46. 51. Renner S, Weisz J, Krajewski S et al. Expression of BAX in plasma cell dyscrasias. Clin Cancer Res 2000; 6:2371–80. 52. Feinman R, Koury J, Thames M et al. Role of NF-κB in the rescue of multiple myeloma cells from glucocorticoid-induced apoptosis by Bcl-2. Blood 1999; 93:3044–52. 53. Xu F, Sharma S, Gardner A et al. Interleukin 6-induced inhibition of multiple myeloma cell apoptosis: support for the hypothesis that protection is mediated via inhibition of the JNK/SAPK pathway. Blood 1998; 92:241–51. 54. Chauhan D, Hideshima T, Rosen S et al. Apaf-1/cytochrome c-independent and Smacdependent induction of apoptosis in multiple myeloma (MM) cells. J Biol Chem 2001; 276:24 453–6. 55. Damiano J, Cress A, Hazlehurst L et al. Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. Blood 1999; 93:1658– 67. 56. Mitsiades C, Treon S, Mitsiades N et al. TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: therapeutic applications. Blood 2001; 98:795–804. 57. Hideshima T, Richardson P, Chauhan D. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 2001; 61: 3071–6. 58. Jazirehi A, Ng C, Gan X et al. Adriamycin sensitizes the Adriamycin-resistance 8226/Dox40 human multiple myeloma cells to Apo2L/tumor necrosis factor-related apoptosis-inducing ligand-mediated (TRAIL) apoptosis. Clin Cancer Res 2001; 7:3874–83.

50 Treatment of small cell lung cancer in the elderly Frances A Shepherd, Andrea Bezjak Introduction Worldwide, the incidence of lung cancer is increasing at a rate of 0.5% per year, with the result that it is now the leading cause of cancer mortality for both men and women in most countries.1 Although, in North America, the age-adjusted incidence rates for men began to decline in the 1980s, they continue to increase for women to this day. The average age of patients with lung cancer is also rising, and currently the age-specific incidence peaks at 75–79 years for men and at 70–74 years for women. Incidence rates decline thereafter in both genders, likely owing to the lower prevalence of smoking in the population at the beginning of the 20th century. In some areas of the world, all-cancer mortality rates in the elderly have increased considerably over the past two decades, owing almost exclusively to an increase in lung cancer and other tobacco-related cancers in both men and women.2,3 Small cell lung cancer (SCLC) accounts for 20–25% of all pulmonary neoplasms, and appears to be distributed equally over all age groups.4,5 Some investigators have shown an inverse relationship between age and stage of disease.5,6 Although this trend has been shown more clearly for patients with non-small cell lung cancer (NSCLC), it has also been reported in several series of SCLC patients.5–7 Although there are large numbers of elderly patients with lung cancer, including SCLC, there are few data on how treatment for this group of patients differs or should differ from that of younger patients. Until recently, elderly patients were excluded from many clinical research trials, and there have been few studies designed specifically for the elderly population. Goodwin et al8 reported that while 31% of all adult patients with cancer were over age 70, only 7% of patients enrolled in Southwest Oncology Group (SWOG) trials were in that age group. Specifically, in the SWOG lung cancer trials, only 18% of the patients were over age 65, and 9% over age 70. Dajczman et al9 reported that only 1 of 81 elderly patients was enrolled on an experimental protocol for SCLC, compared with 19% of patients aged 60–69 and 28% of patients younger than 60. Furthermore, several investigators have shown that treatment of any kind may be withheld from elderly patients with SCLC despite a high expectation of benefit and even a chance of cure for patients with limited-stage disease.7–10 The University of Toronto group reported that between 1976 and 1988, only 78 of 123 patients (63%) aged 70 or greater were treated with chemotherapy (only one-third over age 80), and 25 patients received no treatment at all.7 The most important determinant in the decision to treat or not to treat was performance status: only 38% of patients with performance status 3 or 4

Treatment of small cell lung cancer in the elderly

1151

received treatment, compared with 66% of patients with performance status 0, 1, or 2. Similar observations were made by de Rijke et al10 from the Netherlands, who found that 52% of patients over age 70 were offered no treatment whatsoever, compared with 14% and 22% for patients aged 50–59 and 60–69, respectively. The reasons for not referring older-aged patients for investigation and treatment of SCLC are not clearly defined, and seem to be based on personal belief and perception rather than on well-documented scientific data. Some physicians assume that elderly patients have a limited life-expectancy and therefore do not warrant treatment of malignant disease in general, and lung cancer in particular. In fact, the life-expectancies of woman and men who reach age 70 are 15 years and 8–10 years, respectively.11 It is also a commonly held belief that elderly patients have a poorer prognosis and tolerate therapy less well than younger patients, perhaps because of the presence of other comorbid illnesses that occur frequently in this population. Finally, some physicians view the elderly as emotionally as well as physically frail, which may lead to the extreme of withholding not just treatment, but even the diagnosis from older patients. This view does not seem to be justified, as shown by Nerenz et al12 and Ginsburg et al.13 In view of these attitudes, it is clear that the treatment of elderly patients with SCLC requires critical evaluation. Should all elderly patients be offered the same therapy as younger patients, and if not, what guidelines are available to help determine which patients are most likely to benefit from treatment? Should treatment be attenuated in dose or duration, and is combined-modality therapy appropri-ate in the older population? Should specific protocols be designed to meet the needs of the elderly patient? Because, until recently, elderly patients were excluded from most clinical research trials, it is difficult to address these questions with data that are not heavily influenced by referral bias and physician treatment bias. Furthermore, even in the overviews of large cooperative group databases, the extremely elderly population of over 75 or over 80 is very under-represented. Clearly, more clinical trials designed specifically for older patients are needed.14 Age as a prognostic factor Several of the cooperative groups have analyzed their databases to determine the prognostic importance of various baseline clinical and laboratory factors in SCLC.15–18 All of the analyses showed that stage is the most important determinant of prognosis, with median survival times of 12–16 months reported for limited stage, compared with only 7–11 months for extensive-disease patients. Other important clinical parameters include performance status, gender, and baseline level of lactate dehydrogenase (LDH).15,16 The prognostic significance of age from the cooperative group analyses is shown in Table 50.1. The largest study was that from SWOG reported by Albain et al15 They found that age over 70 was unfavorable in both limited-and extensive-stage patients. Furthermore, age remained significant even when entered into the Cox regression model of multiple prognostic indices. In a retrospective review of 1521 patients, the Cancer and Leukemia Group B (CALGB) identified female gender and performance status as important predictors of survival in both limited-and extensive-stage disease.17 Limited-

Comprehensive Geriatric Oncology

1152

stage patients older than 60 years of age had a higher mortality rate than younger patients (p<0.008), but older age was not was not associated with shorter survival in patients with extensive disease. Sagman et al16 analyzed 614 patients from the University of Toronto database, and reported poorer survivai advantage for patients over 70 years of age (relative risk (RR) 1.32, p=0.023). However, using recursive partitioning and amalgamation modeling (RECPAM) techniques, age was not significant, and did not appear in any of the terminal pods of the four prognostic groups identified by the model. Albain et al15 also applied the RECPAM technique to the SWOG dataset, and identified four separate prognostic groups. Age was important only in the two limited-stage subgroups. Similar results were reported by Spiegelman et al17 for CALGB. Siu et al18 analyzed the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) BR.3 and BR.6 trials in limited-stage SCLC to determine the influence of age on both outcome and chemotherapy delivery. This analysis is of particular interest, since all 618 patients received the same chemotherapy. They showed that, when analyzed as a continuous variable, age was of modest prognostic significance (p=0.02), but when the survival of patients younger than 70 was compared with that of the older patients (Figure 50.1), there was no significant difference (p=0.14). In fact, survival was similar for patients of all age groups, with the exception of the 13

Table 50.1 Prognostic importance of age in small cell lung cancer Authors

Age break Limited stage and number Univariate Multivariate in cohort analysis analysis

Extensive stage Univariate analysis

Multivariate analysis

Albain et al15

70 n=2580

Hazard ratio 1.4 (p≤ 0.0001)

Hazard ratio 1.5 Hazard ratio (p≤ 0.00005) 1.3 (p=0.002)

Hazard ratio 1.3 (p=0.006)

Sagman et al16

70 n=614

Relative risk 1.32 (p=0.023)a

Not significant

—

Not significant

Spiegelman et al17

60 n=1521

—

Relative hazard 1.23 (p=0.008)

—

Relative hazard 1.03 (p=0.74)

Siu et al18

70 n=608

Age as a continuous variable: p=0.02 Age 0–69 vs ≥70: p=0.14

Not significant

—

—

a

The effect of age was examined together for limited- and extensive-stage disease.

Treatment of small cell lung cancer in the elderly

1153

Figure 50.1 Comparison of survival by age group: 0–69 and 70+. patients aged 75–80, who had significantly poorer survival than the rest of the group (Figure 50.2). Pignon et al19 reported the results of a meta-analysis of 2140 patients who participated in 13 randomized trials designed to assess the importance of thoracic radiotherapy in limited-stage SCLC. The relative risk of death in the chemotherapy and radiotherapy group compared with the chemotherapy-alone group was 0.86 (95% confidence internal (CI) 0.78–0.94, p=0.001), and the benefit in terms of overall survival at 3 years was 5.4%. There was a trend toward a larger reduction in mortality in younger patients, with the relative risk of death in the radiation group being 0.72 for patients under 55. In contrast, the relative risk of death was actually increased at 1.07 (95% CI 0.70–1.64) when radiotherapy was added to chemotherapy in patients over 70. The 3-year survival rates were 9.2% for chemotherapy alone compared with 17.4% for chemotherapy and radiotherapy in patients under 55. For patients over 70 years, the rates were 10.2% and 8.75%, respectively.

Comprehensive Geriatric Oncology

1154

Chemotherapy With the exception of two studies that included elderly patients among other poorprognosis populations,20,21 there have been no randomized clinical trials of chemotherapy for SCLC in the elderly. Therefore, it is necessary to rely on retrospective reviews of large datasets that have compared the results achieved by elderly patients with those of younger patients treated in the same way, or on small prospective trials designed specifically for

Figure 50.2 Comparison of survival by age group: 0–64, 65–69, 70–74, and 75+. the elderly population. The definition of ‘elderly’ has not been standard in these studies, and has even been as low as 55 years.23 Most reports dealing with SCLC, however, have used age 70 or greater to dichotomize between the young and the elderly.

Treatment of small cell lung cancer in the elderly

1155

Retrospective reviews The results of nine retrospective reviews are summarized in Table 50.2.7,9,18,22–27 Several authors reported that many patients with SCLC were not offered treatment of any kind.7,9,22,24 In the Toronto General Hospital review,7 25 of 123 patients received no therapy, and 20 were offered palliative radiation only. Survival correlated significantly with treatment received, ranging from 1.1 months for those not treated to 10.7 months for those who completed four to six cycles of combination chemotherapy (p= 0.0001). Dajczman et al9 also reported that suboptimal treatment was given to 57% of patients aged 60–69 and 77% of patients over 70. Once again, the administration of suboptimal treatment was associated with significantly poorer survival, although this was true across all age groups studied. Shepherd et al7 and Dajczman et al9 examined the possible reasons for withholding treatment or delivering suboptimal treatment to elderly patients, and both investigators reported that performance status was the most important determinant in decision making. In the Toronto study,7 only 38% of patients with Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 were treated with chemotherapy. In fact, performance status played a greater role than age itself, stage of the tumor, or the presence of other comorbid

Table 50.2 Summary of retrospective analyses of response, survival, and toxicity in elderly patients treated with chemotherapy for small cell lung cancera Authors

Number: young/old

Drugs

Response rate (%)

Median survival

Toxic death

Young

Old

Young

Old

Young Old

Shepherd et al7

0/78

CAV or EP

NA

62

NA

LD: 11.9mos ED:5.2 mos

Dajczman et al9

231/81

CAV or EP

50

51

~9 mos

6 mos

Siu et al18

520/70

CAV and EP

78

82

15 mos (11% 5yr)

13 mos (8% 5-yr)

Clamon et al22

0/20

Various

NA

50

NA

Poplin et al23

164/49

CAE

LD: 60b ED: 44b

Kelly et al24

62/34

Various

Findlay et al25

0/64

Various

NA

0

12

4

9

4

10 mos

NA

1

LD:75b — ED: 40b

~12 mos

19

10

NR

NR

27 wks

25 wks

0

3

NA

67

NA

25 wks

NA

3

Comprehensive Geriatric Oncology

1156

Nou26

235/110

CAV or CME

NR

NR

10.9 mos 7.4 mos

Tebbutt et al27

73/29

CAV or EC

LD: 71 ED: 65

LD: 68 ED: 38

LD: 45 wks ED: 39 wks

LD: 36 wks ED: 23.5 wks

15

9

0

3

a

Results are summarized only for patients treated with chemotherapy in each series. Only complete remission rates were reported. CAE, cyclophosphamide, doxorubicin, etoposide; CAV, cyclophosphamide, doxorubicin, vincristine; EP, etoposide, cisplatin; EC, etoposide, carboplatin; CME, lomustine (CCNU), methotrexate, etoposide; LD, limited disease; ED, extensive disease; NA, not applicable; NR, not reported. b

diseases. It is well recognized that the elderly have more comorbid illnesses than their younger counterparts.7,9,22 However, even serious illnesses such as chronic obstructive pulmonary disease (COPD), atherosclerotic heart disease, hypertension, and diabetes do not seem to influence the decision to treat the elderly patient, nor do they affect the ability to deliver therapy. Once a decision has been made to treat with chemotherapy, elderly patients may be given lower doses than younger patients. Physician decision to reduce doses for the elderly is based largely on the perception of poorer bone marrow reserve in the elderly and poorer tolerance for other toxicities. Although there are theoretical reasons why physiological changes in the elderly might lead to higher ‘area under the curve’ (AUC) drug concentrations, and hence increased toxicity, this does not always seem to be the case in clinical practice.28 Begg and colleagues29,30 reported that with the exception of semustine (methyl-CCNU) and methotrexate (agents that are now seldom used in the treatment of SCLC), neither the frequency nor the severity of toxicity was increased in the elderly. Shepherd et al7 showed that the decision to reduce initial doses correlated most frequently with performance status. Recent studies have shown that elderly patients, if they meet the criteria for entry into SCLC clinical trials, do not experience increased rates of toxicity.18,31 Siu et al18 reported that grade 3 and 4 toxicity was not increased in elderly patients treated on two NCICCTG trials of limited SCLC in which patients received three cycles of cyclophosphamide, doxorubicin, and vincristine (CAV) and three cycles of etoposide and cisplatin (EP). However, in a study that used the more myelosuppressive CAE regimen of doxorubicin, cyclophosphamide and etoposide, Poplin et al23 reported that the incidence of fever and infection increased with age. Nou26 also found that although nadir blood counts were similar in patients younger than or older than 70, the rates of septicemia per course and lethal septicemia were significantly higher in the older patients. However, Nou’s group also used highly myelosuppressive chemotherapy combinations that included both methotrexate and lomustine (CCNU). With the possible exception of peripheral neuropathy,24 significantly increased non-hematologic toxicity has not been reported in any series to date. It would appear, therefore, that elderly patients of good performance status tolerate chemotherapy well, and that when regimens

Treatment of small cell lung cancer in the elderly

1157

Figure 50.3 Kaplan-Meier survival plots for different ages: all patients had limited-stage disease.

Figure 50.4 Kaplan-Meier survival plots for different ages: all patients had extensive-stage disease. associated with modest degrees of myelosuppression are used, the risk of severe or fatal infectious complications is not increased. Even though toxicity rates in elderly patients do not appear to be higher than those seen in younger patients, several authors have reported that elderly patients receive

Comprehensive Geriatric Oncology

1158

significantly fewer chemotherapy cycles than younger patients, and this appears to be so even in the stricter setting of a clinical research trial.7,9,18,27 Siu et al18 reported that only 69% of elderly patients completed six chemotherapy cycles, compared with 82% of younger patients (p=0.01) in two NCIC-CTG trials. They did not find that the elderly patients had higher rates of dose reduction, although this has been reported by other authors.9,27 When initial dose reductions and subsequent dose reductions for toxicity are added to dose omissions, the elderly population may actually receive only half to twothirds the treatment given to younger patients. Clearly, the most important question to be asked is whether this attenuation of treatment in the elderly has a significant effect on survival. The results for the patients who received chemotherapy in several reported series are summarized in Table 50.2. All studies were retrospective reviews, and some looked only at an elderly population, whereas others compared the results in elderly and young patients using various definitions of elderly. Siu et al18 showed that for patients with limited-stage disease, response rates and median and 5-year survival rates were similar for elderly and young patients (Figure 50.1). These observations are of particular importance since all patients were treated on a clinical trial and received the same chemotherapy. Poplin et al23 showed wider variations among four age groups of patients with limited-stage disease (Figure 50.3), but it is interesting to note that the patients with the poorest survival were those in the youngest age group (<55 years). Less difference was seen for patients with extensivestage tumors (Figure 50.4). When relatively uniform chemotherapy combinations were given to both age groups, similar response rates for the elderly and the young were reported by several inves-

Table 50.3 Prospective phase II trials of chemotherapy for elderly patients with small cell lung cancer Authors

Drugs

No. of patients

Response rate (%)

Median survival

Toxic deaths

Smit et al32

Etoposide 160mg/m2 p.o. daily×5 days

35

ORR 71

LD: 16 mos ED: 9 mos

Gatzemeier et al33

Etoposide 500mg/m2 over 3 days q8–10 days

55

ORR 57

LD: 7.5 mos ED: 6.6 mos

Keane et al34

Etoposide 200mg p.o. daily×5 days

63

CR 20 PR 56

38 wks

0

Bork et al35

Teniposide 60mg/m2 daily×5 days

33

90

8+ mos

0

Cerny et al36

Teniposide 100mg/m2 daily×5 days

30

33

5.6 mos

5

Byrne et al37

Etoposide 200mg p.o. daily×5, carboplatin 300mg/m2 day 1

70

CR 28 PR 51

40 wks

1

Treatment of small cell lung cancer in the elderly

1159

Michel et al38

Teniposide 80mg/m2 weekly, carboplatin 80mg/m2 weekly

24

CR 21 PR 46

33 wks

1

Evans et al39

Etoposide 100mg/m2 47 p.o. daily×7 days, carboplatin 150mg/m2 day 1

CR 23 PR 37

46 wks

4

Cascinu et al40 Teniposide 60mg/m2 daily×5 days

22

CR 5 PR 18

Not reported

0

Westeel et al41 PAVE

66

CR 44 PR 18

LD: 70 wks ED: 46 wks

1

CR, complete response; PR, partial response; ORR, overall response rate; LD, limited disease; ED, extensive disease; PAVE, cisplatin 30 mg/m2 day 1, doxorubicin 40mg/m2 day 1, vincristine 1mg/m2 day 1, etoposide 100mg/m2 i.v. day 1 and p.o. days 3 and 5.

tigators.9,26,27 The Montreal group showed that median survivals and 2-year survival rates were similar for patients in three age groups if they were of good performance status and received chemotherapy.9 However, both Nou26 and Tebbutt et al27 reported shorter survival for elderly patients, although the difference was statistically signifi- cant only in the multivariate analysis of the Nou study.26 A closer examination of Table 50.2 shows that for each report that compared young with elderly patients, survival in the older group was less. Frequently the differences were not statistically different in the individual studies, and further deductions are probably not justified in view of the variability in treatment delivered and the differing definitions of elderly. However, these data suggest that the true impact of age on treatment outcome still requires further examination. Furthermore, very little can be said about chemotherapy for the very elderly. Siu et al18 reported that the patients with the worst survival in the NCIC trials were those in the 75–80 age group. Only 46% of patients completed all six courses of chemotherapy, and no patient survived beyond 2 years (Figure 50.2). Patients over the age of 80 were excluded from these two NCIC trials, and from all research trials until recently. Some authors have reported that patients in this age group are seldom offered chemotherapy of any kind, even that which is considered to be ‘gentle’.7 As the likelihood of surviving past age 80 increases, more attention will have to be paid to determining appropriate treatment for this group. Prospective trials for the elderly It is clear that some elderly patients can derive significant benefit from combination chemotherapy for SCLC. However, many investigators continue to question whether such treatment is appropriate for the elderly, and some have suggested that less aggressive treatment might be more appropriate even if this results in some compromise in overall response or survival rates.25 Findlay et al25 reviewed their results for 72 elderly patients treated with either intensive combination chemotherapy or less rigorous treatment using either single agents or reduced doses of combination chemotherapy. Despite three

Comprehensive Geriatric Oncology

1160

treatment-related deaths in the intensive group, median survival was longer (36 weeks versus 16 weeks), particularly for patients with limited-stage disease (43 weeks versus 26 weeks). The authors summarized by saying that intensive chemotherapy for elderly patients results in higher response rates and higher toxicity, but not a major survival benefit. Other investigators might have reached a

Table 50.4 Prospective randomized trials for elderly patients with small cell lung cancer Authors

Drugs

No. of patients

Overall Median response rate survival (%) (days)

Toxic deaths

Medical Research Council21

Etoposide 50mg p.o. bid x 10 days versus EV or CAV2

171 61 168 73

130 (11% 1yr) 183 (13% 1yr)

17 10

London Lung Etoposide 100mg Cancer Group20 p.o. bid×5 days versus CAV1 alternating with EP

75 33 80 46

146 (6.5% 1yr) 189 (17% 1yr)

2 1

CAV1, cyclophosphamide 600mg/m2, doxorubicin 50mg/m2, vincristine 2mg; EP, etoposide 120mg/m2 i.v. day 1 and 100mg p.o. twice daily days 2 and 3, cisplatin 60mg/m2; EV, etoposide 120mg/m2 i.v. day 1 and 240mg/m2 p.o. days 2 and 3, vincristine 1.3mg/m2; CAV2, cyclophosphamide 750mg/m2, doxorubicin 40mg/m2, vincristine 1.3mg/m2.

different conclusion in view of the doubling of survival time achieved with combination chemotherapy. In an attempt to avoid the toxicity of combination chemotherapy without compromising efficacy, several groups have developed treatment strategies specifically for elderly patients with SCLC. The results of several prospective trials are summarized in Table 50.3.32–41 The epipodophyllotoxins etoposide and teniposide are among the most active agents for the treatment of SCLC, and as single agents produce response rates of 70% or more. Three trials of single-agent teniposide in the elderly produced conflicting results. Borke et al35 treated 33 patients (27 over age 70), and reported a 90% response rate, a median survival longer than 8 months, and low toxicity. In contrast, Cerny et al36 reported only a 48% response rate and an unacceptably high toxic death rate of five patients during the first cycle despite using the same dose and schedule of teniposide. This may have been due to the inclusion of seven patients with ECOG performance status 3. However, Cascinu et al40 also reported a low response rate of only 23% without toxic deaths. Etoposide may be administered orally, and when used this way, is associated with only modest toxicity.42 The Dublin group was among the first to use single-agent oral etoposide in the treatment of elderly SCLC patients.32 Keane and Carney34 treated 63 elderly patients with etoposide, 200mg orally daily for 5 days, and reported an overall response rate of 76% and a median survival of 38 weeks. As shown in Table 50.3, other

Treatment of small cell lung cancer in the elderly

1161

investigators have also found similar response and survival rates, although various doses and schedules of etoposide have been employed. These phase II results led to two randomized trials of single-agent oral etoposide in the UK: one by the Medical Research Council (MRC) Lung Cancer Working Party21 and the other by the London Lung Cancer Group.20 The two studies are summarized in Table 50.4. The MRC compared oral etoposide, 50mg twice daily for 10 days, with two standard combinations of chemotherapy. The survival of patients treated with singleagent etoposide was significantly shorter than that of those treated with combination chemotherapy (130 days versus 183 days; p =0.03). Furthermore, the etoposide group experienced more life-threatening side-effects (19% versus 10%; p= 0.05). The London group compared etoposide, 100 mg twice daily for 5 days, with alternating combination chemotherapy in a trial that was limited to the extremely elderly aged over 75 or to younger patients with extensive disease and poor performance status. Overall response rates (39% versus 61%; p=0.01), median survival (146 days versus 189 days) and 1-year survival rates (6.5% versus 17%) all favored the combination chemotherapy arm. Although toxicity was greater in the combination arm, severe grade 3 and 4 toxicities were uncommon in both arms. Although the above studies show that elderly patients of good performance status may tolerate combination chemotherapy, several investigators have attempted to modify current regimens to improve the therapeutic index for this patient population. The most frequent maneuver has been to substitute carboplatin for cisplatin and to combine it with either etoposide or teniposide. The results of three trials are shown in Table 50.3.37–39 All investigators reported response rates that ranged from 60%39 to 89%37 and median survivals that ranged from 33 weeks38 to 40 weeks.39 In general, the regimens were well tolerated, although Evans et al39 reported that 4 of 40 patients suffered toxic treatmentrelated deaths. Westeel et al41 elected to use the standard chemotherapy agents cisplatin, doxorubicin, vincristine, and etoposide given in smaller doses to elderly patients in their PAVE regimen (cisplatin, doxorubicin, vincristine, and etoposide). For patients with limitedstage tumors, thoracic irradiation was administered concurrently with cisplatin and etoposide in cycle 2. They reported a very favorable overall response rate of 89%, and median survival times of 70 and 46 weeks for limited and extensive stages, respectively. Radiotherapy Radiotherapy plays an important role in the treatment of patients with SCLC. Thoracic irradiation has been shown to improve response rates, as well as survival rates in patients with limited-stage disease,19,43 with two large meta-analyses reporting a 5.4% improvement in survival. Prophylactic cranial irradiation leads to a decreased risk of isolated cranial metastases for treated patients; a meta-analysis has shown the same degree of survival benefit as above, in patients achieving a complete clinical response.44 Radiation also has an important role to play in symptom palliation in patients who have relapsed or who are not candidates for aggressive treatment.

Comprehensive Geriatric Oncology

1162

Toxicity of radiotherapy There have been only a few analyses of the efficacy and tolerability of thoracic radiation in older patients with SCLC. Quon et al45 undertook a retrospective review of two NCICCTG randomized studies of combined-modality treatment for limited-stage SCLC, BR.3 and BR.6. Of 608 patients, 88 (13%) were aged 70 or older. The details of radiation timing and dose, and chemotherapy agents, differed according to the study schema and randomization arm (sequential or alternating, early or late radiation; dose 25 Gy in 10 fractions, 37.5 Gy in 15 fractions, or 40 Gy in 15 fractions). No tendency was found to reduce field size in the elderly, even at the higher radiation doses. Once radiation started, there was no significant difference between the age groups with respect to the proportion of patients who completed treatment, and no differences were seen in time to complete radiotherapy, dose delivered or incidence of acute and late radiation toxicity. Some trends were noted, with elderly patients being somewhat less likely to complete late radiation (with cycle 6 of chemotherapy) in the BR.6 study. Elderly patients also tended to have lower rates of complete response in the BR.3 trial, although this was not the case in the BR.6 trial, in which chemotherapy and radiotherapy were delivered concurrently. Local control rates were similar for both age groups in both trials. Pignon et al46 analyzed the effect of age on acute and late toxicity of curative thoracic irradiation given to 1208 patients who participated in six randomized trials of lung and esophageal cancer conducted by the European Organization for Research and Treatment of Cancer (EORTC). The largest of these trials compared sequential with alternating radio-chemotherapy in 389 patients with limited-stage SCLC.46 Patients received either 50 Gy in 20 fractions after chemotherapy (sequential design), or four courses of 12.5 Gy in 5 fractions (alternating with chemotherapy). Of 389 patients, 95 (24%) were aged 65– 70, and 29 (7%) were older than 70. This study contributed to the analysis of the effect of age on pulmonary and esophageal toxicity, although results were reported collectively for all of the sk EORTC trials. There were no differences in the rates of either acute or late pneumonitis or esophagitis with increasing age. The analysis of other toxicities revealed no difference with age in the severity or incidence of nausea, weakness, or late sideeffects. The only difference related to age was a significantly greater weight loss seen in older patients, which suggests that the clinical impact of esophagitis may have been greater in this population. This, however, was not accompanied by a greater decline in performance status in the elderly compared with the younger patients. The authors concluded that good general condition and performance status, rather than age alone, are the best predictors of tolerance of curative thoracic radiotherapy. Other reports of radiation side-effects in older patients treated for a variety of tumors document that radiation is well tolerated by patients 80 and older47,48 and even by patients over 90.49 The high degree of tolerability of radiation in the elderly population with SCLC may be due to the relatively modest doses of radiation traditionally employed to treat this type of cancer. The standard dose is 40–50 Gy delivered in 15–25 fractions, although an increasing number of studies of dose escalation and hyperfractionation have been conducted,50–52 and these may affect future practice. Despite the good overall tolerance of thoracic irradiation, one cannot ignore the physiological decline in organ function, including a decline in pulmonary reserve, that

Treatment of small cell lung cancer in the elderly

1163

occur with increasing age. Studies of radiological changes of radiation pneumonitis have documented a lower tissue density of lung with increasing age,53 which would lead to a greater dose transmission through the lung in an older patient. This is even more pronounced in patients with emphysema or other lung disease. In addition, the impact of radiation damage is clinically more apparent in patients whose lung reserve is reduced owing to COPD or other factors. The radiation portals for SCLC traditionally include the initial tumor volume (prior to any treatment), although whether or not uninvolved nodes need to be included is controversial. If a large volume needs to be irradiated, the potential for radiation toxicity is greater. For this reason, some investigators have suggested that there might be merit in giving a higher radiation dose to a smaller volume by treating areas of residual disease only.54 However, the review by Quon et al45 does not suggest that practising radiation oncologists feel that it is necessary to reduce field size in the elderly. There was no evidence of increased pulmonary toxicity in the older patients, even when radiation was administered concurrently with chemotherapy.

Table 50.5 Prospective trials of abbreviated combined-modality treatment for elderly patients with limited-stage small cell lung cancer Authors

Treatment

No. of patients

Response rate (%)

Median survival

Toxic deaths

Westeel et al41

PAVE×5

25

ORR 92

70 wks

0

CR 76

25% 5-yr

ORR 75

15 mos

CR 57

(32% 2-yr;

TRT (variable doses and fractionation) Jeremic et al55

EC×2

75

Accelerated hyperfractionated TRT 1.5 Gy bid x 15 days, starting day 1 Murray et al56

CAV×1 EP×1 TRT 20–30 Gy with EP

0

13% 5-yr) 55

ORR 89

12.5 mos

CR 51

(28% 2-yr;

3

18% 5-yr)

ORR, overall response rate; CR, complete response; TRT, thoracic radiotherapy; CAV, cyclophosphamide 1000mg/m2, doxorubicin 50mg/m2, vincristine 2mg; EP, etoposide 100mg/m2 i.v. days 1–3, cisplatin 25mg/m2 i.v. days 1–3; EC, etoposide 50mg/m2 p.o. days 1–21 and 29–49 and carboplatin 400mg/m2 i.v. days 1 and 29; PAVE, cisplatin 30mg/m2 day 1, doxorubicin 40mg/m2 day 1, vincristine 1mg/m2 day 1, etoposide 100mg/m2 i.v. day 1 and p.o. days 3 and 5.

Radiation side-effects may also be influenced by the type of chemotherapy used either previously or when administered concurrently with radiotherapy. This is especially true

Comprehensive Geriatric Oncology

1164

when doxorubicin is employed, since the incidence of esophagitis increases greatly when it is administered concurrently or soon after radiation. In the NCIC-CTG trials reviewed by Quon et al,45 chemotherapy included a doxorubicin-containing regimen, but radiation was administered concurrently with cisplatin and etoposide. No differences in the rates of esophagitis were seen between the two age groups. Prospective trials in the elderly A number of studies described in the chemotherapy section of this chapter included radiation. Although a proportion of patients in these studies were elderly, these studies were not designed specifically for the elderly. Several combined-modality trials of chemotherapy and radiation have been undertaken especially for elderly patients;41,55,56 their results are summarized in Table 50.5. Westeel et al41 treated 66 elderly patients with PAVE chemotherapy given every 3 weeks for five cycles. The 25 patients with limited-stage tumors also received concurrent thoracic irradiation (dose and schedule were variable) administered with etoposide and cisplatin in cycle 2. The overall response rate for the limited-stage patients was 92%, and 76% achieved complete remission. Their median survival was 70 weeks, and 25% remained alive at 5 years. There were no toxic deaths in this group, although one patient with extensive disease died from neutropenic sepsis and the febrile neutropenia rate for patients treated with combined-modality therapy was 18%. Jeremic et al55 administered accelerated hyperfractioned radiotherapy, giving 1.5 Gy twice a day to a total dose of 45 Gy over 3 weeks, administered concurrently with carboplatin given intravenously on days 1 and 29 and oral etoposide on days 1–21 and 29–49. No further chemotherapy was given beyond the two cycles. They treated 77 patients aged 70–77. All patients had limited-stage disease, but 12 had a Karnofsky performance status of only 60% or 70%, and 18 had weight loss of more than 5% of body weight. The patients tolerated treatment remarkably well, with only 2.8% grade 3 esophagitis, 8.3% grade 3 leukopenia, and 4.2% grade 3 infection. Despite the very abbreviated chemotherapy, the overall response rate was 75% and survival rates were very promising (74% at 1 year, 32% at 2 years, and 19% at 3 years). In a trial of similar design, Murray et al56 gave only two cycles of chemotherapy (CAV followed by EP) and radiation consisting of either 20 Gy in 5 fractions or 30 Gy in 10 fractions concurrently with EP to the frail elderly (>70 years) as well as to younger patients who had significant comorbidity or who refused standard chemotherapy. Sixtyone percent of patients were older than 70, with 22 older than 75 and 4 older than 80. Three patients died of treatment-related complications, although two of these deaths were acute cardiac events that may have had other etiologies in this elderly or infirm patient cohort. Other toxicities were no different than expected. The overall response rate was 89%; the median survival was 12.5 months, with 28% and 18% of patients alive at 2 and 5 years, respectively. The results of these phase II studies are quite compelling, and they raise interesting questions for the treatment of both elderly and younger patients. As shown from the analyses in the chemotherapy section, elderly patients complete fewer cycles of chemotherapy than younger patients even when participating in clinical research protocols. However, their overall outcome does not seem to be significantly worse

Treatment of small cell lung cancer in the elderly

1165

because of this. The results of the Murray and Jeremic pilot studies suggest that when combined with early concurrent thoracic irradiation, chemotherapy may be further abbreviated to as few as two cycles without compromising efficacy. This approach deserves further study in a randomized clinical trial of elderly or infirm patients. Radiation alone If a patient is not only elderly but also frail and not suitable for or interested in standard chemotherapy or combined-modality treatment, radiation alone may be considered with the intent of improving symptoms and palliating the disease. Given the radiosensitive nature of SCLC, symptom improvement is likely, especially in patients with thoracic symptoms, painful bone lesions, or symptomatic soft tissue, nodal, or brain metastases. In this clinical setting, shorter fractionation courses are appropriate, since symptom improvement is not necessarily dependent on complete eradication of the local tumor. This is especially true for patients with extensive-stage disease, who may require, and benefit from, palliative radiotherapy to a number of symptomatic disease sites. Although the intent of such treatment is largely palliative, some patients with localized thoracic disease may achieve prolonged symptom-free survival with radiation alone. In the Toronto Hospital review,7 20 of the 123 patients over the age of 70 received radiation only. Their median survival was 7.8 months; this was superior to the 1.1 month survival of the 25 patients who had no treatment, and the 3.9 months survival of the 27 patients who had fewer than three courses of chemotherapy without radiation (Figure 53.4). This degree of potential benefit from radiation alone, especially given its high degree of tolerance by most elderly patients, emphasizes the need for informing patients of this therapeutic option should they decline to have chemotherapy. However, that is not to say that it should be recommended as an equal alternative to all elderly patients. Yellen et al,57 in a survey of cancer patients given hypothetical vignettes of different disease stage and treatment toxicity, showed that older patients are as likely as younger ones to accept both curative and palliative chemotherapy. They were, however, less willing to accept higher degrees of treatment toxicity for a given treatment benefit. Thus, all treatment options need to be presented to elderly patients and discussed in the frame-work of their values and goals of therapy in order to determine the optimal treatment plan for each patient.

Comprehensive Geriatric Oncology

1166

Summary To summarize, it appears that elderly patients can derive benefit from treatment for SCLC that is similar to that achieved by younger patients. However, this can only be stated with a word of caution, due to the limitations of the studies undertaken for elderly patients to date. To tolerate therapy, older patients must be of good performance status, and this should be the major determinant in reaching the decision to treat, and how to treat. Firm recommendations cannot be made for the extremely elderly population of 75 or more, and further studies for this subgroup, and for all elderly patients, must be encouraged in the future. References 1. Schottenfeld D. Epidemiology of lung cancer. In: Lung Cancer: Principles and Practice (Pass HI, Mitchell JB, Johnson DH, Turrisi AT, eds). Philadelphia: Lippincott-Raven, 1996:305. 2. Grulich AE, Swerdlow AJ, dos Santos Silva I, Beral V. Is the apparent rise in cancer mortality in the elderly real? Analysis of changes in certification and coding of cause of death in England and Wales 1970–1990. Int J Cancer 1995; 63:164–8. 3. Levi F, La Veccia C, Luccini F, Negri E. World-wide trends in cancer mortality in the elderly, 1955–1992. Eur J Cancer 1996; 32A: 569–71. 4. O’Rourke MA, Crawford J. Lung cancer in the elderly. Clin Geriatr Med 1987; 3:595–623. 5. Di Maria LC, Cohen HJ. Characteristics of lung cancer in elderly patients. J Gerentol 1965; 42:540–5. 6. Teeter SM, Holmes SF, McFarlane MJ. Lung carcinoma in the elderly population. Influence of histology on the inverse relationship of stage to age. Cancer 1987; 60:1331–6. 7. Shepherd FA, Amdemichael E, Evans WK et al. Treatment of small cell lung cancer in the elderly. J Am Geriatr Soc 1994; 42:64–70. 8. Goodwin JS, Hunt WG, Humble CG, Key CR, Samet JM. Cancer treatment protocols. Who gets chosen? Arch Int Med 1998; 148: 2258–60. 9. Dajczman E, Fu LY, Small D et al. Treatment of small cell lung carcinoma in the elderly. Cancer 1996; 77:2032–8. 10. de Rijke JM, Schouten LJ, Schouten HC et al. Age-specific differences in the diagnostics and treatment of cancer patients aged 50 years and older in the province of Limburg, the Netherlands. Ann Oncol 1996; 7:677–83. 11. Festen J. Lung cancer in the elderly. Eur J Cancer 1991; 27:1544–5. 12. Nerenz DR, Love RR, Leventhal H et al. Psychological consequences of cancer chemotherapy for elderly patients. Health Serv Rev 1986; 20:961–75. 13. Ginsburg ML, Quirt C, Ginsburg AD et al. Psychiatric illness and psychosocial concerns of patients with newly diagnosed lung cancer. Can Med Assoc J 1995; 152:701–8. 14. Kennedy BJ. Needed: clinical trials for older patients. J Clin Oncol 1991; 9:718–20. 15. Albain K, Crowley J, LeBlanc M, Livingston RB. Determinants of improved outcome in smallcell lung cancer: an analysis of the 2580-patient Southwest Oncology Group data base. J Clin Oncol 1990; 8: 1563–74. 16. Sagman U, Maki E, Evans WK et al. Small-cell carcinoma of the lung: derivation of a prognostic staging system. J Clin Oncol 1991; 9: 1639–49. 17. Spiegelman D, Maurer H, Ware JH et al. Prognostic factors in small-cell carcinoma of the lung. J Clin Oncol 1989; 7:344–54.

Treatment of small cell lung cancer in the elderly

1167

18. Siu L, Shepherd FA, Murray N et al. Influence of age on the treatment of limited-stage smallcell lung cancer. J Clin Oncol 1996; 14:821–8. 19. Pignon J-P, Arriagada R, Ihde D et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 1992; 327: 1618–24. 20. Harper P, Underhill C, Ruiz de Elvira MC et al. A randomized study of oral etoposide versus combination chemotherapy in poor prognosis small cell lung cancer. Proc Am Soc Clin Oncol 1996; 15:27. 21. Medical Research Council Lung Cancer Working Party. Comparison of oral etoposide and standard intravenous multi-drug chemotherapy for small cell lung cancer: a stopped multicentre trial. Lancet 1996; 348:563–6. 22. Clamon GH, Audeh MW, Pinnick S. Small cell lung carcinoma in the elderly. J Am Geriatr Soc 1982; 30:299–302. 23. Poplin E, Thompson B, Whitacre M, Aisner J. Small cell carcinoma of the lung: influence of age on treatment outcome. Cancer Treat Rep 1987; 71:291–6. 24. Kelly P, O’Brien AAJ, Daly P, Clancy L. Small-cell lung cancer in elderly patients: the case for chemotherapy. Age Aging 1991; 20:19–21. 25. Findlay MPN, Griffin A-M, Raghaven D et al. Retrospective review of chemotherapy for small cell lung cancer in the elderly: Does the end justify the means? Eur J Cancer 1991; 27:1597– 601. 26. Nou E. Full chemotherapy in elderly patients with small cell bronchial carcinoma. Acta Oncol 1996; 35:399–406. 27. Tebbutt NC, Snyder RD, Burns WI. An analysis of the outcome of treatment of small cell lung cancer in the elderly. Austr NZ J Med 1997; 27:160–4. 28. Smit EF, Postmus PE, Sleijfer DTH. Small cell lung cancer in the elderly. Factors influencing the results of chemotherapy: a review. Lung Cancer 1989; 5:82–91. 29. Begg CB, Chohe JL, Ellerton J. Are the elderly predisposed to toxicity from cancer chemotherapy? An investigation using data from the Eastern Cooperative Oncology Group. Cancer Clin Trials 1980; 3:369–74. 30. Begg CB, Carbone PP. Clinical trials and drug toxicity in the elderly. The experience of the Eastern Cooperative Oncology Group. Cancer 1983; 52:1986–92. 31. Giovanazzi-Bannon S, Rademaker A, Lai G, Benson AB. Treatment tolerance of elderly cancer patients entered onto phase II clinical trials: an Illinois Cancer Center study. J Clin Oncol 1994; 12: 2447–52. 32. Smit EF, Carney DN, Harford P. A phase II study of oral etoposide in elderly patients with small cell lung cancer. Thorax 1989; 44: 631–3. 33. Gatzemeier U, Neuhauss R, Heckmayr M. Single agent oral etoposide in advanced non-small cell lung cancer, and in elderly patients with small cell lung cancer. Lung Cancer 1991; 7(Suppl): 102 (abst). 34. Keane M, Carney DM. Treatment for elderly patients with small cell lung cancer. Lung Cancer 1993; 9(Suppl 1): S91–8. 35. Bork E, Hansen M, Dombernowsky P et al. Teniposide (VM-26), an overlooked highly active agent in small cell lung cancer. Results of a phase II trial in untreated patients. J Clin Oncol 1986; 4:524–7. 36. Cerny T, Pedrazzini A, Joss RA, Brunner KW. Unexpected high toxicity in a phase II study of teniposide (VM-26) in elderly patients with unresected small cell lung cancer. Eur J Cancer Clin Oncol 1988; 24:1791–4. 37. Byrne A, Carney D. Small cell lung cancer in the elderly. Semin Oncol 1994; 3(Suppl 6): 43–8. 38. Michel G. Leyvraz S, Bauer J et al. Weekly carboplatin and VM-26 for elderly patients with small cell lung cancer. Ann Oncol 1994; 5: 369–70. 39. Evans WK, Radwi A, Tomiak E et al. Oral etoposide and carboplatin. effective therapy for elderly patients with small cell lung cancer. Am J Clin Oncol 1995; 18:149–55.

Comprehensive Geriatric Oncology

1168

40. Cascinu S, Del Ferro E, Ligi M et al. The clinical impact of teniposide in the treatment of elderly patients with small cell lung cancer. Am J Clin Oncol 1997; 10:477–8. 41. Westeel V, Murray N, Gelmon K et al. New combination of the old drugs for elderly patients with small-cell lung cancer: a phase II study of the PAVE regimen. J Clin Oncol 1998; 16:1940–7. 42. Carney D, Grogan L, Smit EF. Single-agent oral etoposide for elderly small cell lung cancer patients. Semin Oncol 1990; 17(Suppl 2): 29–35. 43. Warde P, Payne D. Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 1992; 10:890–5. 44. Auperin A, Arriagada R, Pignon JP et al. Prophylactic cranial irradiation for patients with small cell lung cancer in complete remission. N Eengl J Med 1999, 341:476–84. 45. Quon H, Shepherd FA, Payne DG et al. The influence of age on the delivery, tolerance and efficacy of thoracic irradiation in the combined modality treatment of limited stage small cell lung cancer. Int J Radiat Oncol Biol Phys 1999; 43:99–45. 46. Pignon T, Gregor A, Koning CS et al. Age has no impact on acute and late toxicity of curative thoracic radiotherapy. Radiother Oncol 1998; 46:239–48. 47. Gregor A, Drings P, Schuster L et al. Acute toxicity of alternating schedule of chemotherapy and irradiation in limited small-cell lung cancer in a pilot study (08877) of the EORTC Lung Cancer Cooperative Group. Ann Oncol 1995; 6:403–5. 48. Zachariah B, Balducci L, Venkattaramanbalaji GV et al. Radiotherapy for cancer patients aged 80 and older: a study of effectiveness and side effects. Int J Radiat Oncol Biol Phys 1997; 39:1125–9. 49. Oguchi M, Ikeda H, Watanabe T et al. Experience of 23 patients >90 years of age treated with radiation therapy. Int J Radiat Oncol Biol Phys 1998; 41:407–13. 50. Choi NC, Hemdon J, Rosenman J et al. Phase I study to determine the maximum tolerated dose (MTD) of radiation in standard daily (QD) and accelerated twice daily (bid) radiation schedules with concurrent chemotherapy (CT) for limited stage small cell lung cancer: CALGB 8837. J Clin Oncol 1998; 16:3528–36. 51. Johnson DH, Kim K, Sause W et al, for the Eastern Cooperative Oncology Group. Cisplatin (P) and etoposide (E)+thoracic radiotherapy (TRT) administered once or twice daily (bid) in limited stage (LS) small cell lung cancer (SCLC): final report of Intergroup trial 0096. Proc Am Soc Clin Oncol 1996; 15:374. 52. Takada M, Fukuoka M, Furuse K et al, for the JCOG-Lung Cancer Study Group. Phase III study of concurrent versus sequential thoracic radiotherapy) (TRT) in combination with cisplatin (C) and etoposide (E) for limited-stage (LS) small cell lung cancer (SCLC): preliminary results of the Japan Clinical Oncology Group (JCOG). Proc Am Soc Clin Oncol 1996; 15:372. 53. Mah K, Keane TJ, Van Dyk J et al. Quantitative effect of combined chemotherapy and fractionated radiotherapy on the incidence of radiation-induced lung damage: a prospective clinical study. Int J Radiat Oncol Biol Phys 1994; 28:563–74. 54. Lichter AS, Turrisi AT III. Small cell lung cancer: the influence of dose and treatment volume on outcome. Semin Radiat Oncol 1995; 5:44–9. 55. Jeremic B, Shibamoto Y, Acimovic L, Milisavljevic S. Carboplatin, etoposide, accelerated hyperfractionated radiotherapy for elderly patients with limited small cell lung cancer. A phase II study. Cancer 1998; 82:836–41. 56. Murray N, Grafton C, Shah A et al. Abbreviated treatment for elderly, infirm or non-compliant patients with limited small cell lung cancer. J Clin Oncol 1998; 16:3323–8. 57. Yellen SB, Cella DF, Leslie WT. Age and clinical decision making in oncology patients. J Natl Cancer Inst 1994; 86:1766–70.

51 Breast cancer in the older woman: An oncologic perspective Lodovico Balducci, Rebecca A Silliman, Nils Diaz Introduction Breast cancer is the most common malignancy and the most common cause of cancer death in women aged over 65.1–4 The control of breast cancer in older individuals may be improved by the study and the understanding of some critical questions that are still unanswered.5,6 These include age-related changes in the biology of breast cancer, agerelated barriers to cancer prevention and treatment, the value of screening asymptomatic older women for breast cancer, optimal management of primary breast cancer, the optimal duration of adjuvant treatment with tamoxifen, the place of adjuvant chemotherapy, and the optimal management of metastatic disease. We shall explore these questions after an overview of the epidemiology of breast cancer in the older woman. Extent of the problem General epidemiology The incidence of breast cancer increases with age.6,7 According to data from the US National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) program (Figure 51.1), the incidence of breast cancer increases up to age 80, plateaus between ages 80 and 85, and may decline thereafter.6 Lack of reliable information in persons over 85 may explain the late decline. Some autopsy data from Trieste support a real decrement in the incidence of breast cancer in the oldest old (see Chapter 16 of this volume8). The pathologists from Trieste regularly searched for occult breast cancer all women coming to autopsy. In an autopsy population of approximately 30000 women, they found that the prevalence of occult breast cancer was highest between ages 50 and 60 and declined progressively thereafter; virtually no cases of occult breast cancer were detected in women aged 80 and older. More data are needed to confirm these preliminary

Comprehensive Geriatric Oncology

1170

Figure 51.1 Age-related incidence of breast cancer. From reference 6, with permission. findings: at present, the information related to the incidence of breast cancer after age 85 is inadequate. Two-thirds of breast cancers occur after age 50, 50% after age 65, while 56% of breast cancer-related deaths affect women aged 65 and older.1–8 At the present rate of growth of the older population, one can expect 65% of all breast cancers and 70% of all breast cancer deaths to occur in women aged 65 and over by the year 2010. Risk factors Breast cancer has been associated with a number of conditions (Table 51.1), some of which may be relevant to the elderly.1 Madigan et al9 studied the proportion of breast cancer cases in the USA that may be explained by well-established risk factors, and found that family history, reproductive history, and higher income may account for as many as 47% of cases. Of interest, the relative risk for breast cancer for women aged 70 or older was 2.4 in the presence of positive family history, 1.9 for nulliparity, 3.0 for first pregnancy after age 30, and 2.3 for income. This project stemmed from the National Health and Nutrition Examination Survey I (NHANES I), and consequently had a limited scope. In particular, it could not include other

Table 51.1 Risk factors for breast cancer • Age • Family history of the disease • Endocrine history: –

Age at menarch and menopause

Breast cancer in the older woman: An oncologic perspective

–

Age of first pregnancy

–

Number of pregnancies

–

Therapeutic use of estrogens

1171

• Body shape • Nutritional factors • Exposure to ionizing radiation

risk factors such as hormone replacement therapy (for lack of information) or body size (which was dealt with in a separate study). Still, these results are very important, since as they demonstrate that many risk factors remain significant throughout old age. Family history Frequently, breast cancer appears to be a familial disease. Goldstein and Amos10 calculated that approximately 60% of postmenopausal ductal breast cancers detected in the Cancer and Steroid Hormone Study (CASH) were familial. Thus, family history is an important risk factor, even for older women. The relation of familial and inheritable cancer is complex. Familiarity does not necessarily imply inheritance.11 Environmental conditions prevalent in the same household may cause a cluster of cancers in the same family. For a long time, it was held that inheritable cancers tend to occur in a population younger than that in which sporadic cancers occur.11 A new insight into the different categories of persons at risk for cancer (oncodemes) may explain how inheritable cancer develops in older persons.12 Four types of oncodemes have been defined:12 • background oncodeme—in these persons, cancer is independent of both genetic and environmental factors; • genetic oncodeme—in these persons, cancer is inheritable; • environmental oncodeme—in these persons, cancer is due exclusively to environmental factors; • interactive oncodeme—in these persons, cancer requires both inherited predisposition and environmental influences. It is not unreasonable to construe an interactive oncodeme for women with a family history of breast cancer who develop cancer late in life. It should be underlined that even genetic oncodemes may occasionally include older persons. Two recently defined breast cancer oncodemes appear to be genetic, in that the majority of the population carrying the gene develops breast cancer.13 Although independent from each other, both are associated with increased incidence of breast and ovarian cancer in the same family. One oncodeme involves mutations in the BRCA1 gene, on chromosome 17q,14 the other a mutation in the BRCA2 gene, on chromosome 13q.15 Abnormalities of either gene account for 5–10% of breast cancer in the USA.13 The penetrance of BRCA1 (or cumulative risk of developing breast cancer for members of a breast cancer family carrying the mutation) was calculated to be 59% by age 50 and 87% by age 70.16 The penetrance of BRCA2 increases at around age 40, and is approximately 75% by age 80.17 In one BRCA2 family, 17% of

Comprehensive Geriatric Oncology

1172

breast cancers occurred after age 60.18 Thus, a sizable portion of older women with the mutations are also at risk. Both BRCA1 and BRCA2 are tumor suppressor genes. Other mutations, such as alterations of oncogenes and of DNA-repair genes, are also likely to cause inheritable breast cancer.19 Seemingly, other inheritable genetic mutations leading to breast cancer are yet to be recognized, since neither BRCA1 nor BRCA2 mutations were found in some families at high risk of breast cancer. The clinical implications of the discovery of these mutations include screening individuals at high risk of breast cancer and institution of prophylactic measures, which may involve bilateral mastectomy, intensive mammographic screening, and chemoprevention.13 The exact role of these measures is still to be defined, however.13,20 Of special interest are the interactions between the genetic predisposition to breast cancer and endocrine risk factors, which are, to some extent, modifiable.21 These interactions may be explored in the laboratory with the help of transgenic mice models.22 Endocrine factors Of the endocrine factors, hormone replacement therapy (HRT) is of particular concern to older women. This issue involves two major questions: Does estrogen replacement increase the risk of breast cancer? Does the addition of progestins to estrogen modulate the risk of breast cancer? Two meta-analyses of case-control studies related to estrogen replacement have been performed.23,24 Dupont et al23 failed to demonstrate a definitive association between postmenopausal estrogens and breast cancer, but found that the relative risk of breast cancer increased with prolonged use of estrogens, at doses equivalent to 1.25mg or more of conjugated estrogens. The risk of breast cancer declined almost immediately after discontinuance of the hormones. Most importantly, these authors also established that doses equal to or lower than 0.625mg of conjugated estrogens did not increase the risk of breast cancer, irrespective of treatment duration. The low doses of estrogen were effective in preventing osteo-

Table 51.2 Hormone replacement therapy with estrogen and progestins, and risk of breast cancer Case-control studies Study Ewertz26 27

Kaufman et al 28

Palmer et al Yang et al

29 30

Stanford et al Ross et al

31

No. of subjectsa

Age range (years)

Odds ratiob

2822

All ages

1.36 (0.98–1.87)

3763

40–69

1.7 (0.9–3.3)

1821

<70

0.9 (0.6–1.2)

1384

<75

1.2 (0.6–2.2)

1029

50–64

0.9 (0.7–1.3)

3534

≥50

1.24 (1.07–1.45)

Breast cancer in the older woman: An oncologic perspective

1173

1.38 (1.13–1.68) for intermittent use Cohort studies Study Bergkvist et al32 33

Hunt et al

Risch and Howe Schairer et al35 36

Colditz et al

34

No. of subjectsa

Age range (years)

Relative riskb

23 244

≥35

4.1 (0.9–22.1)

4 544

45–54

1.59 (1.18–2.10)

33 003

43–49

NRc (p=0.48)

49 017

≥55

1.2 (1.0–1.6)

121 700

≥54

1.41 (1.15–1.74)

a

Includes all study subjects: untreated controls, those treated with estrogen only, and those receiving combinations of estrogens and progestins. b 95% confidence interval in parentheses. c Not reported: there were no cases of breast cancer.

porosis and coronary artery disease, but did not always ameliorate disabling symptoms of menopause, such as hot flashes and vaginal atrophy. Colditz et al24 found a small but definitive increase in the risk of breast cancer for women receiving estrogen replacement therapy (relative risk 1.40; 95% confidence interval (CI) 1.20–1.63) The risk abated upon treatment cessation. Previous estrogen users who had discontinued the therapy had a relative risk of 1.02 (95% CI 0.93–1.12). The combination of estrogen and progestins has been proposed as HRT to reduce the risk of endometrial cancer. Recent studies showed that progestins did not lessen the benefits of estrogen on osteoporosis, lipid profile, or postmenopausal symptoms.25 The effects of this promising combination of hormones on breast cancer risk has been explored both in case-control26–31 and in cohort studies32–36 (Table 51.2). The earlier studies involved different populations, of different ages and at different times; not surprisingly, the results were highly variable. With the exception of the study by Stanford et al,30 involving 537 patients aged 55–64 and 492 matched and randomly selected controls, all other studies included women taking both estrogen and estrogen-progestins in combination. The study by Stanford et al is a model case-control study in terms of methodology. However, the small number of subjects might have limited the statistical power to detect small differences. Also, the selection of women in a relatively narrow age range, close to the menopause, might have prevented adequate assessment of long-term hormone replacement. In earlier studies, patients treated with combination therapy were a minority and the results of these studies are not conclusive.26–29,32–34 for example, Risch and Howe34 did not find a single case of breast cancer among women receiving combination hormonal therapy, but only 171 of 33 003 women were treated exclusively with combination therapy. An additional 646 women received both estrogen alone and estrogens in combination with progestins at some time in their postmenopausal years; of these, 3 developed breast cancer. The Swedish study reported a staggering relative risk of 4.1 for women using combination HRT.32 Several reasons make this study an outlier. The large confidence interval indicates that the relative risk is far from precise. Also, the Swedish study used a combination of estradiol compounds and levonorgestrel for

Comprehensive Geriatric Oncology

1174

hormone replacement. This treatment is quite different from the combinations of hormones used in the USA, and may have a more pronounced carcinogenic effect.32 Three studies deserve special attention.31,35,36 Ross et al31 conducted a case-control study involving incident breast cancer case in postmenopausal women diagnosed in LA County over 4½ years. They found that the risk of breast cancer was not significantly increased for women taking estrogen alone for 10 years or less, but was substantially increased for those taking an estrogen-progestin combination. These authors were able to establish that the relative risk of breast cancer was 20% higher in women utilizing intermittent progestin than in those taking continuous treatment. This is the first study that could distinguish between continuous and intermittent progestin use. Schairer et al35 followed a cohort of 46355 postmenopausal women involved in the Breast Cancer Detection Demonstration Project for a median of 12.3 years; 85% of the patients completed the study, and of those who failed to complete the study, 5% did so because of death. Of these patients, 42% received no HRT, 38% estrogen alone, and 10% estrogen-progestin combinations; in the remnant, the use of progestin was unknown. These authors reported several interesting results: (i) The risk of breast cancer was limited to current users and disappeared in past users; it was also related to the duration of therapy. (ii) The majority of tumors were carcinomas in situ, which may reflect the high use of mammography in this population. (iii) The relative risk increased with the combination, and the increment was on the order of 5% per year. The study by Colditz et al36 is particularly important for several reasons. This was a cohort study with a large number of patients and with a particularly prolonged follow-up (16 years), involving professional individuals (nurses) with a high comprehension of the nature and the goals of the study, so that the compliance was unusually high and the data collection very reliable. The authors had the opportunity to study the effects of both estrogen alone (until 1986) and estrogens in combination with progestins (after 1986). It was found that the relative risk of breast cancer increased with estrogen alone (1.32; 95% CI 1.14–1.54) and with the combination (1.41; 95% CI 1.15–1.74). Also, the relative risk increased with the duration of treatment and with the age of the patients; for women aged 60–65, the relative risk was 1.71. Seemingly, there was a relation between age and treatment duration. The addition of progestins to estrogen appeared to enhance the risk of breast cancer. The risk of breast cancer declined almost immediately upon discontinuance of the hormones—both for estrogen and for combination treatment. Of special concern is the high breast cancer-related mortality in this population, suggesting that hormone replacement may cause invasive and aggressive cancers in the majority of cases. This conclusion has been challenged in other studies. For example, the Iowa Women’s Health study reported that HRT was associated with cancer with less malignant characteristics.37 Likewise, Schairer et al38 studied the survival of women diagnosed with breast cancer in the Breast Cancer Detection Demonstration Project (BCDDP), and found that those using HRT at time of diagnosis had decreased breast cancer mortality with respect to non-users or past users, for the first 4 years after diagnosis. This survival advantage might have been limited to individuals treated with estrogen alone. Fowble et al39 studied the outcome of women with invasive breast cancer treated at the Fox Chase Cancer Center, and established that the use of HRT at the time of diagnosis did not affect survival or recurrence rate. An improvement in breast cancer-related mortality from HRT has also been suggested by two analyses, including a review of 51 epidemiological studies.40,41

Breast cancer in the older woman: An oncologic perspective

1175

An additional study added to the worry regarding HRT. The American Cancer Society (ACS) Cancer Prevention Study II showed that estrogen replacement for 10 or more years was associated with a 50% increased risk of ovarian cancer mortality.42 Given the rarity of this neoplasm, however, the absolute increment was low. HRT has a major impact on the quality of life and possibly on the physical health of million of women, and should not be discouraged lightly.43 Recent information suggests that HRT may delay the development of dementia44 and prevent colorectal cancer,45 in addition to other established benefits.43 As postmenopausal women, and especially older women, are most likely to benefit from HRT, a discussion of benefits and risk is germane to this chapter. A 1999 consensus conference related to estrogen replacement on survivors of breast cancer concluded the following:43 • There is no medication of comparable efficacy to HRT for the relief of the vasomotor and genitourinary symptoms of menopause. • The is not enough evidence to justify the use of HRT for the prevention of cardiovascular disease. • HRT definitely prevents osteoporosis, but other interventions are available for this purpose, including the use of selective estrogen receptor modulators (SERMs) such as raloxifene, bisphosphonates, and calcitonin. • Other alleged benefits of HRT, such as prevention of dementia and colorectal cancer, have not been conclusively proven. Although the antidepressant venlafaxine46 and transdermal clonidine may relieve the hot flushes related to menopause, their activity is not as complete as that of HRT. Furthermore, these medications have no effect on dyspareunia and atrophic cystitis. Although the effectiveness of HRT in preventing coronary artery disease (CAD) and coronary events was taken as given in the past, recent studies have questioned this common tenet. A prospective randomized trial, the Heart and Estrogen Progestin Replacement study (HERS), showed that HRT did not prevent the progression of CAD and might have been harmful to women with history of CAD during the first 2 years of treatment.47 Likewise, in a randomized controlled study in women with angiographically proven CAD, HRT did not affect the progression of the disease.48 At the same time, in a cohort study, the Nurses Health Study, HRT appeared to be associated with a reduced risk of CAD in the general population.49 A possible explanation of these divergent findings was provided by Psaty et al,50 who demonstrated that HRT was prothrombotic in women with the 20210 G→A prothrombin variant, who are also at increased risk of CAD. Also, it is important to notice that the more recent studies have concerned estrogen-progestin combinations, whereas the older studies dealt with estrogen alone in the majority of cases. Thus, the question whether the hormonal combination is less cardioprotective than estrogen alone persists. The Woman Health Study, a randomized placebo-controlled study of HRT in postmenopausal women demonstrated that the use of the combination of estrogen and progestins was associated with increased risk of breast cancer, and of cognitive impairment, without any benefit in prevention of coronary artery disease.50a,50b Based on these data, the combination of estrogen and progestins can only be recommended in women whose quality of life has been seriously compromised by menopausal syndrome, and have a uterus. The benefits and risks of estrogen alone are still under study.

Comprehensive Geriatric Oncology

1176

A common question related to HRT concerns the effects of therapy in women with a personal or family history of breast cancer. Several series of patients who had received HRT after breast cancer have been reported (Table 51.3).51

Table 51.3 Hormone replacement therapy (HRT) in breast cancer survivorsa Study

No. of patients

Disease-free interval prior to HRT

Recurrence rate and Relative duration of follow-up since riskb initiating HRT

Controlled Eden

90

60 6 (7%), 24 months

0.40 (0.17– 0.93)

Beckman

64

0 6 (10%), 32 months

0.67 (0.28– 1.61)

Ursic-Vrscaj

21

62 4 (25%), 28 months

1.60 (0.48– 5.34)

VassiloupolouSellin

39

114 1 (3%), 40 months

0.51 (0.07– 3.79)

Natarjan

50

3 (4%)

Wile

23

26 3 (12%), 35 months

Powles

35

31 2 (7%), 15 months

DiSaia

71

24 7 (10%), 27 months

Decker

45

44 5 (11%), 26 months

Peters

42

57 0, 37 months

0.34 (0.11– 0.92)

Uncontrolled

Bluming

132

59 12 (12%), 29 months

Espie

107

96 5 (4%), 29 months

a b

Data from references 51–53. 95% confidence interval in parentheses.

The recurrence rate of breast cancer was not higher than among untreated patients. A recent analysis of different studies calculated that the risk of breast cancer recurrence was 4.2% per year for women taking HRT and 5.2% per year for those not receiving HRT.52

Breast cancer in the older woman: An oncologic perspective

1177

The relative risk of recurrence was 0.82 (95% CI 0.58–1.15) for HRT. The median time from diagnosis of breast cancer to the initiation of HRT was 52 months and the mean follow-up 30 months. In a cohort study of 76 patients, 50 of whom received HRT and 26 did not, HRT (consisting of pure estrogen) was associated with reduced breast cancer mortality.53 While these studies confirm that women may safely receive HRT after breast cancer, they leave a number of questions unanswered, including: • How long after the primary diagnosis of breast cancer is it safe to initiate HRT? • Is there a safe treatment duration? • May women with metastatic breast cancer receive HRT? Some of these issues are being addressed in an ongoing randomized controlled trial in the UK. In conclusion, existing evidence indicates that: • HRT with a combination of estrogen and progestin is associated with a 40–70% risk of breast cancer. In these patients, there is also an increased risk of breast cancer-related death. The risk is higher for intermittent than for continuous administration of progestins. • HRT with estrogen alone is associated with a small increased risk of breast cancer, but possibly with a reduced risk of breast cancer-related death.38–41 For estrogen doses of 0.625mg or less, the risk of breast cancer has not been demonstrated. • HRT does not seem to be associated with an increased risk of recurrence of breast cancer, but it is not clear whether it is safe to institute HRT immediately after treatment of primary breast cancer or instead it is more prudent to wait 1–2 years. • HRT is the most effective treatment for the relief of the vasomotor and genitourinary symptoms of menopause. Body shape The association of breast cancer and central (android) obesity was reported in several studies and was related to decreased concentrations of circulating sex hormone-binding globulin (SHBG) in the presence of android obesity.54–56 Android obesity was defined as a ratio of 0.71 or more between the body circumferences measured at the waists and at the hips.56 As the prevalence of android obesity increases with age, this association is of special concern for older women.57 Sellers et al58 described an association between the prevalence of breast cancer and of android fat distribution in the same family. Android obesity is due to accumulation of fat in preexisting adipose cells, and is easily reversed by a negative caloric balance through diet and exercise.59

Comprehensive Geriatric Oncology

1178

Diet Of dietary factors, alcohol has a definite etiologic role,60–62 while controversy persists concerning the role—if any—of dietary fat.63 Several studies have documented an association between animal fat intake and incidence of breast cancer in different populations.64–66 Likewise, immigrant studies have shown that the incidence of breast cancer among Asian women increased after they moved to the USA and adopted an American diet, which was richer in fat than in their country of origin.67–68 However, large cohort studies of fat intake, including the Iowa Study,69 NHANES I,70 the Nurses Health Study,71 and the Amsterdam Study,72 failed to show a relationship between individual fat intake and individual risk of breast cancer. Only a cohort study from Canada suggested a marginal increase in breast cancer risk related to fat intake.73 Possibly, the high baseline fat content of most Western diets (even those that are ‘low-fat’) may account for the lack of a dose/effect of fat on breast cancer. In other words, there may be a ‘threshold’ for fat intake beyond which the risk of breast cancer is uniformly increased. Another hypothesis is gaining some credit, however, namely that in most diets fat and fiber intakes are inversely related.74 Thus, a scarcity of fiber rather than an excess of fat may be responsible for enhanced breast cancer risk. This hypothesis is supported by the discovery of a group of natural dietary components, called phytoestrogens, with antiestrogenic activity, that are abundant in soya and tofu.75 Interestingly, the phytoestrogens do not seem to interfere with a woman’s reproductive life, and their antiestrogenic activity may be limited to breast and endometrium. Whereas it is prudent to limit the percentage of fat-related calories in the diet, it may also be advisable to enhance the intake of phytoestrogen-rich fiber. This issue is very pertinent to older individuals. Phytoestrogens may represent a physiological, non-toxic form of chemoprevention of breast cancer. Possibly, phytoestrogens may also prevent systemic recurrence of primary breast cancer, without the toxicity of adjuvant chemotherapy. Influence of age on diagnosis and treatment of breast cancer Controversy exists as to whether breast cancer is more advanced at presentation in older women.76,77 In 1986, a report from the New Mexico Tumor Registry77 suggested that this was the case in women over 65, while a review of the Rhode Island Cancer Registry over 10 years failed to demonstrate any correlation between patient age and stage of disease at presentation.78 More recently, a review of SEER data also failed to demonstrate a correlation between age and stage of breast cancer at presentation.79 There are two possible, non-mutually exclusive explanations for this discrepancy. The first is regional variation in the pursuance of medical care and cancer screening in general and in particular among the aged.80,81 The second is an improved utilization of screening mammography by older women in recent years.82,83 More widespread awareness of breast cancer in older women among public and professionals alike has played a major role in increased detection. Clearly, ethnic and socioeconomic factors influence the presentation of breast cancer. In most reviews of this issue, breast cancer was more advanced at presentation among low-income, Afro-American, and Hispanic women.84,85

Breast cancer in the older woman: An oncologic perspective

1179

The SEER data showed that the percentage of inadequately staged breast cancers increased with the age of the patient.6 This indicates that some older individuals do not receive standard cancer care and reiterates previous observations that the pattern of cancer care tends to become less aggressive with the age of the patient.86–88 The central question raised by these reports is whether and when less aggressive care is appropriate. The appropriateness of the treatment received by individual patients is determined by considerations of life-expectancy and quality of life for the elderly. Aging is highly individualized: different persons develop disability and diseases at different ages.89 Clearly, the number of breast cancer patients who die of unrelated conditions increases with age,90,91 and is strictly related to the prevalence and seriousness of comorbid conditions. Likewise, deteriorating functional status is associated with higher mortality and poorer tolerance of antineoplastic treatment.89 Thus, in many cases, departure from standard care is justified and commendable. A review of the care received by older women with breast cancer indicated that this care was appropriate for the degree of comorbidity and life-expectancy of individual patients.92 It is important to underline, however, that in the absence of serious comorbidity or functional impairment, age itself does not justify less aggressive care. Biology of breast cancer in the aged A common view holds that breast cancer becomes more indolent in the aged. We shall address this issue with three questions: Do older women develop a form of breast cancer that is intrinsically less aggressive? Does the older organism represent an unfavorable soil for the growth of breast cancer? Is the clinical course of breast cancer more indolent in older individuals? Theoretical considerations suggest that older individuals may have a higher prevalence of more indolent tumors than younger individuals. In general, the growth rate of a tumor is related to its aggressiveness: if more indolent tumors take more time to grow, they are also more likely to become manifest later in life and to be more prevalent among older individuals.93 Clinical observations support this hypothesis. A number of tumor markers (Table 51.4) may be used to assess the aggressiveness of breast cancer94–96 (see Chapter 12 of this volume97). Nixon et al98 and Lyman et al,99 among others, have shown that the prevalence of poorly differentiated (grade 3) tumors decreases, while the prevalence of hormone receptor-rich tumors increases with the age of the patient population. Valentinis et al100 showed, in more than 1400 women, that the proliferation rate of breast cancer cells, measured by the incorporation of [3H]thymidine, decreased with the patient’s age. The relation of other tumor markers to age is currently under study. Circumstantial evidence suggests that the growth and metastatic spread of breast cancer are slower in older than in younger organisms. In a series of 819 Finnish women, Holmberg et al101 found that for tumors of similar size, the prevalence of axillary lymph node involvement decreased with the age of the patient, after age 55. Kurtz et al102 studied the relationship between the growth of primary

Comprehensive Geriatric Oncology

1180

Table 51.4 Markers of tumor aggressiveness • High nuclear grade • High histologic grade • Low concentration of estrogen and progesterone receptors • High tumor cell proliferation rate • High expression of the HER2/neu oncogene • High degree of vascularization and concentration of anglogenic factors

breast cancer and the degree of mononuclear cell infiltration of the tumor in a group of French women. They found a direct correlation between tumor growth rate and degree of mononuclear cell infiltration, and hypothesized that mononuclear cells produced a tumor growth-stimulating cytokine. They also found that the degree of mononuclear cell response was inversely related to the age of the patient. This study is particularly important since it contradicts the common tenet that immune senescence favors cancer development (see Chapter 13 of this volume103). At least in the case of breast cancer, the opposite appears to be true. Nixon et al98 confirmed the observation of Kurtz et al102 in a group of American women. They also found that the likelihood of lymphatic invasion decreased with the age of the patient. An area of research that appears particularly promising is the study of tumor growth factors in persons of different ages.104 Of special interest are age-related variations in the concentration of insulin-like growth factor I (IGF-I) and IGF-I-binding protein (IGFBP).105 Lonning et al106 reported that the concentration of IGFBP increased during treatment with tamoxifen and speculated that one of the mechanisms of action of tamoxifen was a blockage of IGF-I activity. Agerelated variations in the serum concentration of these substances appear to be likely. Germane to this issue is the concept of somatopause that has recently been developed.107 Somatopause is a prevalently catabolic condition due to increased concentration of catabolic cytokines (tumor necrosis factor (TNF) and interleukin-6 (IL-6)) in the circulation and reduced secretion of growth hormone; these substances regulate the tissue production of IGF-I. Seemingly, patients experiencing somatopause do not provide an optimal soil for the growth of breast cancer. Also of interest is the transforming growth factor β (TGF-β) family of growth factors, which oppose the growth of breast cancer.108 Age-related variations in the production and in the serum concentration of TGF-β are unknown. Tamoxifen stimulates the release of TGF-β from stromal tissues, and this response may be enhanced in older individuals.109 The factor responsible for tumor angiogenesis also deserves special mention. The concentration of new blood vessels appears to be one of the most powerful prognosticators of recurrence in breast cancer.96 The production of vascular endothelial growth factor (VEGF) and tumor-related angiogenesis appear to be reduced in older individuals.110 With regard to the natural course of breast cancer, the prevalence of soft tissue, bony, and nodular pulmonary metastases becomes higher and that of hepatic and lymphangitic pulmonary metastases becomes lower with the age of the patient.111 In a review of older series of patients, studied prior to the modern chemotherapy era, Holmes111 found that the risk of dying of breast cancer among patients with metastatic disease decreased with the

Breast cancer in the older woman: An oncologic perspective

1181

age of the patient (see Table 51.5 below). This finding may indicate that breast cancer is more indolent in older women—or, alternatively, that serious and lethal comorbid conditions are more prevalent. Satariano and Ragland90 explored the role of comorbidity in causing the death of older women with breast cancer. They found that the relative risk of breast cancer death declined with the number of comorbid conditions. In conclusion, there is clear evidence that the prevalence of more indolent tumors increases with the age of the population, and there is a reasonable suggestion that older individuals present somewhat unfavorable conditions to tumor growth. It is uncertain whether this translates into a more benign natural course of breast cancer in older individuals. It is important at this point to underline that breast cancer is frequently lethal in older women. The detection of more benign biological characteristics may give important insights into the interactions of the tumor and the host and may provide new important prognostic clues. They should not, however, deceive the clinician into complacency. Breast cancer is a lethal disease at any age, and should be treated timely and aggressively. A simple mathematical calculations may highlight this point. Let us assume that the prevalence of hormone receptor-rich tumors is 80% for women aged 70 and older and 20% for women under 35. If the prevalence of breast cancer is 400/100000 in the older group of women and 30/100000 in the younger, the prevalence of aggressive tumors will be 80/100000 and 24/100000, respectively. Prevention and early detection Primary prevention of breast cancer involves the elimination of breast carcinogens or the administration of substances that block carcinogenesis in its late stages (chemoprevention).112 Known carcinogens include alcohol60–62 and estrogen or estrogen/progesterone in combination.38 Reduction of alcohol intake to less than three ounces of whisky daily or equivalent amounts of other alcoholic drinks is advisable. Complete abstinence from alcohol may have an adverse impact on a person’s lifestyle without appreciable health benefits. As far as HRT is concerned, one has to balance a modest increase in the risk of breast cancer with the benefits of HRT for the older woman (as discussed above). Chemoprevention of breast cancer with selective estrogen receptor modulators (SERMs) has been convincingly demonstrated in three different human models:113–117 • In women with a personal history of breast cancer who had received adjuvant treatment with tamoxifen, the Oxford meta-analysis showed a 36% reduction in new contralateral breast cancers113 over 15 years. • In women with ductal carcinoma in situ (DCIS), which is a premalignant lesion, tamoxifen reduces by more than 50% the risk of progression to invasive tumor, according to the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-24 study.114 • Five randomized and prospective clinical trials of SERMs were conducted in women at risk of breast cancer. The NSABP study P-1 demonstrated that tamoxifen for 5 years reduced by more than 50% the risk of breast cancer in women whose relative risk of breast cancer was at least 1.66 over 5 years, according to the Gail model.115 All

Comprehensive Geriatric Oncology

1182

women aged 60 and older present this risk level for breast cancer. The primary objective of the international study116 and of the MORE (Multiple Outcomes of Raloxifene Evaluation) study117 was prevention of osteoporosis with raloxifene. The use of this SERM was associated with a reduction in the incidence of breast cancer greater than 70% over 5 years. Although patients had not been randomized to either arm of the study according to their relative risk of breast cancer, it is unreasonable to ascribe this difference in breast cancer incidence only to randomization imbalance. Two European studies failed to demonstrate any breast cancer-preventive activity by tamoxifen.118,119 These studies had a number of flaws, however, including high dropout rates (around 25% in each study) and enrollment of patients not at increased risk of breast cancer. The number of patients enrolled in the two studies might also have been inadequate to detect significant differences. Furthermore, the report of the UK study was an interim report, while the Italian study had been prematurely closed. Of interest, tamoxifen reduced the incidence of breast cancer among women receiving HRT in the Italian study.119 While the scientific interest of chemoprevention of breast cancer with SERMs cannot be overrated, the clinical application of chemoprevention is uncertain. The value of chemoprevention is reduced by the following considerations: • SERMs reduced the risk of hormone receptor-rich tumors, which are generally those with a more indolent clinical course; the risk of the more aggressive hormone receptor-poor tumors was unchanged. • Chemoprevention of breast cancer has not led so far to a reduction in breast cancerrelated deaths. Thus, it is reasonable to ask whether regular screening may not lead to the same results with lower cost and risk of complications. Chemoprevention was associated with a number of therapeutic complications: tamoxifen increased the risk of endometrial cancer; both tamoxifen and raloxifene were associated with increased risk of thromboembolic complications, including deep vein thrombosis, pulmonary embolism, and cerebrovascular accidents. The risk of these complications increased with age. For completeness, it should be added that both SERMs prevented osteoporosis and the risk of hip fractures. Based on these considerations, one may try to delineate the profile of patients for whom chemoprevention of breast cancer is clearly indicated or contraindicated: • Chemoprevention with tamoxifen is reasonable in women at risk of osteoporosis and breast cancer who have undergone hysterectomy. • Chemoprevention with either tamoxifen or raloxifene is contraindicated in women with a history of spontaneous deep vein thrombosis or pulmonary embolism, transient ischemic attacks, or cerebrovascular accidents. Clearly, these criteria fail to address the majority of women who may benefit from chemoprevention. For these, the treatment needs to be individualized according to individual risk of breast cancer and individual degree of cancerophobia. Gail et al120 have proposed a decision analysis model that may help clarify individual issues. According to this model, a 70-year-old woman would benefit from chemoprevention only when her relative risk of breast cancer is 7 or more. The era of chemoprevention had just begun; interesting developments in the field include the following:

Breast cancer in the older woman: An oncologic perspective

1183

• A randomized controlled study is comparing the effectiveness and complications of tamoxifen and raloxifene. The major potential advantage of raloxifene is a reduced risk of endometrial cancer. • A number of new hormonal agents, including the pure estrogen antagonist fulvestrant (ICI 182, 780, Faslodex)121 and the second-generation aromatase inhibitors122 may prove to be as effective or more effective in the chemoprevention of breast cancer. A major concern related to these substances is the risk of osteoporosis. • Other, non-hormonal, substances that may have a chemopreventive effect include retinoids, difluoromethylornithine (DFMO), and oltripaz.123,124 Older individuals may represent ideal candidates for chemoprevention, because aging is associated with a number of carcinogenic changes that may be arrested or reversed with chemoprevention (see Chapters 8 and 9 of this volume125,126). The best established form of breast cancer prevention is secondary prevention, which involves screening asymptomatic persons. The aim of screening is detection of breast cancer at early stages.127 With aging, a number of factors influence the value of screening tests for breast cancer: • Aging is associated with an increasing prevalence of breast cancer: consequently, the positive predictive value of screening tests improves with the age of the population screened. • By the time they are 65 and older, most women have already undergone some screening for breast cancer. This initial screening generally detects the ‘prevalence cases’, whereas follow-up screening detects new, ‘incidence cases’. Thus, serial screening tests in older women may become less and less productive. • The clinical course of breast cancer may become more indolent with age. Thus, breast cancer detected through screening may never become clinically relevant in older women. • The life-expectancy of a person progressively decreases with age and the risk of comorbid conditions increases.90,128,129 In women with limited life-expectancy from advanced age and severe comorbidity, early detection of breast cancer may have only a marginal impact on cancer-specific mortality. Currently, screening tests include breast self-examination (BSE), clinical breast examination (CBE), and mammography. The value of BSE is controversial.130,131 None of 2 cohort and 11 case-control trials assessing BSE could demonstrate a reduction in breast cancer-related mortality.131,132 In developing countries without radiological facilities, BSE may represent an effective form of cancer screening, but in the USA and other Western countries, the value of this practice is marginal at best. The main potential benefit of BSE is enhanced awareness of the risk of breast cancer and of the need for health maintenance. The main risk of BSE is a false sense of security from a negative examination that may dissuade more effective screening strategies. CBE by a trained health professional is a valuable form of cancer screening, both alone and in combination with mammography. Approximately 5–10% of early breast cancers diagnosed at CBE escape mammographic detection.133,134 CBE may be particularly productive in older women for the following reasons:

Comprehensive Geriatric Oncology

1184

• With age, the breast atrophies, and physical examination of the breast becomes more sensitive to cancer-related abnormalities. • With age, healthcare consumption increases dramatically. Most older women attend a physician’s office several times a year. These office visits represent a unique opportunity for breast cancer screening, and may spare the inconvenience of an additional trip to a screening center, which may become particularly burdensome for older individuals.

Table 51.5 Prospective clinical trials of screening mammography Trial HIP136 Malmö

137 138

Edinburgh

Kopparberg

137 137

Östergotland

139

Canadian 2

Interval (months)

No. of examinations

Relative risk of cancer deatha

40–64

12

4

0.65 (0.46–0.92)

45–69

18–24

6

0.81 (0.62–1.07)

45–64

24

4

0.84 (0.63–1.12)

40–74

24–33

5–6

0.64 (0.45–0.90)

40–74

24–33

5–6

0.74 (0.55–0.99)

50–59

12

5

0.97 (0.62–1.52)

138

40–64

28

2

0.8 (0.53–1.22)

138

40–59

18

2

0.86 (0.54–1.37)

Stockolm Göteborg

Age range (years)

a

95% confidence interval in parentheses.

In a very poignant editorial, Mitra133 made the case for breast cancer screening with CBE only and without mammography. His main argument was that the majority of cancers diagnosed at mammography only, both in the BCDDP135 and in the Canadian study134 were carcinoma in situ, with negligible malignant potential. In addition, the Canadian study randomized women aged 50–59 to mammography and CBE and to CBE only, and could not demonstrate any decrease in mortality from the addition of mammography to the screening program.134 The issue whether CBE may substitute for mammography in the general population is highly charged and certainly beyond the scope of this chapter. For our purposes, it is important to underline that in the older population, CBE may have a major role as a screening tool. The best established strategy for breast cancer screening is serial mammography. Eight prospective controlled trials conducted worldwide (Table 51.5) showed a reduction in breast cancer-related mortality of 20–30% for women aged 50–70, and in three cases the difference was statistically significant.136–139 Several historically controlled studies supported these findings (Table 51.6).135,140–143 In the BCDDP study, the reduction in breast cancer death rate was approximately 26% for women aged 59–74. A recent metaanalysis of these trials showed a relative risk (RR) of breast cancer death of 0.77 (95% CI 0.69–0.87) for the prospective trials and 0.45 (95% CI 0.29–0.70) for case-control trials.144 The benefits of screening mammography over age 70 are less well established. Only two prospective trials involved women aged 70–74, and these showed a trend

Breast cancer in the older woman: An oncologic perspective

1185

toward reduced mortality (RR 0.94; 95% CI 0.60–1.64).137 The meta-analysis of these trials failed to demonstrate a statistically significant reduction in mortality for older women (RR 0.89; 95% CI 0.67–1.42).144 Especially provocative are the results of the Nijmegen study.142 This trial started more than a decade ago as a historically controlled trial, and involved only subjects up to age 70. More recently, the invitation to participate in

Table 51.6 Historically controlled clinical trials of screening mammography Trial

Age range (year)

Interval (months)

No. of examinations

Relative risk of cancer deatha

Yearly

5

—

50–64

25

5

0.52 (0.32–0.83)

40–70

30

3–7

0.53 (0.33–0.85)

Nijimegen

35–65

24

4

0.51 (0.26–0.99)

143

45–64

24

4

0.76(0.54–1.08)

Breast Cancer 59–74 Detection Demonstration Project135 DOM140 Florence

141 142

UK a

95% confidence interval in parentheses.

the screening program has been extended to women of all ages. The most recent analysis of the trial revealed a significant reduction in cancer-specific mortality for women aged 65–75 (RR 0.89; 95% CI 0.71–0.98). Interestingly, after age 75, the breast cancer mortality has increased with the utilization of screening mammography.142 Seemingly, the majority of women who underwent mammography after age 75 had a personal history of breast cancer, which explains the increased mortality. The benefits of mammography after age 70 were suggested by McCarthy et al.145 They studied the causes of death of women aged 70 and older included in the SEER program. This program, based on Medicare records, allows investigators to correlate outcomes and diagnostic procedures paid for by Medicare. Women who had not undergone any mammogram after age 70 were more than twofold more likely to die of breast cancer than women who had obtained at least two mammograms between ages 70 and 79. An alternative explanation of these results is that women compliant with breast cancer screening after age 70 are also those who had been more compliant at a younger age. The reduction in breast cancer deaths may be a result of screening before, rather than after, age 70. Some considerations of the design of the clinical trials of mammography are necessary to outline the limits of our information and to formulate a reasonable program for screening asymptomatic older women. First, the majority of the trials involved serial CBEs in addition to mammography. The respective contribution of the two procedures to early detection of breast cancer has not always been well established, especially in older

Comprehensive Geriatric Oncology

1186

women. Second, most studies involved a limited number of mammographic examinations (between four and seven): the advantages of additional examinations have not been demonstrated. Third, the intervals between screening tests varied between 1 and 3 years in different studies. Mammography appeared to be equally effective at 2 years and at shorter intervals. In terms of convenience and cost, an interval of 2 years appears to be the most appropriate for older women, whose cancer may have a more indolent natural course. Fourth, the benefits of screening in terms of mortality reduction became apparent 3–7 years since the beginning of the screening program.132,144 Seemingly, only women with a life-expectancy of 3 years or longer may benefit from screening. Clearly, the decision whether to screen asymptomatic older women for breast cancer is not based on conclusive evidence but rather on commonsense consideration. We favor some type of screening program for the following reasons: • Mammography and CBE are harmless and relatively inexpensive. • Early diagnosis and timely treatment of breast cancer in older women may lead to significant reductions in morbidity and management cost, even if they have minimal effects on mortality. • Older women were under-represented or completely excluded from previous trials of screening mammography. It is reasonable to postulate that the failure to demonstrate the effectiveness of screening in older individuals might have been due to inadequate numbers. • The life-expectancy of the older population is in continuous expansion. This expansion is associated with improved functional preservation. Thus, early detection of breast cancer may play an increasingly important role in reducing the mortality and in preserving the quality of life of older women. • A decision analysis has estimated that screening mammography may prolong the lifeexpectancy of women as old as 85.146 • The best circumstantial evidence, based on the SEER data, suggests that mammography may reduce breast cancer-related mortality, at least until age 80.145 • Another study, based on SEER data, suggests that women with breast cancer aged 80 and older are in better general condition than the general population of that age group.79 Breast cancer may represent an important cause of death for these women. • In our opinion, any screening program should be limited to subjects with a lifeexpectancy of 3 years and longer, should involve CBE at any physician visit, and mammography at biennial intervals. In the meantime, more information about the value of screening older women should be gathered. New randomized clinical trials of CBE or mammography in older individuals are unlikely and even undesirable, because the results of these trials may not be available for a decade, when new, more effective screening strategies (e.g. molecular screening) may be available. Important information may be generated by analyzing the results of current practices. These practices may be validated by answers to crucial questions such as: How many cancers are diagnosed with CBE of older women? How many are diagnosed with mammography? How many of these cancers are carcinomas in situ and how many are invasive cancers? How many of the women who have undergone screening develop metastatic cancer during their lifetimes and die from cancer?

Breast cancer in the older woman: An oncologic perspective

1187

The progressive increase in the life-expectancy of the population generates concerns about the cost of screening. These concerns were addressed by Kerlikowke et al146 in an elegant decision analysis based on the fact that the risk of breast cancer increases with bone density and that virtually all postmenopausal women undergo serial bone density evaluation. The author calculated the cost-effectiveness of screening for breast cancer all women aged 70–79 or only those in the upper quintile of bone density. By limiting screening to women with the highest bone density, still more than 95% of all detectable cancers would be diagnosed, at a cost of $60000 per year of life saved, while the costeffectiveness of screening the whole population would be around $112000 per year of life saved. This interesting model needs to be verified in the clinical arena, before being recommended. In particular, it would be important to calculate the real prevalence of mammographic breast cancer in women with lower bone density. A unique problem related to older individuals involves cultural and social barriers to cancer screening (see Chapter 30 of this volume147). Several studies have examined this problem. Lack of information and motivation, economic restrictions, inadequate transportation, and poor social support have been responsible for a sharp decline in women undergoing breast cancer screening after age 65. In a very well-documented study in Southern California, Fox et al showed that lack of physician support was the weightiest factor in preventing the screening of older women (see Chapter 30147). Fortunately, these barriers have been largely overcome in recent years. Coleman et al83 reported in 1994 that for the first time the majority of women aged 65–74 have undergone at least one screening mammography throughout the institutions belonging to the Breast Cancer Screening Consortium. Professional and public education, as well as decreased cost of mammography and implementation of mobile mammographic units, might have played a central role in this change.127 It is also important to recognize the effort that many professional centers and voluntary organizations, such as the ACS, have focused on older women in recent years. Programs involving individualized interventions, such as personal yearly letters reminding older women of screening deadlines, have been particularly successful. The massive participation of older women in screening programs in recent years represents a new opportunity to study issues of effectiveness and cost-effectiveness. In the future, the screening of asymptomatic persons for cancer will certainly involve molecular screening.148 In the case of breast cancer, one may predict two different approaches to molecular screening: identification of carriers of genotypes associated with breast cancer, and discovery of early carcinogenic changes in breast tissue. It seems that the latter approach may be of interest to older women. As the techniques for molecular diagnosis of cancer are developed, validated, and evaluated in clinical trials, serial mammographies and CBE will remain the mainstay of diagnosis of breast cancer at early stages. Pathologic and clinical aspects of breast cancer Although a comprehensive presentation of the pathologic aspects of breast cancer is not the purpose of this book, a summary of pathologic features with either prognostic significance or predictive of therapeutic response is in order.

Comprehensive Geriatric Oncology

1188

Invasive ductal carcinoma and its variants comprise approximately 85% of invasive carcinomas; invasive lobular carcinoma constitutes 5–15%. Invasive ductal carcinomas (Figure 51.2) are distinguished by tubular formation (or its absence in high-grade tumors—hence the designation ‘invasive ductal carcinoma, not otherwise specified’ preferred by some observers); invasive lobular carcinomas classically demonstrate small bland cells infiltrating the mammary stroma in an ‘Indian file’ and/or targetoid pattern. Invasive carcinomas with mixed ductal and lobular features occur less frequently (5%).149–151 Although the subtyping of certain variants of invasive ductal carcinoma is usefiil, the general division of invasive carcinoma into ductal and lobular types does not add

Figure 51.2 Coexistence of DCIS and infiltrating ductal carcinoma. significant prognostic information regarding survival to the following factors: axillary lymph node status, tumor size, histologic grade, and mitotic rate count.149–151 Its value largely consists in pointing to invasive lobular carcinoma’s greater risk of bilateral breast carcinoma152 and more frequent metastatic involvement of the gastrointestinal and gynecologic tracts, the peritoneum, and bone. Variants of invasive ductal carcinoma with an especially good prognosis have been identified. These include tubular carcinoma and its close relative invasive cribriform carcinoma, adenoid cystic carcinoma, and mucinous carcinoma (Figure 51.3a).149–151 These variants have been grouped as ‘favorable’ or ‘excellent’ prognosis invasive ductal carcinomas. Medullary carcinoma, a ductal subtype characterized by well-circumscribed tumor edges and a syncytial growth pattern of high-grade cells surrounded and infiltrated by lymphocytes (Figure 51.3b), was until recently included in the latter group. However,

Breast cancer in the older woman: An oncologic perspective

1189

because of difficulty arriving at a consensus for reproducible diagnostic criteria, the prognostic value of designating an invasive ductal carcinoma as medullary is unknown.149 Some subtypes of breast carcinoma are given a special designation based on a specific clinical presentation. For example, inflammatory carcinoma is a clinical diagnosis of invasive breast carcinoma presenting with skin erythema and edema. Dermal lymphatics are involved by invasive carcinoma on histologic examination in most, but not all, cases and are not required for staging. In Paget’s disease, carcinoma in situ involves the epidermis of the nipple-areolar complex (Figure 51.3c), causing variable clinical signs of erythema, eczema, and erosion. Paget’s disease of the breast is nearly always associated with either underlying DCIS or invasive carcinoma. Malignant phylloides tumor is a rare form of breast cancer, but the most common sarcoma. The neoplastic component of this fibroepithelial tumor is the stroma (Figure 51.3d). Metastases are rare, occur after several recurrences or in the setting of high-grade and overtly sarcomatous tumor areas, and involve the lung most commonly. Because axillary lymph nodes are rarely involved by malignant phylloides tumors,149 axillary lymph node sampling is not appropriate. Carcinoma in situ of the breast, defined by malignant epithelial cells limited to the normal ducts of the breast, is classified, like invasive carcinoma, into ductal and lobular types. Unlike invasive carcinoma, however, this division carries significant prognostic and therapeutic implications. Specifically, because DCIS (Figure 51.4) is associated with a significant risk of developing invasive carcinoma in the area in which it was previously biopsied, DCIS is considered a pre-invasive lesion and merits complete excision.153 Conversely, the risk of developing invasive carcinoma after the biopsy of lobular carcinoma in situ (LCIS) is not confined to the area of the prior biopsy site, but rather involves both breasts equally.154

Figure 51.3 (a) Mucinous carcinoma. (b) Medullary carcinoma. (c) Paget’s disease. (d) Cystosarcoma phylloides.

Comprehensive Geriatric Oncology

1190

Thus, LCIS is considered a ‘marker lesion’ of increased risk and is not typically managed by surgery. Careful follow-up by physical examination and mammography is, however, indicated. Studies have shown that certain features of DCIS, such as size, nuclear grade, and the presence of necrosis, are indicators of a high risk of occult invasive carcinoma elsewhere in the breast or of developing invasive carcinoma following lumpectomy.155–156 However, determination of margin status may be the most significant component of the pathologic analysis of lumpectomy specimens involved by DCIS.157 Given this, and the fact that DCIS is largely unicentric, the disease may be treated exclusively by lumpectomy in some cases.158 Analysis of estrogen receptor (ER) and progesterone receptor (PgR) status was shown to be predictive of response to hormonal therapy more than two decades ago and is standard after the diagnosis of invasive carcinoma. Immunohistochemical analysis of routinely processed tissue, when done under appropriate quality controls, provides direct assessment of tumor cell hormone receptor expression and good correlation with the biochemical dextran-coated charcoal assay, which it has largely replaced. Studies indicate that quantitative immunohisto

Figure 51.4 Ductal carcinoma in situ (DCIS) contrasted with normal breast tissue. chemistry may a better predictor of response to hormonal therapy than the biochemical method.159 Recently, the availability of trastuzumab (Herceptin), a humanized antibody directed at the membrane-bound HER2/neu (c-ErbB-2) oncoprotein, has made the analysis of HER2/neu status standard, when the diagnosis of invasive breast carcinoma is made,

Breast cancer in the older woman: An oncologic perspective

1191

especially in the setting of metastatic disease. HER2/neu status is determined either by analysis for protein overexpression by immunohistochemistry (IHC) or by analysis for gene amplification by fluorescence in situ hybridization (FISH). A consensus is emerging whereby IHC is used to screen invasive tumors.160 If the result is negative (0 or 1+ using a scale similar to the HercepTest) or strongly positive (3+), the result may accepted. If the IHC result is weakly positive (2+), the tumor is analyzed by FISH for confirmation. This scheme is certain to continue to evolve as the applications of trastuzumab and other HER2/neu inhibitors in clinical trials expand. Recent reports illustrating the ability of surgeons to map and biopsy the sentinel lymph node draining breast carcinoma and reduce the need for complete axillary dissection has resulted in the potential for significantly decreased morbidity associated with such dissection.161 However, sentinel lymph node biopsy and testing by IHC for cytokeratin to detect micrometastases may result in the upstaging of patients who may not benefit from therapy for metastatic disease.162 Prospective trials to address this issue are currently underway. Moreover, some epithelial cells identified in the sentinel node by IHC may be the result of mechanical transport, rather than truly metastatic behavior.163 Tumor markers of breast cancer include carcinoembryonic antigen (CEA), CA15–3, and CA27–29. CA15–3 and CA27–29 are both more specific and more sensitive for breast cancer than CEA, and are increased in approximately 90% of cases.164 The proper clinical use of tumor markers is controversial. A rise in the serum concentration of CA15–3 or CA27–29 is often the first sign of recurrence of breast cancer after surgery and adjuvant therapy. In the follow-up of patients with metastatic disease receiving systemic treatment, variations in these markers may reflect therapeutic response and obviate the need for more expensive imaging tests.153 Given the low positive predictive value of these markers in situations where the risk of recurrence is low, and given the lack of prove that early diagnosis of recurrence is beneficial to patients, the American Society of Clinical Oncology (ASCO), does not recommend serial monitoring of these markers in all postoperative patients.165 The ASCO guidelines recognize, however, that they may have a role to play in the follow-up of more advanced disease (stage IIB and III). In older women with widespread metastases, we often follow CA27– 29 to establish the course of the disease, and use other tests only in the presence of new symptoms or a rise in the CA27–29 level. The diagnosis of breast cancer is established by biopsy; fine-needle aspiration biopsy is performed for palpable lesions, and wire-guided core biopsy for mammographic lesions.166 Staging of the patient involves a complete physical examination, complete blood counts, automated chemical panel, tumor markers, and chest radiograph. More extensive staging, such as bone scan and brain and liver imaging, is indicated when physical or chemical abnormalities suggest involvement of these organs or for locally advanced (stage IIB and III) disease. The optimal follow-up of patients after treatment of localized or locally advanced breast cancer is controversial. In most practices, patients are followed every 3–4 months for 2 years, every 6 months for 3 years, and yearly thereafter. Follow-up includes physical examination, chemical panel, and tumor markers at each visit, and chest radiograph and mammography yearly.1 Some authors feel that even this limited approach is excessive and that chemical panel, tumor markers, and chest radiograph could be eliminated. They support a minimalist approach for two reasons. First, the majority of

Comprehensive Geriatric Oncology

1192

recurrences are diagnosed because the patient presents new complaints, not as a result of follow-up visits. Second, the early diagnosis of systemic recurrences does not seem to improve the prognosis of breast cancer.166–168 Treatment General considerations The treatment of breast cancer is according to the stage of disease (Table 51.7). For each stage, we shall describe standard treatment and illustrate specific issues related to older individuals. Carcinoma ‘in situ’ DCIS is generally a multicentric disease with a high risk of local recurrence after local excision.169 Local recurrence may involve progression to invasive cancer. The risk of local recurrence may be estimated by a number of prognostic factors, including tumor grade, aneuploidy, presence of comedonecrosis, size, and involvement of the resection margin.149–152,169–170 The treatment of DCIS involves total mastectomy, or partial mastectomy followed by postoperative irradiation.169–172 The advent of mammography has been associated with a dramatic increase in the incidence of DCIS (from 3% to 30%) and with important changes in clinical presentation.135,150,170 Prior to mammography, most DCIS were large tumors necessitating mastectomy. The majority of DCIS detected at mammography are small tumors that might be completely excised with partial mastectomy. From the new presentation of DCIS stemmed the question whether DCIS could be managed with partial mastectomy only. The NSABP addressed this

Table 51.7 Staging of breast cancer Stage 0

Tis

N0

M0

Stage I

T1

N0

M0

Stage IIA

T0

N1

M0

T1

N1

M0

T2

N0

M0

T2

N1

M0

T3

N0

M0

T0

N2

M0

T1

N2

M0

T2

N2

M0

T3

N1

M0

Stage IIB

Stage IIIA

Breast cancer in the older woman: An oncologic perspective

Stage II IB

Stage IV

1193

T3

N2

M0

T4

Any N

M0

Any T

N3

M0

Any T

Any N

M1

Tx, primary tumor cannot be assessed T0, no evidence of primary tumor Tis, Paget’s disease without a tumor: carcinoma in situ T1, largest diameter of primary tumor ≤2cm T2, largest diameter of primary tumor 2–5 cm T3, largest diameter of primary tumor >5cm T4, tumor of any size with extension to the chest wall or to the skin Nx, regional lymph nodes cannot be assessed N0, no regional lymph node metastasis N1, metastases to ipsilateral movable lymph nodes N2, metastases to ipsilateral axillary lymph nodes fixed to each other or to other structures N3, metastases to ipsilateral internal mammary lymph nodes Mx, presence of distant metastases cannot be assessed M0, no evidence of distant metastases M1, distant metastases including ipsilateral supraclavicular lymph nodes

question in 1985, by comparing lumpectomy with and without postoperative irradiation in 818 women with DCIS.169 Radiation consisted of 50 Gy administered at a rate of 2 Gy/day 5 days a week. Patients were stratified according to age, type of tumor (DCIS or LCIS), axillary lymph node dissection, and method of diagnosis. The risk of local recurrences of both DCIS and invasive cancer during the first 5 postoperative years was reduced by postoperative irradiation (Figure 51.5). Postoperative irradiation did not affect the risk of lymph node and distant metastases, contralateral breast cancer, second primary cancers, and non-cancer deaths. Of special interest to readers of this book, 36% of women were over 60. The NSABP study left some important questions unanswered. The trial did not explore the possibility that poor histologic differentiation and aneuploidy were associated with higher recurrence rate, nor did it address the issue of margins.153,170 These questions are important because radiation therapy adds substantial cost and inconvenience to the treatment. An intergroup study is being conducted to examine the need for irradiation in women with tumors that are 2.5cm or less in diameter and without comedocarcinoma. As postoperative irradiation appears to have minimal (if any) impact on survival, another important issue is whether postoperative irradiation is preferable to local re-excision upon recurrence. This question is critical for older women, for whom the daily trips to the radiation therapy unit may be very burdensome. The benefits of radiation therapy after partial mastectomy for DCIS were confirmed by a study by the European Organization for the Research and Treatment of Cancer (EORTC).171 For tumors less than 5cm in diameter and completely excised, radiation therapy was associated with reductions in local recurrence rate as well as in recurrence of invasive disease. Unfortunately, even this study failed to address the issue of radiation therapy in women with DCIS with very favorable characteristics. A consensus conference on the issue concluded that while

Comprehensive Geriatric Oncology

1194

radiation therapy is beneficial to all groups of patients, in some groups the risk of recurrence is so small that it could safely be omitted.172 Another unresolved issue in the management of DCIS is the role of axillary dissection. Since the cumulative incidence of microscopic lymph node involvement in several studies is less than 1%, many practitioners feel that lymph node dissection and its associated morbidity are not warranted in this disease. Lymph node mapping techniques (see below) may avoid this issue, since they allow axillary staging without a complete dissection.

Figure 51.5 Incidence of recurrence of non-invasive and invasive cancer after treatment of DCIS with lumpectomy with (closed circles) and without (open circles) postoperative irradiation. From reference 172, with permission. Adjuvant treatment with tamoxifen reduces by more than 50% the risk of invasive cancer in patients treated with partial mastectomy and radiation.115 As in the case of chemoprevention, SERMs have not significantly decreased breast cancer-related deaths. The decision to use tamoxifen in these circumstances should be individualized according to the risk of breast cancer recurrence and the risk of tamoxifen complications. The management of LCIS involves either local excision or bilateral mastectomy. Postoperative irradiation of the breast is not indicated in this condition, given the likelihood of recurrence in both breasts. As the benefits of bilateral mastectomy in terms of survival have never been demonstrated, local excision with mammographic follow-up appears to be the most sensible treatment. Patients with LCIS were enrolled in the NSABP P1 chemoprevention trial, and tamoxifen effected a 50% reduction in contralateral breast cancer.116

Breast cancer in the older woman: An oncologic perspective

1195

Treatment of localized breast cancer (stages I and II) The treatment of localized breast cancer is a multidisciplinary task that often requires a combination of surgery, radiation therapy, and systemic treatment (chemotherapy or hormonal therapy). Several controlled studies from the USA173–174 and Europe175–176 have clearly demonstrated the equivalence of total mastectomy and partial mastectomy in combination with postoperative irradiation in the management of primary breast tumors. It should be underlined that different forms of partial mastectomy were used in these trials: in some cases a quadrantectomy and in other cases a lesser procedure were employed. Also, some studies involved only women with a tumor diameter of 2.5cm or less163 and others women with tumor diameters of 5cm or less.173–174 Thus, the results of these studies may not be comparable with each other. Based on these studies, a consensus conference recommended that breast-conserving surgery be performed when an adequate esthetic result can be assured and wound healing is not impaired by underlying disease.177 The conference did not address issues related to tumor size. Both partial and total mastectomy are now simple procedures that can be performed under local anesthesia, with minimal risk even for the oldest old.178,179 Last, but not least, the preference of individual patients should be accommodated whenever possible. It should not be assumed that breast preservation is preferred by the vast majority of women. A metaanalysis of several quality of life studies comparing simple and partial mastectomy failed to demonstrate a clear gain in quality of life with partial mastectomy.180 Axillary dissection is part of the management of localized invasive breast cancer. The aim of axillary dissection is twofold: staging, and elimination of residual disease.177 Axillary dissection may be associated with increased morbidity, such as lymphedema of the arm and brachial neuropathy. Furthermore, axillary dissection may prolong the duration of surgery and mandate general anesthesia in patients who might have otherwise been managed with local anesthesia. According to the NIH consensus conference, the extent of the dissection may be limited to axillary levels I and II when the lymph nodes at these levels are free of tumor.177 Axillary dissection may soon be reserved for a minority of patients at risk for lymph node metastases, thanks to the diffusion of lymph node mapping.181 This technique uses a radioactive tracer or a vital stain to identify the socalled ‘sentinel lymph node’, which is the first axillary node to receive lymphatic drainage from the breast tumor area.181 Reports of several large surgical series indicate that lymph node mapping is highly reliable in identifying the sentinel lymph node and in predicting axillary lymph node involvement in the following conditions.182–185 • when it is performed by an experienced surgeon; • for primary tumors 3.0cm or less in diameter. The sensitivity of the technique is enhanced when the sentinel lymph node is examined for cytokeratin by the polymerase chain reaction (PCR).161–163 Cytokeratin is an intermediate filament specific for epithelial cells, which are not normally found in lymphatic tissue. Its presence in a lymph node suggests the presence of submicroscopic metastases.

Comprehensive Geriatric Oncology

1196

The protocol for lymph node mapping at the University of South Florida is illustrated in Figure 51.6. The sentinel lymph node was successfully identified in more than 90% of cases.186 In four large surgical series including more than 1000 patients, the negative predictive value

Figure 51.6 University of South Florida protocol for lymph node mapping. of sentinel lymph node mapping was higher than 90%, and was practically 100% for small tumors (T1 and T2).182–185 AS sentinel lymph node mapping gains acceptance as standard management of the axillae, a number of new questions emerge: • What is the significance of submicroscopic metastases? Do those patients whose lymph nodes are positive for cytokeratin only need full axillary dissection? • Is there a role for axillary lymph node mapping in patients with palpable axillary lymph nodes? • Do sentinel lymph nodes free of tumor predict curability without additional therapy? The practice of irradiating the chest wall after simple mastectomy has been largely abandoned with the advent of adjuvant chemotherapy. In specific conditions involving a high risk of chest wall recurrence, adjuvant radiation therapy may still have an important

Breast cancer in the older woman: An oncologic perspective

1197

role to play. These conditions include a tumor diameter of 5cm or more, involvement of more than four axillary lymph nodes,187 and extranodal spread of the tumor. In a randomized controlled study of adjuvant radiation therapy to the chest in patients receiving adjuvant chemotherapy, by Griem et al,188 radiation therapy reduced the local recurrence rate in patients with more than four positive lymph nodes, without affecting the overall survival of that population. The authors concluded that adjuvant chemotherapy alone is not very effective in preventing local recurrences. It should be noticed that the chemotherapy used in that study might have been inadequate by present standards. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) performed a meta-analysis of clinical trials comparing breast cancer surgery with and without postoperative irradiation.189 A total of 64 clinical trials were reviewed (36 comparing radiation and surgery with the same type of surgery alone, 10 comparing more extensive surgery with less extensive surgery, and 18 comparing more extensive surgery with less extensive surgery plus radiation), including 29175 women. The general conclusion was that radiation therapy prevented local recurrences and deaths from breast cancer, but had no impact on overall survival since it was associated with more deaths unrelated to cancer. A very important age-related trend emerged from this study: the number of deaths associated with breast irradiation and unrelated to breast cancer increased with patient age and was highest for women aged 60 and older. In this group of patients, the number of non-cancer deaths almost doubled in the presence of breast irradiation. Presumably, the non-cancer deaths were mainly due to heart failure in patients who received radiation therapy of the left chest. New techniques to shield the heart from irradiation may prevent a number of these deaths in the future. Two randomized controlled studies of radiation therapy after total mastectomy, from British Columbia and Denmark, showed a survival benefit for premenopausal women receiving postoperative irradiation, irrespective of the number of lymph nodes involved.190–191 A further analysis of the Danish study showed that postmenopausal women with one to three positive lymph nodes benefited from radiation therapy if there was extracapsular invasion by the tumor.192 Of note, the postmenopausal women in the Danish study did not receive adjuvant chemotherapy but only adjuvant tamoxifen. One may wonder whether more aggressive systemic treatment might have prevented local recurrences more effectively. At the same time, a retrospective review of the treatment of more than 5000 women over an 18-year period failed to show any benefit for radiation therapy in terms of either disease-free survival (DFS) or overall survival (OS).193 We recommend that postoperative irradiation after mastectomy be limited to those women who have nodes involved by the tumor or have extracapsular tumor, for the following reasons: • the lack of a definitive survival benefit; • the lack of a demonstrable effect on local recurrences in the majority of cases; • a substantial increase in the risk of non-cancer deaths in patients aged over 60 receiving radiotherapy. In specific clinical situations, adjuvant systemic therapy prolongs DFS and OS of patients with localized breast cancer.113,194–196 Adjuvant chemotherapy prolongs DFS and OS of premenopausal women with involved axillary lymph nodes,195 while adjuvant hormonal therapy with tamoxifen prolongs DFS and OS of postmenopausal women with localized

Comprehensive Geriatric Oncology

1198

breast cancer.113 In other clinical situations, the use of adjuvant chemotherapy is controversial. The guidelines proposed at the St Gallen Conference in 1995 (Table 51.8)194 were amplified in a recent consensus conference by the US NCI that concluded that all breast cancer patients may benefit from adjuvant chemotherapy to some extent. In certain circumstances, including women with very early tumors and women with reduced life-expectancy, the survival advantage from adjuvant therapy may be very small and overshadowed by the risk of therapeutic complications.196 Age may affect all the areas of management of localized breast cancer. We shall examine the following questions: the role of postoperative radiation after partial mastectomy; the role of axillary dissection; primary treatment of localized breast cancer with tamoxifen, and the role of chemotherapy and hormonal therapy in the adjuvant treatment of breast cancer. Postoperative irradiation reduces the local recurrence rate of breast cancer and allows preservation of the breast,

Table 51.8 St Gallen Conference recommendations for adjuvant chemotherapy of breast cancer194 Node-negative patients Postmenopausal patients

Low risk

High risk

ER+

Tamoxifen

Chemotherapy ± tamoxifen

ER−

Not applicable

Chemotherapy ± tamoxifen

ER+

Tamoxifen

Tamoxifen

ER−

Not applicable

Chemotherapy ± tamoxifen

Elderly (>70)

Node-positive patients Postmenopausal patients ER+

Tamoxifen ± chemotherapy

ER−

Chemotherapy ± tamoxifen

Elderly (>70) ER+

Tamoxifen

ER−

Chemotherapy ± tamoxifen

ER+/−, estrogen receptor-positive/negative.

but does not appear to affect overall patient survival.196–200 This practice adds significant cost and inconvenience to the management of breast cancer, especially for older individuals with limited resources and limited access to transportation. Toxicity of radiation therapy does not appear to be an issue in older women. Wyckoff et al197 reported that women aged 65 and older tolerated breast irradiation as well as younger women.

Breast cancer in the older woman: An oncologic perspective

1199

Morrow et al198 reviewed the randomized studies comparing lumpectomy with and without radiation therapy. They found that the local recurrence rate in the absence of radiation varied widely between studies, but they were unable to identify a subset of patients in whom radiation was not necessary to prevent local recurrences. The issue is of serious consequence to older women. We should like to review existing data and draw our conclusions, which differ somewhat from those of Morrow et al with regard to elderly individuals. Several authors studied the influence of patient age on the local recurrence rate of breast cancer after partial mastectomy (Table 51.9).199–205 In three of the studies,199,200,205 there was a definite decline in local recurrence rate with patient age. In two of the studies, 201,204 the local recurrence rate was similar in patients of different ages, but significantly lower than the 38% originally reported by the NSABP.174 One may argue that a local recurrence rate of less than 20% in the absence of radiation therapy may be acceptable for some patients in order to avoid the cost and inconvenience of radiation. The study by Kantorovitz et al203 is an outlier. These authors reported a staggering local recurrence rate of 27%

Table 51.9 Local recurrence rate of breast cancer and patient age Study

Age (years)

Recurrence rate (%)

<35

21

35–50

10

51–65

9

>65

2

30–39

40

40–49

24

50–59

28

60–69

11

≥70

2

>50

13

35–72

18

>60

27

>60

16

≤45

17.5

46–55

8.7

>55

3.8

With radiotherapy Joint Center for Radiation Therapy

199

Without radiotherapy Nemoto et al200

201

Clark et al

Liljegren et al

202 203

Kantorowitz et al Hayman et al

204

Veronesi et al205

Comprehensive Geriatric Oncology

1200

in women over 60, in the absence of radiation therapy. These results must be viewed with caution given the nature of the study. It was a retrospective study reviewing the local recurrence rate of breast cancer in patients treated at different hospitals in New York State, and involved women treated by different surgeons with different techniques at the beginning of the era of breast preservation, when the standards for partial mastectomy had not yet been established. Furthermore, many patients were lost to follow-up. Those who had experienced recurrence were more likely to return for further treatment, and might have biased the overall assessment of the local recurrence rate. The investigators from the Joint Center for Radiation Therapy.199 addressed specifically the issue of age. They studied the incidence of local recurrences in absence of radiation therapy in a population of 90 women, median age 67, with T1 (<1cm diameter) tumors and negative lymph nodes. All patients were managed with partial mastectomy and had no tumor cells within 1cm of the specimen margin. The local recurrence rate was 16% with a median follow-up of 57 months. One may question whether the surgery, which was less than a quadrantectomy, was adequate. Veronesi et al205 compared prospectively the local recurrence rate of breast cancer after partial mastectomy with and without radiation therapy. They found that the local recurrence rate decreased dramatically after age 55 from 19% to 3%, in the absence of postoperative irradiation (Figure 51.7). It should be noted that only patients with tumor diameters of 2.5cm

Figure 51.7 Local recurrence of breast cancer after quadrantectomy without postoperative irradiation in women

Breast cancer in the older woman: An oncologic perspective

1201

aged over 55 and in younger women. From reference 205, with permission. or less were enrolled in this trial and that the surgical procedure was in all cases a quadrantectomy. Thus, the conclusions of the trial are not necessarily valid for women with larger tumors or women undergoing a lesser procedure. One may conclude from this review that the local recurrence rate of breast cancer declines with age and that postoperative irradiation may not be necessary in older women. In women over 55 with small tumors (≤2.5cm) undergoing quadrantectomy and without an extensive DCIS component, postoperative irradiation appears to be avoidable. Three ongoing prospective studies are exploring the need of postoperative irradiation after partial mastectomy.171 NSABP trial B-21 compares the local recurrence rate in women of any age with a tumor of largest diameter of 1cm or less treated postoperatively with breast irradiation and placebo, breast irradiation, and tamoxifen and tamoxifen only. The CALGB 9343 trial concerns women aged 70 or older with a tumor size of 4cm or less and clinically negative nodes, and compares postoperative irradiation and tamoxifen with tamoxifen alone. The EORTC 10932 trial involves women aged 50 or older with an invasive tumor of 2cm or smaller, histologic grade I, minimal or absent DCIS component, and negative axillary lymph nodes, and compares postoperative treatment with irradiation alone or observation. The need for lymph node dissection in older women was called into question when tamoxifen first appeared as

Comprehensive Geriatric Oncology

1202

Figure 51.8 (a) Progressive disease in women aged 70 and over treated with mastectomy and tamoxifen or tamoxifen only. (b) Overall survival of

Breast cancer in the older woman: An oncologic perspective

1203

women aged 70 and older treated with surgery and tamoxifen or tamoxifen only. (c) Breast cancer-specific survival. From reference 207, with permission. the only effective form of adjuvant treatment for postmenopausal women. As all patients were destined to receive tamoxifen, while chemotherapy was not indicated, staging of the axillae appeared unnecessary. Two series of women aged 70 and older, prospectively treated with lumpectomy and no lymph node dissection, were reported—one from the Tufts Medical Center, Boston206 and the other from the Istituto Nazionale dei Tumori in Milan.179 The main difference in treatment plan was the inclusion of postoperative irradiation in the Boston series. In both cases, more than 80% of the women were free of

Figure 51.9 Recurrence rate and mortality of breast cancer in postmenopausal women receiving and not receiving adjuvant tamoxifen. From reference 113, with permission. disease at 5 years. The main problem with this approach is the lack of information related to axillary involvement. This information is vital to study the value of adjuvant chemotherapy in older women. The extent of axillary involvement may also determine the necessity of radiation therapy to prevent locoregional recurrences.188,189 Hopefully, the development of lymph node mapping may allow one to distinguish women whose

Comprehensive Geriatric Oncology

1204

lymph nodes are free of tumor with minimal morbidity, and will put to rest the controversy related to axillary dissection. Several studies have explored the primary treatment of localized breast cancer with tamoxifen in women aged 70 and older. Of these, two studies were randomized. The Breast Cancer Campaign Trial (BCCT)207,208 compared tamoxifen and partial mastectomy followed by adjuvant tamoxifen in 347 women. After 3 years of follow-up, approximately 40% of patients treated without surgery experienced local progression that required excision;207 after 12 years, surgery was associated with decreased risks both of local progression and of breast cancer-related mortality209 (Figure 51.8). More recently, a combined British and Italian study, under the direction of the EORTC, explored the same question and found that women treated with tamoxifen only were at increased risk of dying of breast cancer. From these findings, it is difficult to see the advantage of purely medical management of localized breast cancer, given the safety of both partial and total mastectomy.179 Adjuvant systemic treatment of the older woman with localized breast cancer is an area involving major controversies. These include the indications for and duration of tamoxifen treatment, alternative forms of adjuvant hormonal therapy, and indications for adjuvant chemotherapy. Several studies have demonstrated that adjuvant tamoxifen prolongs both DFS and OS of postmenopausal women with localized breast cancer.128,210–212 The EBCTCG performed a meta-analysis of all randomized tamoxifen trials, and demonstrated an overall reduction of 25% in recurrence rate and of 16% in mortality for post-menopausal women treated for 2 years or longer.113 Of interest, there was a reduction in recurrence rate and mortality also for women with uninvolved axillary lymph nodes (Figure 51.9) A pertinent problem with these trials is that they generally had an upper age limit for enrollment (80 for the Scottish trial and 70 for the others). Thus, it is not clear whether the results may be applied to the oldest old. Two lingering areas of controversy include the value of tamoxifen in women with hormone receptor-negative tumors (ER concentration <5fm/mg) and the optimal treatment duration. Conceptually, tamoxifen may be beneficial even in the case of hormone-unresponsive neoplasms. The antineoplastic activity of tamoxifen includes enhanced production of TGF-β, a substance that opposes tumor growth, from the tumor stroma, inhibition of the secretion of IGF-I, and increased production of IGFBP, which reduces the concentration of free, active, IGF-I.107,109 These mechanisms of action are independent of the antiestrogenic activity of tamoxifen. Both the NATO and the Scottish trials demonstrated an advantage for adjuvant tamoxifen in tumors poor in hormone receptors—albeit not as pronounced as in receptor-rich tumors.200,201 These results can be interpreted differently, however, because the PgR concentration had not been measured and even the ER concentration was unknown in approximately half of the patients. Also, the assays used in those old studies might have not been as accurate as newer assays employing immunohistochemistry.159 Thus, some of the tumors reported as hormone receptor-poor might have contained a modest but significant concentration of receptors. A randomized and controlled study failed to demonstrate any survival advantage from adjuvant tamoxifen in postmenopausal women with hormone receptor-poor tumors, but the power of the study for small survival differences was low.213 The most recent update of the

Breast cancer in the older woman: An oncologic perspective

1205

Oxford meta-analysis also failed to demonstrate any significant benefits for adjuvant tamoxifen in hormone receptor-poor tumors.113 Based on this evidence, endocrine adjuvant treatment in postmenopausal tumors in women with hormone receptor-poor tumors is not recommended. The EBCTCG meta-analysis found that at least 2 years of treatment were necessary for improving patient survival.113 The Swedish Breast Cancer Study Group randomized postmenopausal women to receive 2 or 5 years of tamoxifen, and found that more prolonged treatment was associated with more prolonged disease-free and overall survival.214 NSABP trial B-14 randomized postmenopausal women with uninvolved axillary lymph nodes to receive 5 or 10 years of tamoxifen, and found that more prolonged treatment was associated with a non-significantly increased risk of breast cancer relapse.215 The final analysis of the Scottish trial in which patients were randomized to treatment with tamoxifen for 5 or 10 years also failed to demonstrate any benefits for treatment beyond 5 years.211 In ECOG trial E-4181, postmenopausal women with involved lymph nodes were randomized to receive combination chemotherapy with or without tamoxifen for 12 months; at the end of 12 months, women originally treated with tamoxifen were randomized to continue tamoxifen or to undergo observation. After a 5-year follow-up, the disease-free interval was superior for women receiving tamoxifen for a more prolonged period of time.216 The most recent update of this study showed that prolongation of tamoxifen treatment beyond 5 years led to improved DFS in this group of women at high risk of recurrence.217 These results are also fraught with problems: chemotherapy as a confounding factor, undertreatment of the group of patients who received tamoxifen for only 1 year, and the relatively small number of patients. In women with uninvolved lymph nodes, a duration of 5 years appears optimal. For women with involved lymph nodes, the best treatment duration has not been settled. The completion of ECOG trial E4181 may shed light on this important issue. The benefits of tamoxifen include a reduction in contralateral breast cancer and the prevention of osteoporosis.113,115 The NSABP P1 trial showed that women treated with tamoxifen experienced a reduction in hip fractures.115 Other studies showed that the use of tamoxifen was associated with preservation and improvement of bone density.218–220 No effect of tamoxifen on cardiovascular mortality was observed115,221 outside of the older Scottish trial, in which the apparent benefits of tamoxifen might have been ascribed to an unbalance in cardiovascular risk between the two patient populations.222 In this trial, the risk of lethal myocardial infarction was lower for tamoxifen-treated women. The main lipid effect of tamoxifen is a reduction in circulating levels of low-density lipoprotein223,224 that has not lead to a reduced risk of coronary events. The risks of tamoxifen include exacerbation of vasomotor and genitourinary manifestations of menopause, endometrial cancer,113,218,219 and an increased risk of thromboembolic phenomena, including deep vein thrombosis, pulmonary embolism, transient ischemic attacks (TIA), and cerebrovascular accidents (CVA).113,225–229 An analysis of the risk of endometrial cancer has shown that this increases with treatment duration and with body size.226,227 Thus, the risk should be minimal for women who are not obese, treated for 5 years or less. The risk of CVA has emerged very clearly in NSABP study P-1.115 Of interest, tamoxifen was associated with a decline in TIA that almost mirrored the increase in CVA. Women at risk of cerebrovascular disease clearly should be excluded from tamoxifen treatment.

Comprehensive Geriatric Oncology

1206

In addition, prolonged tamoxifen treatment may lead to resistance.230 In murine models of mammary carcinoma, Osborne et al230 reported tamoxifen resistance after 4–6 months of treatment due to an alteration in metabolism, which led to a predominance of the weak metabolite cis-hydroxytamoxifen over the powerful antiestrogen transhydroxytamoxifen. These experiments also suggested the possibility that tamoxifen itself may start to stimulate tumor growth. Circumstantial evidence suggests that tamoxifen resistance may also develop in human tumors. Osborne et al230 found a high ratio of tumoral concentrations of cis- and trans-hydroxytamoxifen in tumors resistant to tamoxifen. Also, the response of approximately 20% of tamoxifen-resistant breast cancer to tamoxifen withdrawal231,232 suggests that tamoxifen may stimulate tumor growth under certain circumstances. Other causes of tamoxifen resistance may include decreased absorption and increased catabolism of tamoxifen after prolonged use.231 The relevance of these observations to long-term adjuvant therapy is unknown. Tumor resistance does not appear to be a significant problem for at least 5 years, according to NSABP trial B14,225 or the Scottish211 or Stockholm trials.214 A worrisome trend emerged in NSABP trial B-14, however. Women treated with tamoxifen for more than 5 years experienced a non-significant increase in the incidence of tumor recurrence, suggesting that tamoxifen may stimulate tumor growth in some patients.225 The current recommendation of the US NCI is that adjuvant tamoxifen treatment not be continued beyond 5 years. We concur with this recommendation. Germane to the issue of adjuvant hormonal therapy is the management of tamoxifenrelated symptoms, in particular hot flushes, which cause discontinuance of treatment in approximately 15% of women. Two, non-mutually exclusive, approaches may be taken. The antidepressant venaflaxin, at doses of 37.5–75.0mg daily, substantially reduced the number and the seriousness of hot flashes in a randomized, placebo-controlled, clinical trial.46 The main complication of this treatment was insomnia. Simultaneous administration of tamoxifen and estrogen has also been advocated. Although anecdotal reports are very favorable, this combination has not been studied in a proper clinical trial.233 Other remedies include clonidine and belladonna.234 A number of new options are now available for the adjuvant endocrine treatment of breast cancer. The SERM toremifene reached the American market in 1998. Its effectiveness and toxicity profile is similar to those of tamoxifen. In the adjuvant setting, tamoxifen and toremifene were compared in a Finnish trial.235 All postmenopausal women were eligible for the trial, including those whose hormone receptor status was unknown. After 5 years of follow-up, the drugs were substantially comparable in terms of OS, DFS, osteoporosis prevention, and toxicity. Toremifene had a small, non-significant edge over tamoxifen in recurrence rate and survival for women with hormone receptorrich cancer and in risks of cerebrovascular accidents and endometrial cancer. A randomized comparison of these compounds in the adjuvant setting is being conducted in the USA. The pure antiestrogen fulvestrant has proved to be effective in metastatic disease resistant to tamoxifen, and consequently may be more effective as adjuvant treatment, but may also be associated with an increased risk of osteoporosis.236 The new aromatase inhibitors have also proved at least as effective as tamoxifen in metastatic disease, and deserve study as adjuvant treatment.237–239 A major concern is the effect of these compounds on bone mineral density and on menopausal symptoms. Another adjuvant strategy under investigation involves the combination of SERMs and aromatase

Breast cancer in the older woman: An oncologic perspective

1207

inhibitors. The NSABP plans to compare 5 years of tamoxifen with and without the addition of exemestane for 2 years. Until these studies have been completed, the standard adjuvant hormonal treatment of breast cancer involves either tamoxifen or toremifene. The results of the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial have now been reported.240 In this study, more than 9000 postmenopausal women were randomized to receive anastrozole, tamoxifen, or the two drugs in combination. Anastrozole reduced by 17% the recurrence rate over tamoxifen and by 50% the risk of recurrence of contralateral breast cancer. Also, anastrozole was associated with lower risks of endometrial cancer, deep vein thrombosis and CVA than tamoxifen, but with an increased non-significant risk of bone fractures. The ATAC study clearly demonstrated that anastrozole is a reasonable alternative to tamoxifen. It appears prudent to monitor bone density in older women receiving this drug and to institute bisphosphonate treatment in those at risk. The issues related to adjuvant chemotherapy involve three questions: Is chemotherapy of value to older women? Which drugs are effective in older women? Which conditions warrant adjuvant chemotherapy? The question whether adjuvant chemotherapy was beneficial to older women was originally posed by the work of Bonadonna et al.241 Studies initiated more than 20 years ago showed that 8 years after diagnosis, CMF chemotherapy (cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU)) improved DFS by 11% and OS by 23% for premenopausal women with one or three lymph nodes involved by cancer, but had no effects in postmenopausal women. Since then, the adjuvant treatment of postmenopausal women with chemotherapy has been controversial. The EBCTCG explored the activity of adjuvant chemotherapy in a meta-analysis195 (Table 51.10). Clearly, the benefits of adjuvant chemotherapy in terms both of freedom from progression and of survival declined with patient age, and no benefits were seen in patients aged 70 and older. The oldest group of patients represented less than 4% of the total postmenopausal population, and this number is too small to draw firm conclusions. A more recent and yet-unpublished analysis of the data, with more than 1000 patients aged 70 or older, showed that

Table 51.10 Reduction in recurrence rate and mortality rate by adjuvant chemotherapy in postmenopausal women with breast cancer195 Age group (years)

No. of patients

Recurrence rate (%)

Mortality rate (%)

50–59

3128

29±5

13±7

60–69

3874

20±5

10±6

274

—

—

≥70

this group of women may benefit from adjuvant chemotherapy to the same extent as women aged 60–69 (Hy Muss, American Society of Clinical Oncology, San Francisco, May 2001). Several explanations have been put forward to account for a decline in the benefits of adjuvant chemotherapy with age:

Comprehensive Geriatric Oncology

1208

• Competitive causes of death may conceal the benefits of adjuvant chemotherapy in older women. This explanation, which has enjoyed some credence in the past,128 is denied by the data from the meta-analysis itself. Competitive causes of death should lessen to the same degree the benefits of adjuvant hormonal therapy—which is patently not the case. • There is an increased risk of chemotherapy-related mortality. This is also not very plausible. Clinical trials exclude acute therapeutic toxicity as a major cause of death in older women; information on long-term toxicity is scarce, and is being collected in ongoing studies. Although it is possible to assume that older women are more susceptible to long-term toxicity of chemotherapy, the data so far do not support such an increase in chemotherapy-related long-term mortality. • The chemotherapy dose in older individuals is inadequate. This is a reasonable explanation, and is supported by the findings of Bonadonna and Valagussa.242 These authors reviewed the case of postmenopausal women treated with adjuvant CMF and noticed that women who had received at least 80% of the planned treatment dose experienced the same survival gain as premenopausal women. The likelihood of dose reduction increased with the patient’s age. Likewise, the Cancer and Leukemia Group B (CALGB) study revealed a threshold in the dose of adjuvant doxorubicin below which the drug is ineffective.243 It is conceivable that older patients might have been under-treated in clinical trials owing to more severe toxicity. • The effectiveness of adjuvant chemotherapy decreases with age. This explanation is also reasonable, since the prevalence of hormone receptor-rich tumors, for which the benefits of adjuvant chemotherapy in addition to tamoxifen are limited, increases with age.244,245 The observation by Olivotto et al246 is germane to our discussion. These authors compared DFS and OS of breast cancer patients aged 50–89 treated in British Columbia prior to and after the introduction of adjuvant chemotherapy. They found a statistically significant 7% improvement in DFS and a 6% improvement in OS at 7 years from diagnosis. A number of factors, including more widespread use of screening mammography and earlier pursuance of medical attention, may have contributed to such improvement. Adjuvant chemotherapy may well have been one of these factors. Examination of individual clinical trials of adjuvant chemotherapy in postmenopausal women has shed some light concerning the most effective agents and the conditions that warrant adjuvant treatment (Tables 51.11 and 51.12). Table 51.11 summarizes major clinical trials in postmenopausal women with involvement of axillary lymph nodes. Clearly, only treatment regimens employing an anthracycline (doxorubicin or epirubicin) have consistently produced improvement in both DFS and OS.242,249–250,256,257,261,262 It is important to outline some questions elicited by these trials. The NSABP first explored the value of doxorubicin in postmenopausal women in the B-11 and B-12 trials. From the results of previous studies, the NSABP has defined as tamoxifenunresponsive those postmenopausal women aged 50–59 with PgRpoor tumors, and as tamoxifen-responsive all postmenopausal women aged 60 and over and those under 60 with PgR-rich tumors. In the B-11 trial, tamoxifen-unresponsive women were randomized to receive melphalan and 5-FU (PF) or melphalan, doxorubicin, and 5-FU (PAF). PAF proved superior to PF in terms of both DFS and OS. In the B-12 trial, tamoxifen-responsive women were randomized to receive PF and tamoxifen (PFT)

Breast cancer in the older woman: An oncologic perspective

1209

or PAF and tamoxifen (PAFT).250 The addition of doxorubicin did not appear to be beneficial to these patients. In a subsequent trial, (B-16), however,251 tamoxifenresponsive women were randomized to receive doxorubicin, cyclophosphamide, and tamoxifen (ACT) or tamoxifen alone. In the B-16 trial, ACT was superior to tamoxifen alone in terms of both DFS and OS. There is an apparent discrepancy between the results of the B-12 and B-16 trials. One may ask why the ACT combination was not compared with PFT rather than with tamoxifen alone. There were two main reasons for the design of the B-16 trial. First, it was important to establish whether the combination of chemotherapy and tamoxifen was superior to tamoxifen alone in this group of women. Second, it was important to try a combination of chemotherapy of shorter duration and lesser toxicity than PF. The melphalan and 5-FU were administered for 17 treatment cycles and the doxorubicin and cyclophosphamide (AC) for only 4. The question whether PF is comparable to AC is a moot question, since AC proved to

Table 51.11 Triala

No. of Upper Patient patients age limit characteristicsb (years)

Regimensc DFS gain (%)

Survival gain (%)

NSABP B07247

1863 70

LN+

P vs PF

32

27

NCCTG248

234 75

LN+

CFP vs

18

—

CFMP vs

ER+:—

—

CFMPT vs

ER−:18

—

—

—

CEPT vs 0 249

ECOG

265 65

LN+

0 249

ECOG

962 80

LN+

CFMPT×12 vs CFMPT×4

NSABP B11250

281 59

LN+, PgR−

PF vs PAF

7

6

NSABP B12250

758 70

LN+, PgR+

PFT vs PAFT

—

—

NSABP B16251

1245 70

LN+, PgR+

T vs ACT

17

10

267 65

LN+, ER+

T vs CMFE

−25

−12

—

—

P vs CMFVP 14

12

GROCTA252

vs CMFET 253

GBSG

546 70

LN+

CMF×3 vs CMF×6±T

SWOG254

214 Not stated LN+, ER−

Comprehensive Geriatric Oncology

1210

SWOG255

966 87

LN+, ER+

CMFVPT vs — T

—

CALGB243

723 65

LN+

CAh vs CAi

18

8

30

12

vs CAI 256

Milan

188 65

>3 LN+

A→CMF vs A/CMF

257

GABGG

Canada

258

d

T vs CMFT

−23

—

d

‘High risk’

AC vs ACT

21

10

705 Not stated LN+, ER+

T vs CMFT

—

—

0 vs pT vs

20

8

456 65

‘Low risk’

or PgR+ 259

Ludwig III

463 Not stated LN+, HR±

CMFpT IBCSG VII260

608 Any age

LN+

T vs CMFT

Age 52– — 65:13 Age >65:—

—

ICCG261

604 75

LN+, HR+

T vs ET

27.9

11

262

565 75

1–3 LN+, HR+

CEF 50 vs

22

18

>3 LN+, ER±

CEF 100

LN+, HR+

CAFT vs CAF→T vs T

24

12

FASG

263

IGT 0100

a

1470 80

NSABP, National Surgical Adjuvant Breast and Bowel Project; NCCTG, North Central Cancer Treatment Group; ECOG, Eastern Cooperative Oncology Group; GROCTA, Gruppo Ricerca Oncologico Chemoterapia Adiuvante; GBSG, German Breast Cancer Study Group; SWOG, Southwest Oncology Group; CALGB, Cancer and Leukemia Group B; GABGG, Gynecological Adjuvant Study Group Germany; IBCSG, International Breast Cancer Study Group; ICCG, International Cooperative Breast Cancer Group; FASG, French Adjuvant Study Group; IGT, Intergroup trial. b LN, lymph node; PgR, progesterone receptor; ER, estrogen receptor; HR, hormone receptor. c A→CMF, doxorubicin, followed by cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU); A/CMF, doxorubicin, alternated with cyclophosphamide, methotrexate, and 5-FU; AC, doxorubicin and cyclophosphamide; ACT, doxorubicin, cyclophosphamide, and tamoxifen; CAh, cyclophosphamide and doxorubicin (high dose intensity); CAi, cyclophosphamide and doxorubicin (intermediate dose intensity); CAI, cyclophosphamide and doxorubicin (low dose intensity); CAFT, cyclophosphamide, doxorubicin, 5-FU, and tamoxifen; CAF→T, cyclophosphamide, doxorubicin, and 5-FU followed by tamoxifen; CEF, cyclophosphamide, epirubicin, and 5-FU (‘50’ and ‘100’ refer to the epirubicin dose in mg/m2); CFMP, cyclophosphamide, 5-FU, methotrexate, and prednisone; CFMPT, cyclophosphamide, 5-FU, methotrexate, prednisone, and tamoxifen; CFP, cyclophosphamide, 5-FU, and prednisone; CFPT, cyclophosphamide, 5-FU, prednisone, and tamoxifen; CMF, cyclophosphamide, methotrexate, and 5-FU; CMFE, cyclophosphamide,

Breast cancer in the older woman: An oncologic perspective

1211

methotrexate, 5-FU, and epirubicin; CMFET, cyclophosphamide, methotrexate, 5-FU, epirubicin, and tamoxifen; CMFpT, cyclophosphamide, methotrexate, 5-FU, prednisone, and tamoxifen; CMFT, cyclophosphamide, methotrexate, 5-FU, and tamoxifen; CMFVP, cyclophosphamide, methotrexate, 5-FU, vincristine, and prednisone; CMFVPT, cyclophosphamide, methotrexate, 5FU, vincristine, prednisone, and tamoxifen; ET, epirubicin and tamoxifen; 0, observation; P, melphalan; PAF, melphalan, doxorubicin, and 5-FU; PAFT, melphalan, doxorubicin, 5-FU, and tamoxifen; PF, melphalan and 5-FU; PFT, melphalan, 5-FU, and tamoxifen; pT, prednisone and tamoxifen; T, tamoxifen. d ‘Low risk’: 1–3 LN+ plus ER+ and/or PgR+. ‘High risk’: ≥4 LN+, or 1–3 plus ER− and/or PgR−.

Table 51.12 Randomized clinical trials of adjuvant chemotherapy in postmenopausal women: nodenegative patients Studya

No. of patients

Milan NodeNegative265 NSABP B13266,267 Intergroup268 NSABP B-20

269

Upper age Patient limit characteristicsb (years)

Regimenc

Outcomed (%) DFS

OS

90 65

LN−, ER−

CMF vs 0

40

28

280 60

LN−, ER−

0 vs M→F

17

14

153 70

LN−

0 vs CMFP

12

—

LN−, HR+

T vs MFT vs CMFT

25–50 15– 20

2306 75

a

NSABP, National Surgical Adjuvant Breast and Bowel Project. LN, lymph node; ER, estrogen receptor; HR, hormone receptor. c CMF, cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU); CMFP, cyclophosphamide, methotrexate, 5-FU, and prednisone; CMFT, cyclophosphamide, methotrexate, 5-FU, and tamoxifen; M→F, sequential methotrexate, 5-FU; MFT, methotrexate, 5-FU, and tamoxifen; 0, observation; T, tamoxifen. d DFS, disease-free survival rate; OS, overall survival rate. b

be much more manageable. The assumption that all women aged 60 and older are hormone-responsive is no longer supported: the most recent Oxford meta-analysis showed that only women with tumors rich in ER and/or PgR benefit from adjuvant hormonal therapy.113 This incorrect assumption might have accounted in part for the uneven distribution of patients in the B-11 and B-12 trials. The CALGB compared high (60mg/m2 and 600mg/m2), intermediate (40mg/m2 and 400mg/m2) and low (30mg/m2 and 300mg/m2) doses of doxorubicin and cyclophosphamide in breast cancer patients with positive axillary lymph nodes.243 The highest doses were administered for a total of four courses of treatment, and the intermediate and low doses for six courses. Both high and intermediate doses were superior to low doses in both pre- and postmenopausal women. High doses of chemotherapy were superior to intermediate doses for patients with high tumor expression of the HER2/neu oncogene.264 From our standpoint, this study is

Comprehensive Geriatric Oncology

1212

important, since it demonstrates the benefit of adjuvant doxorubicincontaining combination chemotherapy in postmenopausal women. Bonadonna et al256 compared doxorubicin at 75 mg/m2 for three courses followed by six courses of CMF versus doxorubicin at the same dose, alternated with CMF. They demonstrated the superiority of the sequential over the alternating treatment in both preand postmenopausal women with four to eight lymph nodes positive for breast cancer. The main aims of the study were to prove the validity of the theoretical principle ‘best drug first’ in clinical practice and to demonstrate the benefits of adjuvant chemotherapy in women with more than three axillary lymph nodes involved by tumor. From our standpoint, the study proves once more the value of doxorubicin-based adjuvant chemotherapy in postmenopausal women. Of interest is also the GABGG study, which divided patients into ‘low risk’ (1–3 involved lymph nodes and positive for ER and/or PgR) and ‘high risk’ (≥4 positive lymph nodes or 1–3 positive lymph nodes and negative for ER and/or PgR).257 In low-risk patients, tamoxifen proved superior to CMF chemotherapy; in high-risk patients, the combination of doxorubicin, cyclophosphamide, and tamoxifen was superior to doxorubicin/cyclophosphamide without tamoxifen. The International Collaborative Cancer Group (ICCG) compared tamoxifen and epirubicin versus tamoxifen alone in postmenopausal women with involved lymph nodes and positive hormone receptors and found that the addition of chemotherapy improved by 27% the diseasefree survival of these patients.261 The French Adjuvant Study Group (FASG) demonstrated that in the CEF regimen (cyclophosphamide, epirubicin, and 5FU), the use of epirubicin at high doses (100mg/m2) is superior to epirubicin at low doses (50mg/m2), irrespective of patient age and receptor status.262 The Southwest Oncology Group (SWOG) has reported the preliminary results of an Intergroup trial comparing adjuvant chemotherapy with cyclophosphamide, doxorubicin, and 5-FU (CAF) plus tamoxifen versus tamoxifen alone in postmenopausal women with hormone receptor-rich tumors and lymph node involvement, and have found an advantage for chemotherapy in terms of both DFS and OS after 3 years of follow-up263 Only one study, which was carried out in Italy, failed to demonstrate the advantages of an anthracycline in the adjuvant treatment of postmenopausal women.252 In fact, Boccardo et al252 found that a combination of cyclophosphamide, methotrexate, 5-FU, and epirubicin (CMFE) resulted in poorer DFS and OS than tamoxifen alone or CMFE plus tamoxifen (CMFET). Rather then denying the benefits of chemotherapy, however, this study supports the impression already mentioned that tumors rich in hormone receptors are less sensitive to chemotherapy than those poor in hormone receptors. The lack of benefit of chemotherapy in combination with tamoxifen may be explained to some extent by the design of the treatment program, with epirubicin being given after six courses of CMF—in other words, the design contradicted the principle of ‘best drug first’. It is also possible that the significant toxicity of chemotherapy prevented the administration of an effective dose intensity of the drugs. The results with CMF-like combinations of chemotherapy in the presence of lymph node involvement are less clear. The results of NSABP trial B-07 should be scrutinized very carefully. This is an old study (first published in 1977), in which patients were divided by age (under 50 and 50 and over) rather than by menopausal status.247 Probably only a handful of those women were older than 60. It is possible that the benefits seen in the B-07 trial concern mainly old premenopausal women. The SWOG investigators ran

Breast cancer in the older woman: An oncologic perspective

1213

two subsequent studies in post-menopausal women. In the first of these, women were randomized to melphalan for 2 years or to cyclophosphamide, methotrexate, 5-FU, vincristine, and prednisone (CMFVP) for 1 year.254 The combination appeared superior to single-agent melphalan in terms of both DFS and OS. In the second study, which included only women with tumors rich in hormone receptors, the investigators compared tamoxifen and CMFVP plus tamoxifen (CMFVPT), and found that the chemotherapy did not enhance the benefits of tamoxifen.255 It is reasonable to conclude that this type ofchemotherapy may be beneficial to women with hormone receptor-poor tumors, but has no appreciable effects in those with hormone receptorrich tumors. The Ludwig III study is a relatively small study (456 patients), comparing observation versus prednisone and tamoxifen (PT) versus cyclophosphamide, methotrexate, 5-FU, prednisone, and tamoxifen (CMFPT): after 13 years of follow-up, a small survival advantage emerged, but this was limited to women with hormone receptor-poor tumors.259 The International Breast Cancer Study Group (IBCSG) conducted a large study of CMF in postmenopausal women and showed that the benefits in terms of overall survival declined with the age of the patients and disappeared after age 65.260 The Milan Node-Negative study265 reported an improvement in survival for postmenopausal women with negative lymph nodes, but this study had two major flaws: the small number of patients and inadequate patient selection. The only adverse prognostic factor was absence of ER, with no consideration of nuclear grade, tumor size, or more recently identified prognostic factors, such as tumor cell proliferation, HER2/neu concentration, and neovascularization. It is very possible that the marked survival differences resulted from the accidental comparison of different patient populations and not from the effects of treatment. A recent update of the NSABP study B-13266,267 indicates a small advantage in OS for postmenopausal women with node-negative tumors who received adjuvant chemotherapy with methotrexate and 5-FU. The Intergroup study reported improved DFS but not OS with CMF.268 It is very possible that no difference in survival has emerged yet because of the low number of cancer-related deaths expected in the controls, in this patient population with a relatively good prognosis. NSABP trial B20 also reported a minimal benefit of CMF and tamoxifen over tamoxifen alone in women with hormone receptor-rich lymph node-negative tumors, and these benefits were mostly limited to premenopausal or younger postmenopausal women.269 An apparent paradox emerges from the examination of these trials: whereas women with hormone receptor-poor tumors may benefit from the less toxic CMF-like chemotherapy combinations, women with hormone receptor-rich tumors seem to benefit from adjuvant chemotherapy only when an anthracycline is included. This paradox may be explained by the analysis of the HER2/neu status of patients involved in the Intergroup-100 trial.245 In this study, postmenopausal women with involved lymph nodes and high hormone receptor concentration were randomized to receive tamoxifen alone or tamoxifen in combination with CAF. For tumors with low HER2/neu concentrations, chemotherapy did not provide any sizable advantage; for those rich in HER2/neu, however, chemotherapy improved by almost 50% the DFS at 4 years. As anthracyclinecontaining chemotherapy is preferable in the presence of high concentrations of HER2/neu,225,270,271 the low activity of CMF-like chemotherapy in postmenopausal women with hormone receptor-rich tumors is not surprising.

Comprehensive Geriatric Oncology

1214

An important consideration related to these trials of postmenopausal women concerns the under-representation of women over 70, who were included in only a few trials,254,255,261–265 and always in a proportion much lower than the prevalence of cancer in that age group. From the preceding discussion, one can draw the following conclusions: • Adjuvant chemotherapy containing an anthracycline may prolong both DFS and OS of postmenopausal women with positive lymph nodes. In women with hormone receptorrich tumors, this benefit is minimal in the absence of HER2/neu overexpression. The most effective of these regimens has not been established. The AC combination of the NSABP,251 which involves intravenous doxorubicin 60mg/m2 and intravenous cyclophosphamide 600mg/m2 every 3 weeks for a total of four courses, is the most practical and is generally well tolerated. Even for patients in their 70s, we have found this regimen to be very tolerable. In view of a report that this regimen was associated with cumulative myelotoxicitv with advanced age,272 we recommend that granulocyte colony-stimulating factor (G-CSF) be used prophylactically in women aged 70 and older.273,274 Other reasonable combinations include CAF or CEF every 3 weeks for sk courses.255–263 • Non-doxorubicin-based combination chemotherapy may improve the prognosis of node-negative patients, since it may delay disease recurrence and possibly improve the OS and represent a valid alternative for node-positive patients who cannot tolerate doxorubicin A number of controversies related to adjuvant chemotherapy in general are of concern to older women and need to be addressed. These include the following: • The value of different doses of doxorubicin and cyclophosphamide: the Intergroup 9344 study275 clearly showed no advantage of a dose of doxorubicin higher than 60mg/m2, whereas NSABP study B-22 showed no benefits for doses of cyclophosphamide higher than 600/m2—at least when fewer than nine lymph nodes were involved by the tumor.276 • Treatment duration and value of 5-FU: the most recent NIH consensus conference on adjuvant chemotherapy for breast cancer concluded that four courses of AC or six courses of CMF are probably inadequate treatment for women with tumor-involved axillary lymph nodes.196 This conclusion was based on the results of the Canadian trial finding five courses of CEF to be superior to sk courses of CMF277 in premenopausal women. As AC was found to be equivalent to CMF in NSABP study B-15,278 one may conclude that FEC is superior to AC. Even if we grant this difference, it is not clear whether it is due to the more prolonged duration of treatment, to the presence of 5-FU in the combination, or to a combination of both factors. • The benefits of adding taxanes to the treatment: the addition of taxanes to the treatment plan is still controversial, especially for women with hormone receptorrich tumors. The Intergroup trial exploring the addition of paclitaxel showed a benefit in overall survival for women with three or more positive lymph nodes and hormone receptorpoor tumors.275 An update of this study presented at the NIH consensus conference in Washington on November 1–3, 2001196 failed to show any benefit from the addition of paclitaxel in the presence of hormone receptor-rich tumors. Another study exploring the same question was presented at the same conference—NSABP study B-28, with

Breast cancer in the older woman: An oncologic perspective

1215

negative results for all subgroups of women. However, the most recent analysis showed a benefit of taxanes. • The exclusion of metastases to the sentinel lymph node with cytokeratin staining may identify a category of patients who are truly lymph node-negative and may not need adjuvant treatment at all (Sophie Dessureault, General Session, 23rd Annual San Antonio Breast Cancer Symposium, December 6, 2000). At the H Lee Moffitt Cancer Center, no distant metastases were seen over 23 months in 971 patients with sentinel lymph node uninvolved by the tumor. Ongoing clinical trials continue to explore this issue. • A number of new agents have become available that may substantially reduce the toxicity of adjuvant treatment in older women. These include cytotoxic drugs, such as taxanes at low doses, vinorelbine, gemcitabine, and capecitabine, as well as biologic agents, including trastuzumab. Clinical trials with these agents are in progress. Of special interest to us is the CALGB trial with capecitabine in women aged 65 and older. • A German study suggested that the addition of the bisphosphonate clodronate to adjuvant chemotherapy in breast cancer may prevent metastases to the bones as well as to other organs.279 Other studies have failed to support this finding.280,281 It should be noted, however, that the use of clodronate in the German study was limited to women with microscopic involvement of the marrow—i.e. to a group of patients at very high risk of recurrence. This issue deserves further study, especially for the aged, since bisphosphonates may complement or substitute for adjuvant chemotherapy. More information is needed in women over 70; until this information has been accrued, it is reasonable to treat the oldest women like other postmenopausal women, as long as coexisting conditions do not enhance the risk of treatment toxicity. Seemingly, the main benefit of adjuvant chemotherapy in older women may be prolongation of DFS; it is important to ask whether this prolongation results in an improvement in quality of life. Gelber et al259 devised a quality of life-assessing instrument to address this problem. TWiST (time without symptoms and treatment) is currently used by the IBCSG, and assesses quality of life as the time during which the patient is not bothered by symptoms of cancer or by the inconvenience and complications of treatment. These authors found that most patients achieve a substantial gain in quality of life from adjuvant chemotherapy even when there is no appreciable survival gain. In other words, the delay in breast cancer recurrence is worth the transient symptoms of adjuvant treatment. The main advantage of TWiST is that it is an objective measurement. Its main disadvantage is also that it is objective, and unable to accommodate individual reactions to treatment. Altogether, we believe that TWiST reflects faithfully the reactions of most patients with early breast cancer and validates the benefits of adjuvant chemotherapy when a prolongation of survival is not clearly evident. As anthracyclines have a central role to play in the adjuvant treatment of postmenopausal patients, concern about cardiotoxic complications in women aged 70 and older may arise. These women appear to be more susceptible to doxorubicin-related cardiotoxicity (see Chapter 39 of this volume282). A number of options may ameliorate this risk and include:

Comprehensive Geriatric Oncology

1216

• Substitution of epirubicin for doxorubicin, as epirubicin seems to be associated with a decreased risk of cardiotoxicity;283 • Substitution of a liposomal form of doxorubicin for doxorubicin;284 • Use of the cardioprotectant dexrazoxane (ICRF-187);285 • Use of mitoxantrone instead of doxorubicin, but the effectiveness of this drug is controversial.286 The more widespread use of adjuvant chemotherapy in older women may involve a substantial increase in treatment cost. Desch et al287 have studied the cost and costeffectiveness of adjuvant chemotherapy in elderly women with node-negative breast cancer. As expected, they found that the cost increases and the effectiveness decreases with patient age: for example, the cost for 1 year of quality-adjusted life would be $28200 for a 60-year-old; $44400 for a 75-year-old, and $57100 for a 80-year-old. These figures should not discourage the use of adjuvant therapy, but should rather stimulate definition of criteria for better patient selection, so that only patients at high risk for recurrence and low risk of treatment complications enter the chemotherapy program. A decision analysis by Extermann et al288 may assist the practitioner to decide whether adjuvant chemotherapy is of benefit to older women. Considering desirable a decline in breast cancer-related mortality of 1% or more, these authors calculated the risk of breast cancer recurrence at which this goal could be attained for women of different ages. Not surprisingly, this risk increases substantially with age. For women aged 80, it is around 30% Stage IIIA disease The standard treatment of stage IIIA breast cancer involves surgery, which generally requires mastectomy, followed by adjuvant chemotherapy and, in the majority of cases, adjuvant irradiation. A number of investigators have explored the feasibility of treating these patients with neoadjuvant chemotherapy.289–292 The theoretical advantages of this approach include in vivo documentation of tumor chemosensitivity, earlier treatment of micrometastatic disease prior to development of multidrug resistance, treatment of patients in better general condition and more able to tolerate dose-intensive chemotherapy, and the possibility of breast-conserving surgery from reduction of the size of the primary tumor. The main potential disadvantage is inadequate surgical staging.293 NSABP study B-18 compared neoadjuvant and adjuvant chemotherapy in stage IIIA disease, and found comparable effectiveness.294 Neoadjuvant chemotherapy was associated with an increased feasibility of partial mastectomy. Stage IIIB disease The management of stage IIIB breast cancer involves the combination of chemotherapy, generally administered as initial treatment, followed by mastectomy and chest wall irradiation. With this approach, a 5-year survival rate of 30–40% is obtainable.295,296 Chemotherapy is critical in the management of stage IIIB breast cancer. Prior to chemotherapy, the 5-year survival rate with local treatment only was less than 5%.293 In the majority of cases, combination chemotherapy involves an anthracycline (doxorubicin or epirubicin); the role of new drugs such as mitoxantrone, paclitaxel, docetaxel, and

Breast cancer in the older woman: An oncologic perspective

1217

vinorelbine has not yet been established. Generally, inflammatory breast cancer is poor in hormone receptors, and tamoxifen or other hormonal manipulations are not indicated. In the case of hormone receptor-rich tumors, hormonal therapy should be added to combination chemotherapy. Stage IV disease The management of metastatic breast cancer is tailored to the location of the metastases and the hormone responsiveness of the tumor. The location of the metastases is important for several reasons, such as the presence of tumor sanctuaries, the risk of local complications, management of single recurrences to the chest walls, and specific life-expectancy. Tumor sanctuaries include the central nervous system and possibly the eye. Metastases to the brain are treated with surgical excision and radiotherapy when single, and with radiation therapy when multiple; spinal metastases are treated with radiation.297 The treatment of meningeal metastases, which may cause neoplastic meningitis, includes intrathecal administration of cytotoxic agents such as methotrexate, cytarabine, or thiotepa; radiation therapy is reserved for chemotherapy-resistant tumors or when the cranial nerves are involved.298 The management of retinal and choroidal metastases is controversial. Although many authors advocate radiation therapy since the penetration of systemic treatment in these areas is unpredictable, there are reports of good responses to systemic treatment.299 When the patient is asymptomatic, the risk of retinal detachment is not imminent, and the patient’s general conditions allow it, we prefer to use systemic treatment first, to provide systemic coverage of metastatic cancer and to prevent radiation toxicity to the eye. Close ophthalmologic follow-up is imperative under these circumstances. Local complications may be seen with metastases to the long bones, to the spine, and to the skin. Metastases to the long bones involve the risk of pathologic fractures, whereas metastases to the spine may involve the risk of spinal cord compression. Whenever 50% or more of the cortex of the long bones is involved by tumor, emergent orthopedic fixation of the bone is indicated.300 While waiting for surgery, the patient should be instructed not to bear weight on the bone at risk; the use of crutches or of a wheelchair is highly recommended. Painful metastases to the spine should be evaluated with myelogram or magnetic resonance imaging (MRI); in the presence of epidural extension, emergency radiation therapy and steroid treatment are indicated. The management of bone metastases also involves the administration of bisphosphonates. Pamidronate, administered intravenously every 3–4 weeks, delays the progression of metastases, and reduces overall analgesic use, the need for radiation therapy to the bones, and the risk of pathologic fractures.301 Other bisphosphonates that have proved beneficial for bone metastases include clodronate (not available in the USA), zoledronate,302 and ibandronate (also not available in the USA).303 Unlike pamidronate, which requires a 2-hour infusion, zoledronate may be administered over 5 minutes. The initiation of bisphosphonate treatment prior to the clinical diagnosis of bony metastases has no proven value and is not recommended at present. Metastases to the skin may grow into fungating and ulcerative tumors: timely and aggressive local management of skin metastases resistant to systemic treatment with surgery and radiation therapy may prevent this dreadful complication.304

Comprehensive Geriatric Oncology

1218

Single chest wall metastases require both local and systemic treatment.304–306 Local treatment involves surgery (when feasible) or radiation therapy. The duration of systemic treatment is not definitely established. We choose to administer hormonal therapy for at least 5 years for hormone receptor-rich tumors, and six courses of chemotherapy for hormone receptor-poor tumors. With this approach, more than 50% of patients are alive and free of disease 5 years from the time of chest wall recurrence.304–306 Metastases to different organs imply different life-expectancies.111 For example, hepatic metastases or lymphangitic metastases to the lung are associated with a short median survival (3–6 months) when untreated. Under these circumstances, the use of hormonal therapy may be inappropriate, even for hormone-sensitive tumors, because responses to endocrine therapy are seen after 6 weeks of treatment or longer. Bone, skin, and nodular lung metastases, on the other side, are associated with a survival longer than 2 years. The hormone-responsiveness of a tumor is determined by the concentration of hormone receptors.307 Responses to front-line hormonal treatment as high as 80% may be seen in tumors rich in both ER and PgR; the response rate of tumors that are rich in only one of the two types of receptors is around 30–50%. According to old reports, tumors poor in both ER and PgR may be responsive to tamoxifen in 15–20% of cases. At least two, non-mutually exclusive explanations may account for these findings. First, some of the antineoplastic activities of tamoxifen may be independent of estrogen antagonism.107– 109 Second, the ligand technique used in the past for the determination of hormone receptors was not as sensitive as recent immunochemical techniques and may have misclassified hormone receptor-rich tumors.159,308 The hormonal treatment of breast cancer in the older woman includes the agents listed in Table 51.13.1,233–239,309–316 Estrogens in high doses, which act as estrogen antagonists, and androgens are now seldom used,

Table 51.13 Hormonal agents for the treatment of metastatic breast cancer Drug

Dose

Complicationsa

Estrogen antagonists Tamoxifen

20mg daily

Hot flashes, vaginal secretions, deep vein thrombosis, retinopathy, hypercalcemia (in patients with bony metastases)

Toremifene

60mg daily

Same as tamoxifen

Fulvestrant Aromatase inhibitors Non-steroidal Anastrozole

1.0mg daily Hot flashes

Letrozole

2.5mg daily Hypercoagulability, allergic reactions

Steroidal Exemestane

25mg daily

Hot flashes, allergic reactions

Breast cancer in the older woman: An oncologic perspective

1219

Progestins Megestrol acetate

40mg 4 times daily

Weight gain, nausea, fluid retention

Estrogens Diethylstilbestrol 5mg 3 times Deep vein thrombosis, fluid retention, hypercalcemia (in patients daily with bony metastases) Androgens Fluoxymesterone 10mg 3 times daily

Virilization, fluid retention

owing to toxicity. They may have a role to play in patients who require symptom palliation, have failed other forms of hormonal treatment, and are not good chemotherapy candidates. The administration of tamoxifen as a daily dose is more convenient, especially for older individuals, and is equally effective as in divided doses.309 Toremifene has activity and toxicity profiles comparable to those of tamoxifen.310–312 It may be preferable in patients at risk for cerebrovascular accidents.235 Fulvestrant is a pure estrogen antagonist with demonstrated activity in about 25% of patients resistant to tamoxifen.236 Another advantage of this agent is its monthly intramuscular administration, which may insure adequate treatment of older individuals. Two types of aromatase inhibitors have entered clinical practice: the non-steroidals letrozole237 and anastrozole238 and the steroidal 4-hydroxyandrostenedione (exemestane)239 (the latter is sometimes referred to as an aromatase inactivator, since it causes irreversible inactivation of the enzyme). The activities of these two types of compounds are not completely overlapping: apparently 20% of the patients who progress while receiving letrozole and anastrozole will respond to exemestane and some of the patients resistant to exemestane may respond to non-steroidals.313 In randomized controlled studies, both letrozole and anastrozole proved superior to tamoxifen in terms of response rate and time to progression.315 A comparison between exemestane and tamoxifen is ongoing. Currently, aromatase inhibitors are considered an alternative to SERMs as front-line treatment of hormone-responsive metastatic breast cancer. All three drugs may be safer than tamoxifen and toremifene, especially in older individuals, owing to a lower risk of thromboembolic complications. The combination of two hormonal agents does not appear to be more effective than single drugs, and is not recommended.317 The management of metastatic breast cancer in the older woman has been influenced by two major advances: trastuzumab (Herceptin) and the development of new cytotoxic agents with a safer toxicity profile. Trastuzumab is a humanized monoclonal antibody directed against c-ErbB-2, a member of the epidermal growth factor receptor family encoded by the HER2/neu (c-erbB-2) gene.318 Trastuzumab appears to be effective only in women in whom HER2/neu is overexpressed. The ‘gold standard’ for assessing HER2/neu is the fluorescence in situ hybridization (FISH) technique, which is not widely available at present. A reasonable approach is to pretest the tumor with immunochemistry and to reserve FISH to confirm the positivity of those tumors for which immunochemistry is equivocal (2+ expression).160,319 In combination with chemotherapy, including taxanes in low doses,320 vinorelbine,321 and capecitabine,322 trastuzumab has

Comprehensive Geriatric Oncology

1220

produced a response rate of 50–80% and a statistically significant improvement in patient survival with respect to chemotherapy alone.323 Because of potential cumulative cardiotoxicity, the combination of trastuzumab and an anthracycline is not recommended.323 Also, it is not clear whether the addition of chemotherapy is necessary in patients with FISH-positive tumors, but it is recommended, unless contraindications to chemotherapy exist. Of special interest to older individuals are a number of new agents, including taxanes at low doses, vinorelbine, gemcitabine, and capecitabine, that have minimal toxicity.324 Capecitabine allows excellent flexibility of doses and convenience, since it is administered orally: in randomized controlled trials, this drug proved superior to CMF in patients who had not received previous chemotherapy325 and comparable to single-agent paclitaxel in patients whose disease has failed anthracycline treatment.326 The main complication of capecitabine, the hand-foot syndrome, is preventable with daily pyridoxine in the majority of cases. In combination with docetaxel, capecitabine had a survival advantage over docetaxel alone.327 Capecitabine is of special interest to older individuals. Several studies have conclusively demonstrated that age is an independent risk factor for fluorinated pyrimidine-induced mucositis.328,329 Thanks to its particular formulation, capecitabine minimizes the exposure of normal tissues to 5-FU and reduces the risk of mucositis. A recent study by Sledge et al330 has cast doubt about the benefits of combination chemotherapy versus single-agent treatment. This study, which compared doxorubicin, paclitaxel, and a combination of the two, showed that combination chemotherapy was associated with higher response rate but not an improvement in OS. Based on this study, combination chemotherapy appears advisable only when a rapid response is necessary to manage life-threatening situations, such as lymphangitic lung metastases. It is important to notice that this finding is somewhat controversial. An Italian meta-analysis of several studies indicated that combinations of chemotherapy containing an anthracycline were superior to single-agent chemotherapy in terms of survival.307 Some of the most popular regimens are listed in Table 51.14.324 Probably, the most active regimens include a combination of doxorubicin and docetaxel, which proved superior to doxorubicin/cyclophosphamide in a randomized controlled study,331 and a combination of docetaxel and capecitabine, which proved superior to docetaxel alone.332 More traditional regimens, including CMF, CAF, CEF, or cyclophosphamide, mitoxantrone, and 5-FU (CNF),332–335 are now used less commonly in metastatic disease. In older women, the use of epirubicin instead of doxorubicin may reduce the risk of cardiotoxicity.283 For all women over 70 in whom combination chemotherapy is administered at full doses, we do recommend the addition of a hematopoietic growth factor.273,336 How well do older breast cancer patients tolerate combination chemotherapy? Four studies have addressed

Table 51.14 Common cytotoxic chemotherapy in metastatic breast cancer Single agents Drug

Doses (mg/m2)

Response rate (%)

Cyclophosphamide

600–1000 i.v. q3wks

10–60

100 p.o. × 14 days

Breast cancer in the older woman: An oncologic perspective

Doxorubicin

40–60 i.v. q3wks

35–50

Mitoxantrone

10–12 i.v. q3wks

25–40

Epirubicin

60–90 i.v. q3wks

35–50

Vinorelbine

30mg i.v. weekly

20–40

Gemcitabine

1000 i.v. weekly

15–30

Paclitaxel

220 i.v. over 3 h q3wks

25–50

1221

90 i.v. over 1 h weekly Docetaxel

75–100 i.v. q3wks

35–60

35 i.v. weekly Mitomycin C

10 i.v. q6wks

Capecitabine

2000–2500 p.o. d1–14 of a 3-week cycle

Methotrexate

15–30

15–35

50 i.v. weekly 15 p.o. × 3 days q3wks

5-Fluorouracil

600 weekly 200–300 CIVI for 4–6 wks

20–40

Drug combinations

Doses (mg/m2)

Interval (days)

Cyclophosphamide

100 (p.o. d1–14)

Methotrexate

40 (i.v. d1 and 8)

5-Fluorouracil

600 (i.v. d1 and 8)

Cyclophosphamide

500 (i.v. d1)

Doxorubicin

50 (i.v. d1)

5-Fluorouracil

500 (i.v. d1)

Cyclophosphamide

500 (i.v. d1)

Mitoxantrone

10 (i.v. d1)

5-Fluorouracil

500 (i.v. d1)

Methotrexate

160 (i.v. d1)

5-Fluorouracil

600 (i.v. d2)

Leucovorin

25 (p.o. q6h × 6, start

28

21

21

14

24 h after methotrexate) 5-Fluorouracil

200 (CIVI d1–24)

42

Paclitaxel

125 (3 h infusion d1)

21

Doxorubicin

60 (d1)

Comprehensive Geriatric Oncology

Docetaxel

100 (i.v.)

Doxorubicin

50 (i.v.)

G-CSF

(d2–8)

Docetaxel

70 (i.v. d1)

Capecitabine

1500 (p.o. d1–14)

1222

21

21

CIVI, continuous i.v. infusion; G-CSF, granulocyte colony-stimulating factor.

this question in a retrospective fashion.337–340 Gelman and Taylor337 compared the effectiveness and toxicity of CMF in women younger than 65 and in older patients. In older patients, they modified the doses of methotrexate and cyclophosphamide according to the patient’s creatinine clearance. They found that the response rate was similar in the two groups of patients, but the incidence and severity of myelotoxicity were lower for the older patients. Christman et al338 compared the response to chemotherapy and the incidence of complications among three groups of women, subdivided by age, treated according various protocols of the Piedmont Oncology Group, and found no difference between women younger than 45 and those older than 65. Ibrahim et al339 compared the response rate and toxicity of chemotherapy in younger and older women treated at the MD Anderson Cancer Center in Houston, and again they could not demonstrate agerelated differences. More recently, the same group340 reported the safety of doxorubicin combination chemotherapy in women over 70 treated adjuvantly. These results should be received with caution for two reasons. First, the subjects of these studies were enrolled in clinical trials, by virtue of their excellent general conditions. They may not represent the majority of older individuals. Second, very few of the patients were aged 80 and older. For practical purposes, there is no information concerning chemotherapy in the oldest old. In addition to the use of growth factors to prevent myelotoxicity, two other recent advances may ameliorate the toxicity of chemotherapy in older women. These involve the cardiotoxicity of the anthracyclines, whose incidence increases with age (see Chapter 39282). Cardiotoxicity may be lessened with the administration of dexrazoxane285 or with the use of liposomal doxorubicin.284 Dexrazoxane chelates the iron of the sarcomeres and prevents the formation of free radicals that are responsible for cardiomyopathy.285 In a randomized placebo-controlled trial in patients with metastatic breast cancer, this compound enabled patients to receive a substantially higher dose of doxorubicin. The exact timing of dexrazoxane therapy is controversial (see Chapter 39). The current recommendation to institute dexrazoxane treatment after a total dose of doxorubicin of 300mg/m2 of body surface area stems from two considerations: cardiotoxicity is minimal at lower doses of doxorubicin and there is some concern, probably unfunded, that dexrazoxane may prevent the antineoplastic activity of the drug during the early phases of treatment (see Chapter 39). Liposomal doxorubicin is associated with a lower risk of cardiotoxicity, due to the slow release of the drug. Currently, the experience with liposomal doxorubicin in breast cancer is limited. Our most common treatment strategy for women aged 65 and older is illustrated in Figure 51.10. If the patient has life-threatening metastases, defined as lymphangitic metastases to the lung, or hepatic metastases involving more than 50% of the liver

Breast cancer in the older woman: An oncologic perspective

1223

parenchyma, we use chemotherapy in combination as frontline treatment. For HER2/neupositive tumors, we use a combination of trastuzumab and low doses of taxanes; for HER2/neu-negative tumors, we prefer to use a combination of an

Figure 51.10 Our current approach to the treatment of metastatic breast cancer in older women. anthracycline and docetaxel, or capecitabine and docetaxel, if the patient cannot tolerate an anthracycline. In the absence of life-threatening metastases, the treatment is determined by the hormonal status of the tumor. For hormone receptor-rich tumors, the front-line treatment is a new aromatase inhibitor. At present, no adequate information is available to recommend any of the available products over others. Exemestane may be preferable due to a lower risk of thromboembolic complications, but this should be confirmed by a randomized controlled study of existing compounds. In the case of progression on an aromatase inhibitor, it is reasonable to try an alternative aromatase inhibitor, and upon further progression a SERM—either tamoxifen or toremifene.

Comprehensive Geriatric Oncology

1224

Approximately 15% of patients will respond to SERM withdrawal upon progression.341,342 If no response to SERM withdrawal is observed, megestrol acetate represents a reasonable third-line hormonal treatment. Estrogen in high doses or an androgen are used only in special circumstances. The only situation in which we may use a combination of chemotherapy and hormones is life-threatening metastasis from receptor-rich tumors. In all other circumstances, we avoid the simultaneous use of chemotherapy and hormones. This combination has not proven superior to either modality alone, and may augment the cost and the complications of treatment. For hormone receptor-poor tumors or hormone receptor-rich tumors that progress after third-line hormonal treatment, we use as front-line chemotherapy a taxane at low doses or vinorelbine or capecitabine, and an anthracycline only as second-or third-line treatment. Summary In this section, we summarize the most important aspects of breast cancer in the older women, and we propose a research agenda. Epidemiology The incidence of breast cancer increases with age up to 80 and plateaus thereafter. There may be a decline after age 85. Preliminary autopsy data suggest that the incidence of occult breast cancer declines after age 60. The most important questions for future research concern: • the real incidence of breast cancer in the oldest old; • the mortality and morbidity of breast cancer in the oldest old; • the incidence and prevalence of occult breast cancer after age 60; the answer to this question may have a heavy impact on future screening practices. Biology The prevalence of cancers with less aggressive characteristics (high hormone receptor concentration, low histologic grade, and low proliferation) increases with age. There is also evidence that the growth of breast cancer may be delayed in the older organism. In view of these findings, screening mammography may be performed at longer intervals in older than in younger women. Important research questions include: • mechanisms that control tumor growth in older individuals, with particular attention to IGF-I, IGFBP, IL-6, and TGF-β; • mechanisms by which immune senescense may delay tumor growth in older individuals; • the predictive value of immune senescense and host-derived growth factors on the outcome of breast cancer at different stages.

Breast cancer in the older woman: An oncologic perspective

1225

Prevention Primary prevention Primary prevention of breast cancer may involve abstinence from alcohol or only moderate consumption (<3 ounces daily), and weight loss for persons who have an android type of obesity. Of particular concern is HRT. Although HRT is definitely associated with breast cancer, we do not recommend avoidance of HRT, whose benefits seem to grossly outweigh the risks. We do, however, recommend the following: • Estrogen replacement appears to be preferable to the combination of estrogen and progestins, with regard or the risk of breast cancer. • For women who are not bothered by hot flushes, vaginal dryness, or depression, low doses of estrogen (equivalent to ≤0.3mg conjugated estrogen daily) may be adequate. • HRT for a limited period of time (5–10 years postmenopausal) may be considered. The feasibility of chemoprevention of breast cancer with a SERM has been clearly demonstrated; what has not been demonstrated is a benefit of chemoprevention in terms of survival, quality of life, symptoms, and cost. In view of the risks associated with SERM treatment, we feel that the institution of chemoprevention should be individualized according to the risk of breast cancer and the risk of therapeutic complications. The decision analysis proposed by Gail et al120 may be used as a frame of reference for decisions concerning chemoprevention. Important research issues include: • the value of a diet low in fat in the prevention of breast cancer; • the risks of HRT in women with a family history of breast cancer; • the durability of the benefits of HRT of limited duration on bones and a clear demonstration of benefits related to coronary arteries; • chemoprevention of breast cancer with SERMs other than tamoxifen, and with substances different from SERMs, including retinoids, oltripaz and other agents. Secondary prevention (screening) The practice of screening women for breast cancer with serial mammograms and physical examination of the breast has resulted in a 20–30% decline in breast cancer-related mortality for women aged 50–70. One starts to see the benefits of screening 3–7 years after the initial examination. According to the BCCDP study, physical examination of the breast misses approximately 11% of the breast cancers detected at mammography; according to the Canadian study, the two examinations were approximately equivalent. Mammography at 2-year and at 1-year intervals yielded comparable results. The ideal number of mammographic examinations has not been established. We recommend that all women be screened for breast cancer, irrespective of age, when their life-expectancy is 3 years or longer. As screening methods for women over 65, we recommend: • physical examination of the breast at each clinic visit;

Comprehensive Geriatric Oncology

1226

• mammography every 2 years. Important research issues involve: • comparison of the predictive values of physical breast examination and mammography in older women; • the incidence of new breast cancers detected at mammography after age 65, to determine the ideal number of mammograms that should be performed; • the value of molecular screening in older women. Treatment Local disease (stages I and II) The treatment of local disease is a multidisciplinary endeavor involving surgery, radiation therapy, and systemic treatment. In terms of local control, total mastectomy and partial mastectomy with postoperative irradiation have yielded similar results. Axillary dissection is part of current practice, to eliminate local disease, to establish the prognosis of the patients, and to establish which patients are candidates for systemic adjuvant treatment and for irradiation of the chest wall. In early disease (lesions <3cm in diameter), sentinel lymph node mapping has proven reliable in identifying patients who benefit from axillary lymph node resection. In patients with more advanced tumors, this technique should be considered experimental at present. Systemic adjuvant treatment with tamoxifen and with chemotherapy may be indicated according to the circumstances. Adjuvant tamoxifen is beneficial for women with hormone receptor-rich tumors; adjuvant chemotherapy is beneficial in terms of DFS and OS for postmenopausal women up to age 70 who have positive lymph nodes, or negative lymph nodes and a tumor with largest diameter of 1cm or more that is receptor-poor. There is a likely benefit from adjuvant chemotherapy after age 70 according to the most recent Oxford meta-analysis. The decision analysis proposed by Extermann may assist in the identification of patients who may benefit from adjuvant chemotherapy. In hormone receptor-rich tumors, chemotherapy has been proven beneficial conclusively only for HER2/neu-overexpressing lesions. In this case, anthracycline-containing chemotherapy is preferable As the rate of local recurrence may decline with patient age, postoperative irradiation may not be necessary after partial mastectomy in older women, but it is difficult to establish a subgroup of patients in whom this practice may be forgone. Clearly, postoperative irradiation may be avoided for women over 55 when: • the tumor has greatest diameter of 2.5cm or less; • there is minimal or no DCIS component; • the surgical procedure was a quadrantectomy; In all other cases, the treatment should be individualized according to patient preferences. Important research issues involve:

Breast cancer in the older woman: An oncologic perspective

1227

• the definition of subgroups of patients for whom breast irradiation may be avoided after partial mastectomy; • the optimal duration of adjuvant tamoxifen treatment, including potential benefits on morbidity and mortality unrelated to breast cancer (osteoporosis, coronary artery disease, and contralateral breast cancer); • adjuvant chemotherapy of women aged 70 or older; • the benefits of new and more tolerable agents as adjuvant chemotherapy; these include vinorelbine, gemcitabine, taxanes at low doses, and capecitabine Advanced disease (stage IV) The management of advanced disease involves systemic treatment and palliative treatment. The principles of systemic treatment include the following: • For women with hormone receptor-rich tumors, the front-line treatment should be hormonal, in the absence of life-threatening metastases. The preferred sequence includes an aromatase inhibitor followed by a SERM, followed by a progestin. • For tumors overexpressing HER2/neu, any form of treatment should include trastumazab. The combination of this agent with taxanes in low doses should be adequate also for life-threatening metastases. • For tumors unresponsive to endocrine treatment and without HER2/neu overexpression, single-agent chemotherapy is preferable to combination chemotherapy because it is better tolerated. • In presence of life-threatening metastases from tumors that do not overexpress HER2/neu, a combination of an anthracycline and docetaxel, or docetaxel and capecitabine (for patients with cardiac contraindications to anthracyclines), appears to be the treatment of choice. • In the presence of bony metastases, bisphosphonates may reduce the risk of osseous complications.

References 1. Kimmick GG, Balducci L. Breast cancer and aging: clinical interactions. Hematol Oncol Clin North Am 2000; 14:213–34. 2. Silliman RA, Balducci L, Goodwin J et al. Breast cancer and old age: what we know, don’t know, and do. J Natl Cancer Inst 1993; 85:190–9. 3. Balducci L, Lyman GH, Schapira DV. Trends in prevention and treatment of breast cancer in the older woman. In: Facts and Research in Gerontology (Vellas BJ, Albarede JL, Garry PJ, eds). New York: Serdi, 1994:179–92. 4. de Graaf H, Willemse PHB, Sleijfer DT. Review: Breast cancer in elderly patients. Age Aging 1994; 23:427–34. 5. Balducci L, Greenberg H. Breast cancer in the older woman: therapeutic controversies. Cancer Control 1994; 1:350–6. 6. Yancik R, Ries LA. Aging and cancer in America: demographic and epidemiologic perspectives. Hematol Oncol Clin North Am 2000; 14:17–24. 7. La Vecchia C, Franceschi S. International variations and trends in the incidence of cancer in older women. Cancer Control 1994; 1: 327–33.

Comprehensive Geriatric Oncology

1228

8. Stanta G. Morbid anatomy of aging. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman HG, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:187–93. 9. Madigan MP, Ziegler RG, Benichou J et al. Proportion of breast cancer cases in the United States explained by well established risk factors. J Natl Cancer Inst 1995; 87:1681–5. 10. Goldstein AM, Amos CI. Segregation analysis of breast cancer from the cancer and steroid hormone study: histologic subtypes. J Natl Cancer Inst 1990; 82:1911–17. 11. Lynch HT, Watson P, Conway TA et al. Clinical/genetic features in hereditary breast cancer. Breast Cancer Res Treat 1990; 15: 63–71. 12. Knudson AG Jr. Hereditary predisposition to cancer. Ann NY Acad Scie 1997; 833:58–67. 13. Eeles RA, Powles TJ. Chemoprevention options for BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2000; 18(Suppl 1): S93–9. 14. Shattuck-Eidens D, McClure M, Simard J et al. A collaborative survey of 80 mutations in the BRCA1 breast and ovarian cancer susceptibility gene. JAMA 1995; 273:535–41. 15. Wooster R, Bignell G, Lancaster J et al. Identification of a breast cancer gene, BRCA2. Nature 1995; 378:789–91. 16. Easton DF, Bishop DT, Ford D et al. Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families: the Breast Cancer Linkage Consortium. Am J Hum Genet 1993; 52: 678–701. 17. Breast Cancer Linkage Consortium. Carrier risk in BRCA2 mutation carriers. J Natl Cancer Inst 1999; 91:1310–16. 18. Goldgar DE, Neuhausen SL, Steele L et al. A 45 year follow-up of kindred 107 and the search for BRCA2. Monogr Natl Cancer Inst 1995; 17:15–19. 19. Arver B, Du Q, Chen J et al. Hereditary breast cancer: a review. Semin Cancer Biol 2000; 10:271–88. 20. Goodwin PJ. Management of familial breast cancer risk. Breast Cancer Res Treat 2000; 62:19– 33. 21. Martin AM, Weber B. Genetic and hormonal risk factors in breast cancer. J Natl Cancer Inst 2000; 92:1126–35. 22. Hutchinson JN, Muller WJ. Transgenic mouse models and human breast cancer. Oncogene 2000; 19:6130–37. 23. Dupont WD, Page DL. Menopausal estrogen replacement therapy and breast cancer. Arch Intern Med 1991; 151:67–72. 24. Colditz GA, Egan KM, Stampfer MJ. Hormone replacement therapy and risk of breast cancer: results from epidemiologic studies. Am J Obstet Gynecol 1993; 168:1473–80. 25. Nabulsi AA, Folsom AR, White A et al. Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women. N Engl J Med 1993; 328:1069– 75. 26. Ewertz M. Influence of non-contraceptive exogenous and endogenous sex hormones on breast cancer risk in Denmark. Int J Cancer 1988; 42:832–8. 27. Kaufman DW, Palmer JR, deMonzon J et al. Estrogen replacement therapy and the risk of breast cancer: results from the case-control surveillance study. Am J Epidemiol 1991; 134:1375– 85. 28. Palmer JR, Roenberg L, Clarke EA et al. Breast cancer study after estrogen replacement therapy: results from the Toronto Breast Cancer Study. Am J Epidemiol 1991; 34:1386–95. 29. Yang CP, Daling JR, Band PR et al. Noncontraceptive hormone use and risk of breast cancer. Cancer Causes Control 1992; 3:475–9. 30. Stanford JL, Weiss NS, Voigt LF et al. Combined estrogen and progestin hormone replacement therapy in relation to risk of breast cancer in middle-aged women. JAMA 1995; 274:137–42. 31. Ross RK, Paganini-Hill A, Wan PC et al. Effect of hormone-replacement therapy on breast cancer risk: estrogen vs estrogen plus progestin. J Natl Cancer Inst 2000; 92:328–32. 32. Bergkvist L, Adami H-O, Persson I et al. The risk of breast cancer after estrogen and estrogenprogestin replacement. N Engl J Med 1989; 321:293–7.

Breast cancer in the older woman: An oncologic perspective

1229

33. Hunt K, Vessey M, McPherson K et al. Long-term surveillance of mortality and cancer incidence in women receiving hormone replacement therapy. Br J Obstet Gynecol 1987; 94:620–35. 34. Risch HA, Howe GR. Menopausal hormone usage and breast cancer in Saskatchewan: a recordlinkage study. Am J Epidemiol 1994; 139:670–83. 35. Schairer C, Lubin J, Troisi R et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000; 283:485–91. 36. Colditz GA, Hankinson SE, Hunter DJ et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 1995; 332:1589–93. 37. Gapstur SM, Morrow M, Sellers TA. Hormone replacement therapy and risk of breast cancer with a favorable histology. JAMA 1999; 281:2091–7. 38. Schairer C, Gail M, Byrne C et al. Estrogen replacement therapy and breast cancer survival in a large screening study. J Natl Cancer Inst 2000; 91:264–70. 39. Fowble B, Hanlon A, Freedman G et al. Postmenopausal hormone-replacement therapy on diagnosis and outcome in early stage invasive breast cancer treated with conservative surgery and radiation. J Clin Oncol 1999; 17:1680–8. 40. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonereplacement therapy: collaborative reanalysis of the data from 51 epidemiological studies of 52, 705 women with breast cancer and 108, 411 women without breast cancer. Lancet 1997; 350:1047–59. 41. Jenstrom H, Frenander J, Ferno M et al. Hormone replacement therapy before breast cancer diagnosis significantly reduces the overall death rate compared with never use among 984 breast cancer patients. Br J Cancer 1999; 80:1453–8. 42. Rodriguez C, Patel AV, Calle EE et al. Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. JAMA 2001; 285:1460–5. 43. Swain S, Santen R, Burger H, Pritchard K. Treatment of estrogen deficiency syndromes in women surviving breast cancer: executive summary and consensus statement. Oncology 1999; 13:859–75. 44. LeBlanc ES, Janowski J, Chan BKS et al. Hormone replacement therapy and cognition. Systematic review and meta-analysis. JAMA 2001; 285:1489–99. 45. Prihartono N, Palmer JR, Louik C et al. A case-control study of use of postmenopausal female hormone supplements in relation to the risk of large bowel cancer. Cancer Epidemiol Biomark Prev 2000; 9:443–7. 46. Loprinzi CL, Kugler JW, Sloan JA et al. Venlafaxine in the management of hot flashes in survivors of breast cancer in a randomised controlled trial. Lancet 2000; 16:2059–63. 47. Hulley S, Grady D, Bush T et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 208:605–13. 48. Herrington DM, Reboussin DM, Brosnihan KB et al. Effects of estrogen replacement on the progression of coronary artery atherosclerosis. N Engl J Med 2000; 343:522–9. 49. Goldstein F, Manson JE, Colditz GA et al. A prospective observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000; 133: 933–41. 50. Psaty BM, Smith NL, Lemaitre RN et al. Hormone replacement therapy, prothrombotic mutations, and the risk of incident nonfatal myocardial infarction in postmenopausal women. JAMA 2001; 285:906–13. 50a. Shumaker SA, Legault C, Rapp SR et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. JAMA 2003; 289:2663–72. 50b. Chlebowski RT, Hendrix SL, Langer RD et al. Influnce of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women. JAMA 2003; 289:3243–53. 51. Vassiloupoulou-Sellin R, Asmar L, Hortobagyi GN et al. Estrogen replacement therapy after localized breast cancer: clinical outcome of 319 women followed prospectively. J Clin Oncol 1999; 17:1482–92.

Comprehensive Geriatric Oncology

1230

52. Col NF, Hirota LK, Orr RK et al. Hormone replacement therapy after breast cancer: a systematic review and quantitative assessment of risk. J Clin Oncol 2001; 19:2357–63. 53. Natrajan PK, Soumakis K, Gambrell RD et al. Estrogen replacement therapy in women with previous breast cancer. Am J Obstet Gynecol 1999; 181:288–95. 54. Huang Z, Willett WC, Golditz GA et al. Waist circumference, waist/hip ratio and risk of breast cancer in the Nurses Health Study. Am J Epidemiol 1999; 150:1316–24. 55. Folsom AR, Kaye SA, Prineas RJ et al. Increased incidence of carcinoma of the breast associated with abdominal adiposity in postmenopausal women. Am J Epidemiol 1990; 131:794–803. 56. Schapira DV, Kumar NB, Lyman GH et al. Abdominal obesity and breast cancer risk. Ann Intern Med 1990; 112:182–6. 57. Kirschner MA, Samojic E, Drejka M. Androgen-estrogen metabolism in women with upper body vs lower body adiposity. J Clin Endocrinol Metab 1990; 70:473–9. 58. Sellers TA, Kushi LM, Potter JD et al. Effect of family history, body fat distribution, and reproductive factors on the risk of postmenopausal breast cancer. N Engl J Med 1992; 326:1323–5. 59. Schapira DV, Kumar NB, Lyman GH. Estimate of breast cancer risk reduction with weight loss. Cancer 1991; 67:2622–5. 60. LaVecchia C, Decaru A, Franceschi S et al. Alcohol consumption and the risk of breast cancer in women. J Natl Cancer Inst 1985; 75:61–5. 61. Le MG, Hill C, Kramar A et al. Alcohol beverage consumption and breast cancer in a French case-control study. Am J Epidemiol 1984; 120:350–7. 62. Schatzkin A, Jones Y, Hoover RN et al. Alcohol consumption and breast cancer in the epidemiologic follow-up study of the First Health and Nutrition Examination Survey. N Engl J Med 1987; 376: 1169–73. 63. Kushi LH, Sellers TA, Potter JD et al. Dietary fat and postmenopausal breast cancer. J Natl Cancer Inst 1992; 84:1092–9. 64. Kitchevski D. Nutrition and breast cancer. Cancer 1990; 66: 1321–6. 65. Toniolo P, Riboli E, Protta F et al. Calorie-providing nutrients and risk of breast cancer. J Natl Cancer Inst 1989; 81:278–86. 66. Howe GR, Hirohata T, Hislop TG et al. Dietary factors and risk of breast cancer: combined analysis of 12 case-control studies. J Natl Cancer Inst 1990; 82:561–9. 67. Boyle P, Leake R. Progress in understanding breast cancer: epidemiological and biological interactions. Breast Cancer Res Treat 1988; 111:91–112. 68. Ziegler RG, Hoover RN, Pike ML et al. Migration pattern and breast cancer risk in AsianAmerican women. J Natl Cancer Inst 1993; 85:1819–27. 69. Mills PK, Beeson WL, Phillips RL et al. Dietary habits and breast cancer incidence among Seventh Day Adventists. Cancer 1989; 64: 582–90. 70. Jones DY, Schatzkin A, Green SB et al. Dietary fat and breast cancer in the National Health and Nutrition Examination Survey I. Epidemiologic follow-up study. J Natl Cancer Inst 1987; 79: 465–71. 71. Willett WC, Stampferer MJ, Colditz GA et al. Dietary fat and the risk of breast cancer. N Engl J Med 1987; 316:22–8. 72. van den Brandt PA, van’t Veer P, Goldbohm A et al. A prospective cohort study on dietary fat and the risk of postmenopausal breast cancer. Cancer Res 1993; 53:75–82. 73. Howe GR, Friedenreich CM, Jain M et al. A cohort study of fat intake and risk of breast cancer. J Natl Cancer Inst 1991; 83: 336–40. 74. Herman C, Adlercreutz H, Goldin BR et al. Soybean phytoestrogen intake and cancer risk. J Nutr 1995; 125:757S-70S. 75. Adlercreutz H, Mousavi Y, Hockerstedt K. Diet and breast cancer. Acta Oncol 1992; 31:175– 81.

Breast cancer in the older woman: An oncologic perspective

1231

76. Yancik R, Ries LG, Yates GW. Breast cancer in aging women: a population-based study of contrasts in stage, surgery, and survival. Cancer 1989; 63:973–81. 77. Goodwin JS, Samet JM, Key CR et al. Stage at diagnosis of cancer varies with the age of the patient. J Am Geriatr Soc 1986; 34:20–6. 78. Mor V, Guadagnoli E, Masterson-Allen S et al. Lung, breast and colorectal cancer: the relationship between extent of disease and age at diagnosis. J Am Geriatr Soc 1988; 36:873–6. 79. Diab SG, Elledge RM, Clark GM. Tumor characteristics and clinical outcome of elderly women with breast cancer. J Natl Cancer Inst 2000; 92:550–6. 80. Nattinger AB, Gottlieb MS, Veum J et al. Geographic variations in the use of breast-conserving treatment for breast cancer. N Engl J Med 1992; 327:1102–7. 81. Farrow DC, Hunt WC, Samet JM. Geographic variations in the treatment of localized breast cancer. N Engl J Med 1992; 326: 1097–101. 82. Fletcher SW, Harris RP, Gonzalez JG et al. Increasing mammography utilization: a controlled study. J Natl Cancer Inst 1993; 85: 112–20. 83. Coleman EA, Feuer EJ. Breast cancer screening among women from 65 to 74 years of age in 1987–88 and 1991. Ann Intern Med 1992; 117:961–6. 84. Fox SA, Roetzheim RG. Screening mammography and older Hispanic women: current status and issues. Cancer 1994; 74: 2028–33. 85. Roberson NL. Breast cancer screening in older Black women. Cancer 1994; 74:2034–41. 86. Greenfield S, Blanco DH, Elashoff RM, Ganz PA. Patterns of care related to age of breast cancer patients. JAMA 1987; 257:2766–70. 87. McKenna RJ. Clinical aspects of cancer in the elderly. Cancer 1994; 74:2107–17. 88. Goodwin JS, Samet JM. Care received by older women diagnosed with breast cancer. Cancer Control 1994; 1:313–19. 89. Balducci L. Perspectives on quality of life of older patients with cancer. Drugs Aging 1994; 4:313–24. 90. Satariano WA, Ragland DR. The effect of comorbidity on 3-year survival of women with primary breast cancer. Ann Intern Med 1994; 120:104–10. 91. Havlik RJ, Yancik R, Long S et al. The National Institute on Aging and National Cancer Institute SEER collaborative study on comorbidity and early diagnosis of cancer in the elderly. Cancer 1994; 74: 2101–6. 92. Guadagnoli E, Shapiro C, Gurwitz JH et al. Age-related patterns of care: evidence against ageism in the treatment of early-stage breast cancer. J Clin Oncol 1997; 15:2338–44. 93. Life Tables. Washington, DC: USA Government Printing Office, 1995. 94. Figueroa JA, Yee D, McGuire WL. Prognostic indicators in early breast cancer. Am J Med Sci 1993; 305:176–82. 95. Costantino J, Fisher B, Gunduz N et al. Tumor size, ploidy, S-phase, and ERBB-2 markers in patients with node-negative ER-positive tumors: findings from NSABP B-14. Proc Am Soc Clin Oncol 1994; 13:64. 96. Gasparini G, Barbareschi M, Boracchi P et al. Tumor angiogenesis predicts clinical outcome of node-positive breast cancer patients treated with adjuvant hormone therapy or chemotherapy. Cancer J Sci Am 1995; 1:131–41. 97. Ershler WB. Tumor-host intentions, agings and tumor growth. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman HG, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:147–57. 98. Nixon AJ, Neuberg D, Hayes DF et al: Relationship of patient’s age to pathologic features of the tumor and prognosis for patients with stage I or II breast cancer. J Clin Oncol 1994; 12:888– 94. 99. Lyman GH et al. Breast cancer in the older woman: a comparative study of younger and older women with breast cancer. J Gerontol (to be published).

Comprehensive Geriatric Oncology

1232

100. Valentinis B, Silvestrini R, Daidone MG et al. 3H-thymidine labeling index, hormone receptors and ploidy in breast cancer from elderly patients. Breast Cancer Res Treat 1991; 20:19–24. 101. Holmberg L, Lindgren A, Norden T et al. Age as a determinant of axillary node involvement in invasive breast cancer. Acta Oncol 1992; 31:533–8. 102. Kurtz JM, Jacquemier J, Amalric R et al: Why are local recurrences after breast-conserving therapy more frequent in younger patients. J Clin Oncol 1990; 10:141–52. 103. Burns EA, Goodwin JS. Immunological changes of aging. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman HG, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:158–70. 104. Ethier SP. Growth factor synthesis and human breast cancer progression. J Natl Cancer Inst 1995; 87:964–73. 105. Yee D, Sharma J, Hilsenbeck SG. Prognostic significance of insulinlike growth factor binding protein expression in axillary lymph node-negative breast cancer. J Natl Cancer Inst 1994; 86:1785–9. 106. Lonning PE, Hall K, Aakvaag A et al. Influence of tamoxifen on plasma levels of insulin-like growth factor I and insulin-like growth factor I binding proteins in breast cancer patients. Cancer Res 1992; 52:4719–23. 107. Hamermann D. Toward an understanding of frailty. Ann Intern Med 1999; 130:945–50. 108. Roberts AB, Sporn MB. Physiological actions and clinical applications of transforming growth factors beta. Growth Factors 1993; 8: 1–9. 109. Butta A, Maclennan K, Flanders KC et al. Induction of transforming growth factor β in human breast cancer ‘in vivo’ following tamoxifen. Cancer Res 1992; 52:4261–4. 110. Guidi AJ, Abu-Jawdeh G, Berse B et al. Vascular permeability factor (vascular endothelial growth factor) expression and angiogenesis in cervical neoplasia. J Natl Cancer Inst 1995; 87:1237–45. 111. Holmes FF. Clinical course of cancer in the elderly. Cancer Control 1994; 1:108–14. 112. Hong WK, Lippman SM. Cancer chemoprevention. J Clin Oncol 2000; 18(Suppl 1): S1–10. 113. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet 1998; 351:1451–67. 114. Fisher B, Dignam J, Wolmark N et al. Tamoxifen in the treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B24 randomised controlled trial. Lancet 1999; 353: 1993–2000. 115. Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for prevention of breast cancer: report from the National Adjuvant Breast and Bowel Project. J Natl Cancer Inst 1998; 90:1371– 88. 116. Agnusdei D, Liu-Lerage S, Augendre-Ferrant B. Results of international clinical trials with raloxifene. Ann Endocrinol (Paris) 1999; 60:342–6. 117. Cummings SR, Eckert S, Kruger KA et al. The effects of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. JAMA 1999; 281:2189–97. 118. Powles T, Eles R, Ashley S et al. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet 1998; 352:98– 101. 119. Veronesi U, Maisonneuve P, Costa A et al. Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomysed women. Lancet 1998; 352:93–7. 120. Gail MH, Costantino JP, Bryant J et al. Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer. J Natl Cancer Inst 1999; 91:1829–46. 121. Howell A, Osborne CK, Morris C et al. ICI 182, 780 (Faslodex): development of a ‘new’ pure antiestrogen. Cancer 2000; 89:817–25. 122. Santen RJ, Yue W, Naftolin F et al. The potential of aromatase inhibitors in breast cancer prevention. Endocr Rel Cancer 1999; 6: 235–43.

Breast cancer in the older woman: An oncologic perspective

1233

123. LaFollette S, Cobleigh M. Dietary and chemoprevention strategies for breast cancer prevention. Cancer Control 1995; 2:218–23. 124. Minton S. Chemoprevention of breast cancer in the older patient. Hematol Oncol Clin North Am 2000; 14:113–30. 125. Anisimov VN. Age as a risk factor in multistage carcinogeneses. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman HG, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:75–101. 126. Fernanadez-Pol JA. Growth factors, oncogenes, and aging. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman HG, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:102–26. 127. Balducci L, Beghe’ C. Prevention of cancer in the older person. Clin Geriatr Med 2002; 18:505–28. 128. Castiglione M, Gelber RD, Goldhirsch A. Adjuvant systemic therapy for breast cancer in the elderly: competing causes of mortality. J Clin Oncol 1990; 8:519–26. 129. Mandelblatt JS, Wheat ME, Monane M et al. Breast cancer screening for elderly women with and without comorbid conditions. Ann Intern Med 1992; 116:722–30. 130. Champion V. Breast self-examination in women 65 and older. J Gerontol 1992; 47:75–9. 131. O’Malley MS, Fletcher SW. US Preventive Services Task Force: screening for breast cancer with breast self-examination: a critical review. JAMA 1987; 257:2196–203. 132. Fletcher SW, Black W, Harris R et al. Report of International Workshop on screening for breast cancer. J Natl Cancer Inst 1993; 85:1644–56. 133. Mitra I. Breast screening: the case for physical examination without mammography. Lancet 1994; 343:342–4. 134. Miller AB, To T, Baines CJ et al. Canadian National Breast Screening Study-2:13-year results of a randomized trial in women aged 50–59 years. J Natl Cancer Inst 2000; 92:1490–9. 135. Morrison AS, Brisson J, Khalid N. Breast cancer incidence and mortality in the Breast Cancer Detection Demonstration Project. J Natl Cancer Inst 1988; 80:1540–7. 136. Shapiro S. Periodic Screening for Breast Cancer: The Health Insurance Pilot Project and its Sequelae, 1963–1986. Baltimore: Johns Hopkins University Press, 1988. 137. Nystrom L, Rutquvist LE, Wall S et al. Breast cancer screening with mammography: overview of Swedish randomized trials. Lancet 1993; 341:973–8. 138. Wald N, Chamberlain J, Hackshaw A and EUSOMA Evaluation Committee. Report of the European Society for Mastology Breast Cancer Screening Evaluation Committee. J Eur Soc Mastology 1993; 13:1–25. 139. Miller AB, Baines CJ, To T et al: Canadian National Breast Screening Study 2: breast cancer detection and death rates among women aged 50 to 59 years. Can Med Assoc J 1992; 147:1477– 88. 140. Collette HJA, deWaard F, Collette C et al: Further evidence of benefits of a (non randomized) breast cancer screening programme: the DOM project. J Epidemiol Community Health 1992; 46:382–6. 141. Palli D, Del Turco MR, Buiatti E et al. Time interval since last test in a breast cancer screening programme: a case-control study in Italy. J Epidemiol Community Health 1989; 43:241–8. 142. van Dijck JAAM, Holland R, Verbeek, ALM et al. Efficacy of mammographic screening in the elderly: a case-referent study in the Nijmegen program in the Netherlands. J Natl Cancer Inst 1994; 86:934–8. 143. Moss SM, Summerley ME, Thomas BT et al. A case-control evaluation of the effect of breastcancer screening in the United Kingdom Trial of Early Detection of Breast Cancer. J Epidemiol Community Health 1992; 46:362–4. 144. Kerlikowske K, Grady D, Rubin SM et al. Efficacy of screening mammography. A metaanalysis. JAMA 1995; 273:149–54.

Comprehensive Geriatric Oncology

1234

145. McCarthy EP, Burns RB, Freund KM et al. Mammography use, breast cancer stage at diagnosis, and survival among older women. J Am Geriatr Soc 2000; 48:1226–33. 146. Kerlikowske K, Salzmann P, Phillips KA et al. Continuing screening mammography in women aged 70 to 79 years. JAMA 1999; 282: 2156–63. 147. Fox SA, Roetzheim RG, Kington RS. Barriers to cancer prevention in the older person. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman HG, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:376–86. 148. Sidransky D. Molecular markers in cancer diagnosis. Monogr Natl Cancer Inst 1995; 17:27– 30. 149. Ellis IO, Galea M, Broughton N et al. Pathological prognostic factors in breast cancer II. Histological type. Relationship with survival in a large study with long-term follow-up. Histopathology 1992; 20:479–89. 150. Smith JA, Gamez-Araugo JJ, Gallager HS et al. Carcinoma of the breast: analysis of total lymph node involvement versus level of metastasis. Cancer 1977; 399:527–32. 151. Cady B. Use of primary breast carcinoma characteristics to predict lymph node metastases. Cancer 1997; 79:1856–61. 152. Lesser M, Rosen PP, Kinne D Multicentricity and bilaterality in invasive breast carcinoma. Surgery 1982; 91:234–40. 153. Page DL, Dupont WD, Rogers LW et al. Continued local recurrence of carcinoma 15–25 years after a diagnosis of low grade ductal carcinoma in situ of the breast treated only by biopsy. Cancer 1995; 76:1197–200. 154. Rosen PP, Kosloff C, Lieberman PH et al. Lobular carcinoma in situ of the breast. Detailed analysis of 99 patients with average follow-up of 24 years. Am J Surg Pathol 1978; 2:225–51. 155. Lagios MD, Margolin FR, Westdahl PR et al. Mammographically detected duct carcinoma in situ. Frequency of local recurrence following tylectomy and prognostic effect of nuclear grade on local recurrence. Cancer 1989; 63:618–24. 156. Lagios MD, Westdahl PR, Margolin FR et al. Duct carcinoma in situ. Relationship of extent of noninvasive disease to the frequency of occult invasion, multicentricity, lymph node metastases, and short term treatment failures. Cancer 1987; 50:1309–14 157. Silverstein MJ, Poller DN, Waisman JR et al. Prognostic classifkation of breast ductal carcinoma ‘in situ’. Lancet 1995, 345:1154–7. 158. Page DL, Simpson JF. Ductal carcinoma in situ—the focus for prevention, screening, and breast conservation in breast cancer. N Engl J Med 1999; 340:1499–500. 159. Esteban JM, Ahn C, Battifora H, Felder B. Predictive value of estrogen receptors evaluated by quantitative immunohistochemical analysis in breast cancer. Am J Clin Pathol 1994; 102(Suppl 1): S9–12. 160. Ridolfi RL, Jamehdor MR, Arber JM. HER-2/neu testing in breast carcinoma: a combined immunohistochemical and fluorescence in situ hybridization approach. Mod Pathol 2000; 13:866–73. 161. Bass SS, Cox CE, Ku NN et al. The role of sentinel lymph node biopsy in breast cancer. J Am Coll Surg 1999; 189:183–94. 162. Hermanek P, Hutter RVP, Sobin LH et al. Classification of isolated tumor cells and micrometastasis. Cancer 1999; 86:2668–73. 163. Cox CE, Diaz NM. Letter to Editor re: The effects of postinjection massage on the sensitivity of lymphatic mapping in breast cancer. J Am Coll Surg (in press). 164. Hayes DF: Tumor markers for breast cancer. Hematol Oncol Clin North Atn 1994; 8:485–506. 165. Bast RC, Ravdin P, Hayes DF et al: 2000 update of Recommendations for the Use of Tumor Markers in Breast and Colorectal Cancer: Clinical Practice Guidelines of the American Society of Clinical Oncology. J Clin Oncol 2001; 19:1865–78. 166. Phillips DL, Balducci L. Current management of breast cancer. Am Fam Physician 1996; 53:657–65.

Breast cancer in the older woman: An oncologic perspective

1235

167. Shapira DV, Urban N. A minimalistic policy for breast cancer surveillance. JAMA 1991; 256:380–3. 168. Baum M. The endocrine management of postmenopausal women with early breast cancer. Breast Cancer 2004; 11:15–19. 169. Fisher B, Costantino J, Redmond C et al. Lumpectomy compared with lumpectomy and radiation therapy for the treatment of intraductal breast cancer. N Engl J Med 1993; 328:1581–6. 170. Silverstein MJ, Lagios MD, Groshen S et al: The influence of margin width on local control of ductal carcinoma ‘in situ’ of the breast. N Engl J Med 1999; 340:1455–61 171. Julien J-P. Radiotherapy in breast-conserving treatment for ductal carcinoma ‘in situ’: first results of the EORTC randomised phase III trial 10853. Lancet 2000; 355:528–33. 172. Fisher B, Dignam J, Wolmark N et al: Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from the National Surgical Adjuvant Breast and Bowel Project B-17. J Clin Oncol 1998; 16:441–52. 173. Jacobson JA, Danforth DN, Cowan KH et al: Ten-year results of a comparison of conservation with mastectomy in the treatment of stage I and II breast cancer. N Engl J Med 1995; 332:907– 11. 174. Fisher B, Anderson S, Redmond CK et al. Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1995; 333:1456–61. 175. Veronesi U, Banfi A, Salvadori B et al. Breast conservation is the treatment of choice in small breast cancer: long term-results of a randomized trial. Eur J Cancer 1990; 26:668–70. 176. van Dongen JA, Bartelink H, Fentiman IS et al. Randomized clinical trial to assess the value of breast conserving therapy in stage I and II breast cancer: EORTC 10801 trial. Monogr Natl Cancer Inst 1992; 11:15–18. 177. Abrams JS, Phillips PH, Friedman MH. Meeting highlights: a reappraisal of research results for the local treatment of early stage breast cancer. J Natl Cancer Inst 1995; 87:1837–45. 178. Foster RS. Management of primary breast cancer in older patients: treatment options. Cancer Control 1994; 1:339–43. 179. Galante E, Cerrotta AM, Crippa A. Outpatient treatment of clinically node-negative breast cancer in elderly women. Cancer Control 1994; 1:344–9. 180. Kiebert GM, de Haes JCJM, van der Velde CJH et al. The impact of breast conserving treatment and mastectomy on the quality of life of early stage breast cancer patients: a review. J Clin Oncol 1991; 9:1059–70. 181. Giuliano AE, Kirgan DM, Gunther JM et al. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 1994; 220:391–8. 182. Giuliano AE, Haigh PI, Brerman MB et al. Prospective observational study of sentinel lymphadenectomy without further axillary dissection in patients with sentinel lymph node negative breast cancer. J Clin Oncol 2000; 18:2553–8. 183. Cox CE, Pandas S, Cox JM et al. Guidelines for sentinel lymph node biopsy and lymphatic mapping of patients with breast cancer. Ann Surg 1998; 227:645–51. 184. Weaver DL. Sentinel lymph node biopsy in breast cancer: creating controversy and defining new standards. Adv Anat Pathol 2001; 8: 65–73. 185. Miltemburg DM, Miller C, Karamlou TB et al. Meta-analysis of sentinel lymph node biopsy in breast cancer. J Surg Res 1999; 84: 138–42. 186. Cox CE, Salud C, Whitehead GF et al. Sentinel lymph node biopsy for breast cancer: combined dye isotope technique. Breast Cancer 2000; 7:389–97. 187. Harris JR. Postmastectomy radiotherapy. In: Breast Diseases (Harris JR, Hellman S, Henderson IC, Kinne DW, eds). Philadelphia: JB Lippincott, 1992:383–7. 188. Griem KL, Henderson IC, Gelman R et al. The 5 year results of a randomized trial of adjuvant radiation therapy after chemotherapy in breast cancer patients treated with mastectomy. J Clin Oncol 1987; 5:1546–55.

Comprehensive Geriatric Oncology

1236

189. Early Breast Cancer Trialists’ Collaborative Group. Favourable and unfavourable effects on long term survival of radiotherapy for early breast cancer. Lancet 2000; 355:1757–70. 190. Ragaz J, Jackson SM, Le N et al: Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 1997; 337:956–62. 191. Overgaard M, Hansen PS, Overgaard J et al. Postoperative radio-therapy in high risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 1997; 337:949–55. 192. Overgaard M, Jensen MB, Overgaard J et al. Postoperative radiotherapy in high risk postmenopausal breast cancer patient given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82 randomized trial. Lancet 1999; 353:1641–8. 193. Geisler DP, Boyle MJ, Malnar KF et al. Adjuvant radiation after modified radical mastectomy for breast cancer fails to prolong survival. Am Surg 2000; 66:452–9. 194. Goldhirsch A, Wood WC, Senn H-J et al. Meeting Highlight: International Consensus Panel on the Treatment of Primary Breast Cancer. J Natl Cancer Inst 1998; 90:1601–8. 195. Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer; an overview of the randomised trials. Lancet 1998; 352:930–42. 196. Consensus Statement (NIH Consensus Development Program) 114: Adjuvant therapy for breast cancer. http:odp.od.nih.gov/consensus/cons/114. 197. Wyckoff J, Greenberg H, Sanderson R et al. Breast irradiation in the older woman: a toxicity study. J Am Geriatr Soc 1994; 42:153–6. 198. Morrow M, Harris JR, Schnitt SJ. Local control following breast cancer conserving surgery: results of clinical trials. J Natl Cancer Inst 1995; 87:1669–73. 199. Harris JR, Recht A. Conservative surgery and radiotherapy. In: Breast Diseases (Harris JR, Hellman S, Henderson IC, Kinne DW, eds). Philadelphia: JB Lippincott, 1992:388–419. 200. Nemoto T, Patel JK, Rosner D et al. Factors affecting recurrence in lumpectomy without irradiation for breast cancer. Cancer 1991; 67: 2079–82. 201. Clark RM, McCulloch PB, Levine MN. Randomized clinical trial to assess the effectiveness of breast irradiation following lumpectomy and axillary dissection for node-negative breast cancer. J Natl Cancer Inst 1992; 84:683–9. 202. Liljegren G, Holmberg L, Adami H-O et al. Sector resection with or without postoperative radiotherapy for stage I breast cancer: five-year results of a randomized trial. J Natl Cancer Inst 1994; 86:717–22. 203. Kantorowitz DA, Poulter CA, Sischy B et al. Treatment of breast cancer among elderly women with segmental mastectomy or segmental mastectomy plus postoperative radiotherapy. Int J Radiat Oncol Biol Phys 1988; 15:263–70. 204. Hayman J, Schnitt S, Gelman R et al. A prospective trial of conservative surgery (CS) alone without radiation therapy (RT) in selected patients with early stage breast cancer. Int J Radiat Oncol Biol Phys 1995; 32(Suppl 1): 209. 205. Veronesi U, Luini A, Del Vecchio M et al. Radiotherapy after breast preserving surgery in women with localized cancer of the breast. N Engl J Med 1993; 328:1587–91. 206. Wazer DE, Erban JK, Robert NJ et al. Breast conservation in elderly women for clinically negative axillary lymph nodes without axillary dissection. Cancer 1994; 74:878–83. 207. Bates T, Riley DL, Houghton J et al. Breast cancer in elderly women: a Cancer Research Campaign trial comparing treatment with tamoxifen and optimal surgery and optimal surgery with tamoxifen alone. The Elderly Breast Cancer Working Party. Br J Surg 1991; 78:591–4. 208. Bates T, Fennessy M, Riley DL et al. Breast cancer in the elderly: surgery improves survival. The results of a Breast Cancer Campaign trial. Proc Am Soc Clin Oncol 2001; 20:1533. 209. Mustacchi G, Latteier J, Milani S et al. Tamoxifen vs surgery plus tamoxifen as primary treatment for elderly patients with breast cancer: combined data from the GRETA and CRC trials. Proc Am Soc Clin Oncol 1998; 17:99a. 210. Nolvadex Adjuvant Trial Organization. Controlled trial of tamoxifen as single adjuvant agent in the management of early breast cancer. Lancet 1985; i: 836–40.

Breast cancer in the older woman: An oncologic perspective

1237

211. Stewart HJ, Prescott RJ, Forrest AP. Scottish Adjuvant Tamoxifen Trial: a randomized study updated to 15 years. J Natl Cancer Inst 2001; 93:456–62. 212. Ribeiro G, Swindell R. The Christie Hospital Adjuvant Tamoxifen Trial. Monogr Natl Cancer Inst 1992; 11:121–6. 213. Vermorken JB, Burgers JMV, Taat CW et al. Adjuvant tamoxifen in breast cancer: interim results of a Comprehensive Cancer Center Amsterdam trial. Proc Am Soc Clin Oncol 1994; 13:76. 214. Swedish Breast Cancer Cooperative Group. Randomized trial of two versus five years of adjuvant tamoxifen for premenopausal early breast cancer. J Natl Cancer Inst 1999; 88:1543–9. 215. Fisher B, Dignam J, Bryant J et al. Five vs more than 5 years of tamoxifen for lymph node negative breast cancer. Findings from the National Surgical Adjuvant Breast and Bowel Project B-14. J Natl Cancer Inst 2001; 93:684–90. 216. Falkson HC, Gray R, Wolberg WH et al. Adjuvant trial of 12 cycles of CMFPT followed by observation or continuous tamoxifen vs four cycles of CMFPT in postmenopausal women with breast cancer: an Eastern Cooperative Oncology Group phase III study. J Clin Oncol 1990; 8:599–607. 217. Tormey DC, Gray R, Falkson HC. Postchemotherapy adjuvant tamoxifen therapy beyond five years in patients with lymph node-positive breast cancer. Eastern Cooperative Oncology Group. J Natl Cancer Inst 1996; 88:1828–33. 218. Turken S, Siris E, Seldin D et al. Effects of tamoxifen on spinal bone density in women with breast cancer. J Natl Cancer Inst 1989; 81:1086–8. 219. Wright CDP, Mansell RE, Gazet J-C et al. Effect of long term tamoxifen treatment on bone turn-over in women with breast cancer. BMJ 1993; 306:429–30. 220. Love RR, Mazess RB, Barden HS et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 1992; 326:852–6. 221. Bush TL, Blumenthal R, Lobo R et al. SERMs and cardiovascular disease in women. How do these agents affect risk? Postgrad Med 2001; Special Number, March: 17–24. 222. McDonald CC, Stewart HJ. Fatal myocardial infarction in the Scottish Adjuvant Tamoxifen Trial. The Scottish Breast Cancer Committee. BMJ 1994; 303:435–7. 223. Love RR, Wiebe DA, Feyzi JM et al. Effects of tamoxifen on cardiovascular risk factors in postmenopausal women after 5 years of treatment. J Natl Cancer Inst 1994; 86:1534–9. 224. Schapira DV, Kumar NB, Lyman GH. Serum cholesterol reduction with tamoxifen. Breast Cancer Res Treat 1990; 17:3–7. 225. Fisher B, Costantino JP, Redmond CK et al. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 1994; 86:527–537. 226. Bernstein L, Deapen D, Cerhan JR et al. Tamoxifen therapy for breast cancer and endometrial cancer risk. J Natl Cancer Inst 1999; 91:1654–62. 227. Bergman L, Beelen MLR, Gallee MPV et al. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Lancet 2000; 356:881–7. 228. Rutqvist LE, Mattsson A. Cardiac and thromboembolic morbidity among postmenopausal women with early-stage breast cancer in a randomized trial of tamoxifen. The Stockholm Breast Cancer Study Group. J Natl Cancer Inst 1993; 85:1398–406. 229. Rutqvist LE, Johansson H, Signomklao T et al. Adjuvant tamoxifen therapy for early stage breast cancer and second primary malignancies. J Natl Cancer Inst 1995; 87:645–51. 230. Osborne CK, Wiebe VJ, Mcguire WL et al. Tamoxifen and the isomers of 4hydroxytamoxifen in tamoxifen-resistant tumors from breast cancer patients. J Clin Oncol 1992; 10:304–10. 231. Taylor SG, Gelman RS, Falkson G et al. Combination chemotherapy compared with tamoxifen as initial therapy for stage IV breast cancer in elderly women. Ann Intern Med 1986; 104:455–461.

Comprehensive Geriatric Oncology

1238

232. Langan-Fahey SM, Tormey DC, Jordan VC. Tamoxifen metabolites in patients on long term adjuvant therapy for breast cancer. Eur J Cancer 1990; 26:883–8. 233. Cobleigh MA, Berris RF, Bush T et al. Estrogen replacement therapy in breast cancer survivors. A time for change. Breast Cancer Committees of the Eastern Cooperative Oncology Group. JAMA 1994; 272:540–5. 234. Pandya KJ, Raubertas RF, Flynn PJ et al. Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes. A University of Rochester Cancer Center Community Clinical Oncology Program study. Ann Intern Med 2000; 132:788–93. 235. Holly K, Valavaara R, Blanco G et al. Safety and efficacy results of a randomized trial comparing toremifene and tamoxifen in patients with node-positive breast cancer. J Clin Oncol 2000; 18:3487–94. 236. Howell A, De Friend D, Robertson J et al. Response to a specific antiestrogen (ICI182780) in tamoxifen-resistant breast cancer. Lancet 1995; 345:29–30. 237. Goss PE, Strasser K. Aromatase inhibitors in the treatment and prevention of breast cancer. J Clin Oncol 2001; 19:881–94. 238. Dowsett M, Jones A, Johnston SR et al. ‘In vivo’ measurement of aromatase inhibition by letrozole in postmenopausal patients with breast cancer. Clin Cancer Res 1995; 1:1511–15. 239. Wiseman LR, Adkins JC. Anastrozole: a review of its use in the management of postmenopausal women with advanced breast cancer. Drugs Aging 1998; 8:321–4. 240. Baum M, Buzdar AU, Cuzick J et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of post-menopausal women with early breast cancer: first results of the ATAC randomized trial. Lancet 2002; 359: 2131–9. 241. Bonadonna G, Valagussa P, Moliterni A et al. Adjuvant cyclophosphamide, methotrexate and fluorouracil in node-positive breast cancer. N Engl J Med 1995; 332:901–6. 242. Bonadonna G, Valagussa P. Dose-response effect of adjuvant chemotherapy in breast cancer. N Engl J Med 1981; 304:10–15. 243. Wood WC, Budman DR, Korzun AH et al. Dose and dose intensity of adjuvant chemotherapy for stage II node-positive breast carcinoma. N Engl J Med 1994; 330:1253–9. 244. Bonadonna G, DiFronzo G, Tancin G et al. Relationship between estrogen receptors and CMF adjuvant chemotherapy. Rec Res Cancer Res 1984; 91:205–9. 245. Ravdin PM, Green KS, Albain V et al. Initial report of the SWOG correlative study of cERBB-2 expression as a predictor of outcome in a trial comparing adjuvant CAFT with tamoxifen (t) alone. Proc Am Soc Clin Oncol 1998; 17:97a (Abst 374). 246. Olivotto IA, Bajdic CD, Penderpleith IH et al. Adjuvant systemic therapy and survival after breast cancer. N Engl J Med 1994; 330: 805–10. 247. Fisher B, Redmond C, Fisher ER et al. Systemic adjuvant treatment of primary breast cancer. National Surgical Adjuvant Breast and Bowel Project experience. Monogr Natl Cancer Inst 1986; 1:35–43. 248. Ingle JN, Everson LK, Wieand HS et al. Randomized trial of observation vs adjuvant therapy with cyclophosphamide, fluorouracil, prednisone with or without tamoxifen, following mastectomy in postmenopausal women with node-positive breast cancer. J Clin Oncol 1988; 6:1388–96. 249. Taylor SG, Knuiman MW, Sleeper LA et al. Six-year results of the Eastern Cooperative Oncology Group trial of observation versus CMFP versus CMFPT in postmenopausal patients with node-positive breast cancer. J Clin Oncol 1989; 7:879–89. 250. Fisher B, Redmond C, Wickerham DL et al. Doxorubicin containing regimens for the treatment of stage II breast cancer: the National Surgical Adjuvant Breast and Bowel Project experience. J Clin Oncol 1989; 7:572–82. 251. Fisher B, Redmond C, Legault-Poisson S et al. Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: results from the National Breast and Bowel Project B-16. J Clin Oncol 1990; 8: 1005–18.

Breast cancer in the older woman: An oncologic perspective

1239

252. Boccardo F, Rubagotti A, Bruzzi P et al. Chemotherapy versus tamoxifen versus chemotherapy plus tamoxifen in node-positive, estrogen-receptor positive breast cancer patients: results of a multicenter Italian study. J Clin Oncol 1990; 8:1310–20. 253. Schumacher M, Bastert G, Bojar H et al. Randomized 2×2 trial evaluating hormonal treatment and the duration of chemotherapy in node-positive breast cancer patients. J Clin Oncol 1994; 12:2086–93. 254. Rivkin SE, Glucksberg H, Foulkes M. Adjuvant therapy of breast cancer: a Southwest Oncology Group experience. Rec Res Cancer Res 1984; 96:166–74. 255. Rivkin SE, Green S, Metch B et al. Adjuvant CMFVP vs tamoxifen vs concurrent CMFVP and tamoxifen for postmenopausal node-positive and estrogen-receptor-positive breast cancer patients: a Southwest Oncology Group study. J Clin Oncol 1994; 12:2078–85. 256. Bonadonna G, Zambetti M, Valagussa P et al. Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes. JAMA 1995; 273:542–7. 257. Kaufmann M, Abel JU, Hilfrich J et al. Adjuvant randomized trails of doxorubicin/cyclophosphamide vs doxorubicin, cyclophosphamide, tamoxifen and CMF chemotherapy versus tamoxifen in women with node-positive breast cancer. J Clin Oncol 1993; 11: 454–60. 258. Pritchard KI, Zee B, Paul N et al. CMF added to tamoxifen as adjuvant therapy in postmenopausal women with node positive estrogen and/or progesterone receptor-positive breast cancer: negative results of a randomized clinical trial. Proc Am Soc Clin Oncol 1994; 13:65. 259. Gelber RD, Goldhirsch A, Cavalli F. Quality-of-life adjusted evaluation of adjuvant therapies for operable breast cancer. Ann Intern Med 1991; 114:621–8. 260. Crivellari D, Bonetti M, Castiglione-Gertsch M et al. Burdens and benefits of adjuvant cyclophosphamide, methotrexate and fluorouracil and tamoxifen for elderly patients with breast cancer: the International Breast Cancer Study Group trial VII. J Clin Oncol 2000; 18:1412–22. 261. Wils JA, Bliss JM, Marty M et al. Epirubicin plus tamoxifen vs. tamoxifen alone in nodepositive postmenopausal patients with breast cancer: a randomized trial of the International Collaborative Cancer Group. J Clin Oncol 1999; 17:1988–2001. 262. French Adjuvant Study Group. Benefits of a high dose epirubicin regimen in the adjuvant chemotherapy for node positive breast cancer patients with poor prognostic factors: 5-year follow-up results of French Adjuvant Study Group 0–5 randomized trial. J Clin Oncol 2001; 19:602–11. 263. Albain K, Green S, Ravdin P et al. Overall survival after cyclophosphamide, adriamycin, FU and tamoxifen (ACFT) is superior to T alone in postmenopausal receptor (+) node (+) breast cancer: new findings from the phase III Southwest Oncology Group Intergroup trial S8814 (INT-0100). Proc Am Soc Clin Oncol 2001; 20:24a (Abst 94). 264. Muss HB, Thor AD, Berry DA et al. c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med 1994; 330:1260–6. 265. Bonadonna G. Evolving concepts in the systemic adjuvant treatment of breast cancer. Cancer Res 1992; 52:2127–37. 266. Fisher B, Redmond C, Dimitrov NV et al. A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who have estrogen-receptor-negative tumors. N Engl J Med 1989; 320:473–8. 267. Fisher B, Costantino J, Wickerman L et al. Adjuvant therapy for node-negative breast cancer. An update of NSABP findings. Proc Am Soc Clin Oncol 1993; 12:69. 268. Mansour EG, Gray R, Shatila AH et al. Efficacy of adjuvant chemotherapy in high-risk nodenegative breast cancer patients. N Engl J Med 1989; 320:485–90. 269. Fisher B, Dignam J, Wolmark N et al. Tamoxifen and chemotherapy for lymph node negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 1997; 89:1673–82.

Comprehensive Geriatric Oncology

1240

270. Paik S, Bryant J, Park C et al. erbB-2 and response to doorubicin in patients with axillary lymph node-positive hormone-receptor negative breast cancer. J Natl Cancer Inst 1998; 90:1361–70. 271. Paik S, Bryant J, Tan-Chiu E et al. HER2 and choice of adjuvant chemotherapy for invasive breast cancer: National Surgical Adjuvant Breast and Powel Project B-15. J Natl Cancer Inst 2000; 92:1991–8. 272. Dees EC, O’Reilly S, Goodman SN et al. A prospective pharmacologic evaluation of agerelated toxicity chemotherapy in women with breast cancer. Cancer Invest 2000; 18:521–9. 273. Balducci L, Yates J. General guidelines for the management of older patients with cancer. Oncology 2000; 14:221–7. 274. Balducci L, Lyman GH, Ozer H. Patients aged ≥70 are at high risk for neutropenic infections and should receive hemopoietic growth factors when treated with moderately toxic chemotherapy. J Clin Oncol 2001; 19:1583–5. 275. Henderson IC, Berry D, Demetri G et al. Improved disease free survival (DFS) and overall survival (OS) from the addition of sequential paclitaxel but not from the escalation of doxorubicin dose level in the adjuvant chemotherapy of patients with node positive primary breast cancer. Proc Am Soc Clin Oncol 1998; 17: 101a (Abst 390a). 276. Fisher B, Anderson S, Wickerham DL et al. Increased intensification and total dose of cyclophosphamide in a doxorubicincyclophosphamide regimen for the treatment of primary breast cancer: findings from the National Surgical Adjuvant Breast and Bowel Project B22. J Clin Oncol 1997; 15:1858–69. 277. Levine MN, Bramwell VH, Pritchard KI et al. Randomized trial of intensive cyclophosphamide, epirubicin and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate and fluorouracil in premenopausal women with node-positive breast cancer. J Clin Oncol 1998; 16:2651–8. 278. Fisher B, Brown AM, Dimitrov NV et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with six months of a combination of cyclophosphamide, methotrexate and fluorouracil in positive-lymph node breast cancer patients with tamoxifen non-responsive tumors: a report from the National Surgical Adjuvant Breast and Bowel Project. J Clin Oncol 1990; 8:1493–6. 279. Diel IJ, Solomayer E-F, Costa SD et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 1998; 339:357–63. 280. Saarto T, Blomqvist C, Virkunen P et al. Adjuvant clodronate treatment does not reduce the frequency of metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial. J Clin Oncol 2001; 19:10–17. 281. Mardiak J, Bohunicky L, Chovanec J et al. Adjuvant clodronate therapy in patients with locally advanced breast cancer. Long term results of a double blind randomized trial. Slovak Oncology Cooperative Group. Neoplasma 2000; 47:177–80. 282. Cova D, Balducci L. Cancer chemotherapy in the older patient. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman HG, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:463–88. 283. Torti FM, Bristow MM, Lunn BL. Cardiotoxicity of epirubicin and doxorubicin: assessment by endomyocardial biopsy. Cancer Res 1986; 46:3722–7. 284. Fonseca GA, Valero V, Buzdar A et al. Decreased cardiac toxicity by TLC D-99 (liposomal doxorubicin) in the treatment of metastatic breast carcinoma. Proc Am Soc Clin Oncol 1995; 14:99. 285. Speyer JL, Green MD, Zeleniuch-Jacquotte A et al. ICRF-187 permits longer treatment with doxorubicin in women with breast cancer. J Clin Oncol 1992; 10:117–27. 286. Kanno M, Nakamura S, Uotani C et al. Prognosis of node-positive breast cancer patients who underwent parasternal lymph node biopsy during surgery followed by doxorubicin- or mitoxantrone-containing adjuvant chemotherapy. J Chemother 2000; 12:435–41.

Breast cancer in the older woman: An oncologic perspective

1241

287. Desch CE, Hillner BE, Smith TJ et al. Should elderly receive chemotherapy for node-negative breast cancer? A cost-effectiveness analysis examining total and active life-expectancy outcome. J Clin Oncol 1993; 11:777–82. 288. Extermann M, Balducci L, Lyman GH. What threshold for adjuvant therapy in older breast cancer patients? J Clin Oncol 2000; 18:1709–17. 289. Powles TJ, Hickish TF, Makris A et al. Randomized trial of chemoendocrine surgery started before or after surgery for treatment of primary breast cancer. J Clin Oncol 1995; 13:547–52. 290. Fisher B, Rockette H, Robidoux A. Effect of preoperative therapy for breast cancer on localregional disease: first report of NSABP B-18. Proc Am Soc Clin Onol 1994; 13:64. 291. Scholl SM, Fourquet A, Asselain B et al. Neoadjuvant vs adjuvant chemotherapy in premenopausal patients with tumors considered too large for breast-conserving surgery. Preliminary results of a randomised trial. Eur J Cancer 1994; 30A: 645–52. 292. Fisher B, Mamounas EP. Preoperative chemotherapy: a model for studying the biology and therapy of primary breast cancer. J Clin Oncol 1995; 13:537–40. 293. Hortobagyi GN. Comprehensive management of locally advanced breast cancer. Cancer 1990; 66:1387–91. 294. Fisher B, Brown A, Mamounas E et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer. Findings from the National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 1997; 15:2483–93. 295. Mourali N, Tabbane F, Muenz LR et al. Ten-year results utilizing chemotherapy as primary treatment in non-metastatic, rapidly progressive breast cancer. Cancer Invest 1993; 11:363–70. 296. Booser DJ, Hortobagyi GN. Treatment of locally advanced breast cancer. Semin Oncol 1992; 19:278–85. 297. Chidel MA, Suh JH, Barnett GH. Brain metastases: presentation, evaluation and management. Clev Clin J Med 2000; 67:120–7. 298. Formaglio F, Caraceni A. Meningeal metastases: clinical aspects and diagnosis. Ital J Neurol Sci 1998; 19:133–49. 299. Brady LV, Shields JA, Augsburger JJ et al. Malignant intraocular tumors. Cancer 1982; 49:578–85. 300. Jardines L, Callans LS, Torosian MH. Recurrent breast cancer: presentation, diagnosis and treatment. Semin Oncol 1993; 20: 538–50. 301. Lipton A, Thierault AL, Hortobagyi GN et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized placebo controlled trials. Cancer 2000; 88:1082–90. 302. Cheer SM, Noble S. Zoledronic acid. Drugs 2001; 61:799–805. 303. Pecherstorfer M, Steinhauer E, Pawsey SD et al. Ibandronic acid is more effective than pamidronate in lowering serum calcium in patients with severe hypercalcemia of malignancies (HCM) and has at least equal efficacy to pamidronate in HCM patients with lower baseline calcium levels. Result of a randomised open label cooperative study. Proc Am Soc Clin Oncol 2001; 20:385a (Abst 1535). 304. Crow JP, Gordon NH, Antunez AR et al. Locoregional breast cancer recurrence following mastectomy. Arch Surg 1991; 126: 429–32. 305. Janjan NA, McNeese MD, Buzdar AU et al. Loco-regional recurrent breast cancer treated with radiation or a combination of radiation and chemotherapy. Int J Rad Biol Phys 1985; 11(Suppl 1): 152–3. 306. Borner M, Bacchi M, Goldhirsch A et al. First isolated locoregional recurrence following mastectomy for breast cancer: results of a phase III multicenter study comparing systemic treatment with observation after excision and radiation. J Clin Oncol 1994; 12: 2071–7. 307. Fossati R, Confalonieri C, Torri V et al. Cytotoxic and hormonal treatment for metastatic breast cancer: a systematic review of published randomized trials involving 31,510 women. J Clin Oncol 1998; 16:3439–60.

Comprehensive Geriatric Oncology

1242

308. Harvey JM, Clark GM, Osborne CK et al. Estrogen receptor status by immunohistochemestry is superior to ligand-binding assay for predicting response to adjuvant endocrine therapy. J Clin Oncol 1999; 17:1474–9. 309. Buzdar AU, Hortobagyi GN, Frye D et al. Bioequivalence of 20 mg once-daily tamoxifen relative to 10 mg twice daily tamoxifen regimens for breast cancer. J Clin Oncol 1994; 12:50–4. 310. Milla-Santos A, Milla L, Rallo L et al. Phase III randomized trial of toremifene vs tamoxifen in hormone dependant advanced breast cancer. Breast Cancer Res Treat 2001; 65:119–24. 311. Pyrhonen S, Valavaara R, Modig H et al. Comparison of toremifene and tamoxifen in postmenopausal women with advanced breast cancer: a randomized double blind Nordic phase III study. Br J Cancer 1997; 76:270–7. 312. Gams R. Phase III trial of toremifene vs tamoxifen. Oncology (Huntingt) 1997; 11:23–8. 313. Lonning PE, Bajetta E, Murray R et al. Activity of exemestane in metastatic breast cancer after failure of non-steroidal aromatase inhibitors: a phase II trial. J Clin Oncol 2000; 18:2234– 44. 314. Bonneterre J, Thurlimann B, Robertson JFR. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability Study. J Clin Oncol 2000; 18:3748–57. 315. Nabholtz A, Buzdar A, Pollak M et al. Anastrozole is superior to tamoxifen as first line therapy for advanced breast cancer in post menopausal women: results of a North American multicenter randomized trial. J Clin Oncol 2000; 18:3758–67. 316. Mouridsen H, Gershanovich M, Sun Y et al. Superior efficacy of letrozole vs tamoxifen as first line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Study Group. J Clin Oncol 2001; 19:2596–606. 317. Glauber JG, Kiang DT. The changing role of hormonal therapy in advanced breast cancer. Semin Oncol 1992; 19:308–16. 318. Cobleigh MA, Vogel CL, Tripathy D et al. Multinational study of the efficacy and safety of humanized anti HER2 monoclonal antibody in women who have HER2 overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999; 17:2639–48. 319. Sedman AD, Fornier MN, Esteva FJ et al. Weeldy trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol 2001; 19:2587–95. 320. Norton L, Slamon D, Leyland-Jones B et al. Overall survival advantage to simultaneous chemotherapy plus the humanized anti HER2 monoclonal antibody Herceptin in HER2overexpressing (HER2+) metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 1999; 18: 127a. 321. Burstein HJ, Kuter I, Campos SM et al. Clinical activity of trastuzumab and vinorelbine in women with HER2 overexpressing breast cancer. J Clin Oncol 2001; 19:2722–30. 322. Anonymous. Trastuzumab and capecitabine for metastatic breast cancer. Med Lett Drugs Ther 1998; 40:106–8. 323. Feldman AM, Lorell BH, Reis SE. Trastuzumab in the treatment of metastatic breast cancer antitumor therapy vs cardiotoxicity. Circulation 2000; 18:102, 272–274. 324. Ellis MJ, Hayes DF, Lipmann ME. Treatment of metastatic breast cancer. In: Diseases of the Breast (Harris JR, Lippman ME, Morrow M, Osborne CK, eds). Philadelphia: Lippincott Williams & Wilkins, 2000:749–97. 325. O’Shaughnessy J, Moiseyenko V, Bell D et al. A randomized phase II study of Xeloda vs CMF as first line chemotherapy of breast cancer in women aged more than 55 years. Proc Am Soc Clin Oncol 1998; 17:398a. 326. O’Reilly S, Moiseyenko V, Talbot D et al. A randomized phase II study of Xeloda (capecitabine) vs. paclitaxel in breast cancer patients failing previous anthracycline therapy. Proc Am Soc Clin Oncol 1998; 17:627a.

Breast cancer in the older woman: An oncologic perspective

1243

327. Crown J. Nonanthracycline containing docetaxel-based combinations in metastatic breast cancer. Oncologist 2001; 6(Suppl 3): 17–21. 328. Stein BN, Petrelli NJ, Douglass HO et al. Age and sex are independent predictors of 5fluorouracil toxicity. Cancer 1995; 75:11–17. 329. Jacobson SD, Cha S, Sargent DJ et al. Tolerability, dose intensity and benefit of 5FU based chemotherapy for advanced colorectal cancer (CRC) in the elderly. A North Central Cancer Treatment Group study. Proc Am Soc Clin Oncol 2001; 20:384a (Abst 1534). 330. Sledge GW, Neuberg D, Ingle J et al. Phase III trial of doxorubicin (A) vs paclitaxel (T) vs doxorubicin+paclitaxel (A+T) as first-line therapy for metastatic breast cancer. Proc Am Soc Clin Oncol 1997; 16:1a. 331. Nabholtz J-M, Falkson G, Campos D et al. A phase III trial comparing doxorubicin and docetaxel (AT) to doxorubicin and cyclophosphamide (AC) as first line therapy for MBC. Proc Am Soc Clin Oncol 1999; 18:127a. 332. Sledge GW, Antman KH. Progress in chemotherapy for metastatic breast cancer. Semin Oncol 1992; 19:317–32. 333. Hayes DF, Henderson IC, Shapiro CL. Treatment of metastatic breast cancer: present and future prospects. Semin Oncol 1995; 22(Suppl 5): 5–21. 334. A’ Hern RP, Smith IE, Ebbs SR. Chemotherapy and survival in advanced breast cancer. The inclusion of doxorubicin in Cooper’s like regimens. Br J Cancer 1993; 67:801–8. 335. Bennett JM, Muss HB, Doroshow JH et al. A randomized multicenter trial comparing mitoxantrone, cyclophosphamide and fluorouracil with doxorubicin, cyclophosphamide, and fluorouracil in the therapy of metastatic breast carcinoma. J Clin Oncol 1988; 6:1611–20. 336. Balducci L, Lyman GH. Effectiveness and cost-effectiveness of hemopoietic growth factors in cancer treatment. Adv Oncol (to be published). 337. Gelman RS, Taylor SG. Cyclophosphamide, methotrexate and fluorouracil chemotherapy in women more than 65 years old with advanced breast cancer: the elimination of age trends in toxicity by using doses based on creatinine clearance. J Clin Oncol 1984; 2: 1406–14. 338. Christman K, Muss HB, Case D et al. Chemotherapy of metastatic breast cancer in the elderly. JAMA 1992; 268:57–62. 339. Ibrahim N, Frye DK, Buzdar AU et al. Doxorubicin based combination chemotherapy in elderly patients with metastatic breast cancer. Tolerance and outcome. Arch Intern Med 1996; 156:882–8. 340. Ibrahim NK, Buzdar AU, Asmar 1 et al. Doxorubicin based adjuvant chemotherapy in elderly breast cancer patients: the MD Anderson experience with long term follow-up. Ann Oncol 2000; 11:1–5. 341. Muss HB, Smith LR, Cooper MR. Tamoxifen rechallenge: response to tamoxifen following relapse after adjuvant chemohormonal therapy for breast cancer. J Clin Oncol 1987; 5:1556–8. 342. Fournander T, Rutqvist LE, Glas U. Response to tamoxifen and fluoxymesterone in a group of breast cancer patients with disease recurrence after cessation of adjuvant tamoxifen. Cancer Treat Rep 1987; 71:685–8. 343. Kiang DT, Gay J, Goldman A et al. A randomized trial of chemotherapy and hormonal therapy in advanced breast cancer. N Engl J Med 1985; 313:1241–6.

52 Breast cancer: A geriatric perspective Sarah B Blackman, Rebecca A Silliman, Lodovico Balducci Introduction Breast cancer is a disease primarily of older women, with its incidence reaching a maximum in the ninth decade of life.1 It is also a serious disease in older women. For example, 5-year breast cancer-specific survival rates are similar for women younger than 35 and those 85 and older with local and regional disease, and are worse than for women between these ages.1 Furthermore, although the approximate 10-year risk of recurrence for women 70 years and older of age who are node-negative with 1–5 cm tumors is 20– 30%, the risk for women with one to three positive nodes and tumors of any size is 50%, and the risk for women with four or more positive nodes and tumors of any size is 80%.2 These risks have become increasingly important because recent gains in life-expectancy have occurred at the end of life. The average life-expectancy of a 70-year-old woman is 15.7 years (21.3 years for a healthy woman), that of an 80-year-old woman is 8.6 years (13 years for a healthy woman), and that of a 90-year-old woman is 3.9 years (6.8 years for a healthy woman).3 Recurrences have important negative consequences for this group of patients, who are often frail; recurrences complicate medical and personal care, and are difficult for patients, their families, and their physicians to manage. Furthermore, because of gender disparities in life-expectancy, older women are frequently single and have diminished family support.4 Breast cancer screening in older women Many guidelines for breast cancer screening have been promulgated. However, the applicability of these to older women has been questioned because women aged 70 or older have not been enrolled in clinical trials of mammography. As a result, the beneficial and harmful effects of screening older women are not well established. The potential survival benefit of screening is highest in the healthiest older women, and in women who have been routinely screened in the past.3 In contrast, older women expected to live less than 5 years are not likely to benefit from screening.3 In a cohort of frail women, screening mammography resulted in diagnostic evaluations that did not benefit the women, and in some cases the screening tests ultimately resulted in emotional or physical distress.5 Because life-expectancy varies widely among older women of the same age, the decision to screen should incorporate factors that reflect the woman’s potential for benefit: risk of dying of the screen-detected cancer, future life-expectancy, comorbidity, emotional health, physical functioning, and values and preferences.3,5 Quality of care

Breast cancer: A geriatric perspective

1245

judgments in older female populations are often based solely on the number of screening mammograms performed. A more rational approach would be to place more emphasis on promoting screening among those most likely to benefit.5 Eairly-stage disease: management of the primary tumor In 1995, the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) reported the results of a meta-analysis of 18 clinical trials comparing mastectomy versus breastconserving surgery plus postoperative radiation therapy (breast-conserving treatment).6 After 10 years, there was no statistically significant difference in overall survival between the two courses of treatment. From 1995 to 2001, the results of new randomized trials and re-analyses of previous trials confirmed these findings.7–9 Because of salutary effects on body image and quality of life, breast-conserving treatment is the preferred treatment of the two. Total mastectomy should be reserved for those whose cancer is multicentric or in whom cosmetic results are likely to be unacceptable.10 Although breast-conserving treatment is recommended for the majority of women regardless of age and should be offered as a treatment option, several considerations are likely to influence older women’s decisions. First, for many, a mastectomy will seem to be a more definitive procedure, particularly when the risk of disease recurrence within the breast is considered to be an important outcome. Second, by choosing mastectomy, the need for postoperative radiation therapy is generally eliminated. The exception is among women who are at high risk for local recurrence.11 Third, body image considerations are less important to certain subsets of older women. Fourth, and perhaps most importantly, physicians’ recommendations have a powerful influence on older women’s decisions. Our own data indicate that their physicians’ recommendations and minimizing the risk of recurrence are the two most important factors influencing older women’s treatment decisions.12 The challenge for physicians trying to use an evidence-based approach to caring for older women with breast cancer is that there are few scientific data on which to base therapeutic recommendations, since these women have generally been excluded from clinical trials addressing treatment efficacy. As a result, there are two important unresolved controversies involving primary tumor management in older women: (i) the need for postoperative radiation therapy following breast-conserving surgery in older women; (ii) the need for axillary dissection in older women, regardless of the surgical management of the breast. Clinical trials have demonstrated that postoperative radiation therapy reduces local recurrence rates by as much as 20%, regardless of stage,8,13,14 but they have failed to identify any subgroup of women at very low risk of recurrence.13,14 A meta-analysis of the effect of radiation therapy on long-term survival demonstrated a survival benefit beyond 2 years of follow-up, regardless of age, stage, radiation dose, or systemic therapy, although only 575 of 20000 studied were older than 70.14 Another analysis has suggested that among older women (up to age 84) with local disease, radiation therapy may confer a survival benefit, although comorbidity was not well controlled in the analysis.15 The lack of definitive data does not lead us to recommend that breast-conserving surgery not be followed by postoperative radiation therapy. Moreover, current guidelines recommend

Comprehensive Geriatric Oncology

1246

this course of treatment, regardless of age.16 Although the side-effects of radiation are probably no different in older women than in younger women, their impact may be greater for several reasons. First, a 6-week schedule of daily radiation treatment may be difficult because of the need to rely on others for transportation, because of the physical fatigue associated with the treatment itself, and because of travel and waiting times. Second, positioning may be uncomfortable for women with arthritis or those who have had vertebral fractures. Third, underlying cardiopulmonary comorbidities may be exacerbated by radiation treatment and these effects may be manifested several years following treatment. Axillary dissection has been advocated as a therapeutic intervention that both eliminates residual disease and stages patients. The goal of eliminating residual tumor has not been well studied in older women, although observational studies suggest that among women aged 65 and older, those who do not have an axillary dissection have poorer survival compared with those who have the procedure.17 Data from the National Cancer Data Base confirm that rates of axillary dissection continue to decrease with age, with women aged 80 or older being nearly six times less likely to receive axillary dissection than those aged 55 or younger. In addition, the 10-year survival rate is substantially worse when axillary dissection is omitted.18 Axillary dissection is indicated when the decision to prescribe adjuvant therapy is dependent upon pathologically proven involvement of axillary lymph nodes, but may be unnecessary among women who are prescribed and take tamoxifen. Both axillary dissection and clinical evaluation of the axillary nodes present potential harm or burdens that must be considered. There is substantial morbidity associated with axillary dissection,19 but the clinical evaluation of the axillary nodes has a false-negative rate that ranges as high as 35%.20 An emerging alternative to axillary dissection is lymphatic mapping and sentinel node biopsy.16,21,22 The results are promising, although the technique may be less useful in older women because the success rate in them, compared with younger women, is lower. This may be particularly true in low-volume centers, where older women frequently receive their care. Decision-making with respect to choosing mastectomy versus breast-conserving surgery, with or without radiation, and with or without axillary dissection, must take into account body image and upper body function, the logistical difficulties associated with radiation therapy, the emotional impact of disease recurrence, and the ability to tolerate mastectomy at some point in the future should there be an in-breast recurrence.23 Regardless of the type of surgical procedure chosen, careful attention should be paid to preserving upper body, shoulder, and arm function. Ideally, women should receive exercise instructions prior to surgery, as has become the standard approach for patients undergoing elective hip and knee replacement. An exercise program and the judicious use of analgesics in the early postoperative period will help women regain upper body function as quickly as possible. This is particularly important if an axillary lymph node dissection has been performed. Primary medical, rather than surgical, treatment is an additional consideration in the initial management of early-stage breast cancer. Although studies comparing the outcomes of women initially treated with tamoxifen with those surgically treated have found that mortality rates are comparable, patients treated with tamoxifen alone have experienced more local progression than those treated surgically.24–26 These findings

Breast cancer: A geriatric perspective

1247

suggest that tamoxifen should only be considered as a primary treatment option when women are too frail or refuse to undergo surgery. Early-stage disease: adjuvant treatment Tamoxifen Adjuvant tamoxifen decreases rates of recurrence and mortality in older women with early-stage breast cancer. The worldwide meta-analysis of randomized trials of adjuvant tamoxifen versus no tamoxifen demonstrated the importance of estrogen receptor (ER) protein status in predicting treatment effectiveness.27 Women with ER-negative tumors do not benefit from tamoxifen, while women with ER-positive tumors so treated experience significant reductions in recurrence and all-cause mortality. National and international guidelines for the treatment of early-stage breast cancer now recommend adjuvant tamoxifen for all women with ER-positive tumors without regard for age.11,16 Since the majority of older women have ER-positive tumors, older women with an unknown ER status should be treated as if they were ER-positive. The greatest benefits, with respect to both recurrence and mortality, have been achieved in women treated with tamoxifen for 5 years. The benefit of treatment beyond 5 years is not yet established. A recent randomized trial suggests that the beneficial effect of 5 years of treatment persists up to 15 years of follow-up.28 The magnitude of the risk reductions reported in the meta-analysis was similar across the three postmenopausal age groups (50–59, 60–69, and 70 and older), and was greatest among those treated for 5 years.27 Five years of tamoxifen also reduced the annual incidence of contralateral breast cancer by half.27 There may also be non-breast cancer benefits of tamoxifen therapy for postmenopausal women. Tamoxifen may reduce the risk of osteoporotic fractures of the hip, spine, or lower radius.29,30 The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 prevention trial has reported a 19% reduction in the incidence of fractures among women who received tamoxifen treatment versus those who did not.30 Long-term treatment may also lower total serum cholesterol and low-density lipoprotein-cholesterol levels31 and reduce the risk of hospitalization for cardiovascular disease or for fatal myocardial infarction.32,33 The NSABP P-1 trial did not observe significant differences in ischemic heart disease events between the tamoxifen and placebo groups, but this may be because participants in the trial were relatively young.30 Although the benefits of tamoxifen are clear, its use increases the risk of rare, but serious, illnesses. Deep vein thrombosis can complicate the use of tamoxifen, and this risk appears to be greater in women aged 65 and older.34,35 Also, concurrent treatment with tamoxifen and chemotherapy has been associated with an increased risk of thromboembolism when compared with either treatment alone.35,36 Studies from Europe and the USA are relatively consistent in demonstrating an increase in the risk of endometrial cancer.35,37,38 About 75% of endometrial cancers occur in women aged 60 and older, and this already elevated base rate appears to be increased by the addition of tamoxifen treatment. Whether this increase is because tamoxifen actually causes endometrial cancer, or because it unmasks silent disease, is not known.39 Because of this

Comprehensive Geriatric Oncology

1248

increased risk, the American College of Obstetrics and Gynecology Committee on Gynecologic Practice recommends annual pelvic examinations for patients receiving tamoxifen.40 Endometrial cancers associated with tamoxifen therapy can be diagnosed at an early stage and cured.35,38 Cost-benefit analyses of more extensive routine screening, such as transvaginal ultrasonography or endometrial biopsy, have not shown this to be cost-effective.41 In summary, the benefits of adjuvant treatment with tamoxifen have been proven in older women and outweigh its risks.35,42 Until more sensitive indicators of recurrence risk are identified, treatment of most older women with early-stage disease and ER-positive tumors with adjuvant tamoxifen should be recommended. Five years of therapy is the most effective treatment duration, with respect to both risk of recurrence and all-cause mortality.27 Tamoxifen may also reduce a woman’s risk of developing osteoporosis and coronary heart disease. Menopausal symptoms, either caused by or exacerbated by tamoxifen, may limit its use, particularly in the young old. Hot flashes and other vasomotor symptoms such as night sweats are the most common and bothersome side-effects.31,41 Although transdermal clonidine or oral progesterone derivatives are side-effect treatment options, their own side-effects may be equally problematic for older women. This therapeutic dilemma raises the question of whether hormone replacement therapy (HRT) might be a reasonable alternative for the management of menopausal symptoms in these patients, some of whom may have been receiving such treatment prior to the diagnosis of their cancer. HRT reduces the vasomotor symptoms of menopause and the risk of osteoporotic fractures, but also increases the risk of endometrial cancer and deep venous thromboembolism.43 The results of two recent trials suggest that HRT does not decrease the risk of cerebrovascular or cardiovascular events in postmenopausal women with a history of these conditions.44,45 It is unclear whether HRT reduces the risk of cardiovascular disease in women who are disease-free.43 A worldwide meta-analysis has examined the relationship between HRT and the risk of breast cancer in postmenopausal women. The relative risk of breast cancer diagnosis was 1.35 (95% confidence interval 1.21–1.49) for women who received 5 years of HRT compared with no therapy, although only 2% of the women who used HRT were aged 75 or older.46 The effects of HRT on the risk of breast cancer in very old women, and its effects in women treated with adjuvant tamoxifen, are unclear. Chemotherapy Adjuvant chemotherapy alone or in conjunction with tamoxifen has not been well studied in women aged over 70. The meta-analysis of studies worldwide included only 609 women in this age group who were entered into trials testing the efficacy of adjuvant chemotherapy, and these women were not included in the age-specific analyses.47 The overall benefit of chemotherapy in women aged 60–69 (n=6807) included an 18% reduction in the risk of recurrence and an 8% reduction in all-cause mortality, regardless of nodal status or tamoxifen treatment status.47 Whether chemotherapy is efficacious, particularly in high-risk subsets of women of more advanced age, is not known. What is known is that older women who are otherwise generally healthy are able to tolerate

Breast cancer: A geriatric perspective

1249

combination chemotherapy.48,49 Clinical trials of combination chemotherapy that are specifically designed for women aged 70 and older are very much needed. Metastatic disease Survival rates in older women diagnosed with metastatic disease decrease with age. An analysis of data from the US National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program indicates that the 1-year survival rate for women aged 65– 74 is about 42%. This rate declines to 36% in those aged 75–84, and to 29% in those aged 85 and older.50 The 5-year survival rates across all age groups are very low, ranging from 5% to 13%. These figures provide a compelling argument for continued efforts to improve access and use of screening mammography when appropriate, and for the inclusion of elderly women in clinical trials of primary and adjuvant treatment effectiveness. Although endocrine treatment in older women has only a modest effect on survival, symptom palliation is usually possible.51,52 Because it is well tolerated in general, tamoxifen is the preferred first line of treatment. An analysis of four clinical trials of women with metastatic breast cancer treated with tamoxifen found that almost half of women older than 65 responded to therapy, compared with about one-third of women aged 65 or younger.53 The highest response rates are observed in those women with ERpositive tumors, those who have had a long disease-free interval, and those who have soft tissue or bony metastases. If bony metastases are present, calcium levels should be monitored initially, since transient hypercalcemia can occur. Other endocrine agents, such as megestrol acetate, aromatase inhibitors (e.g. aminoglutethimide), or stilbestrol, may be useful when patients relapse, although the side-effects of these agents, especially nausea, weight gain, fluid retention, and fatigue, may be troublesome. The use of chemotherapy in older women with metastatic disease has not been widely studied. Of the chemotheraputic agents, taxanes are used most frequently in patients with metastases. A recent study of weekly docetaxel treatment in elderly women with advanced breast cancer showed that patients tolerated this treatment regimen well.54 Reports indicate there are probably no important age-related differences in response rates, time to progression, survival, or toxic side-effects.48,49 Until more definitive studies have been performed, older women whose disease has become refractory to endocrine treatments should be considered for treatment with combination chemotherapy. Although complete responses are rare, partial responses that last 6–12 months can be expected in about 40% of such patients.2 As with all patients with life-threatening disease, treatment decision-making in women with metastatic disease must take account of risks and benefits and patient preferences. End-of-life care, including advance directives, hospice care, and preferences for site of death, should be discussed with patients and their families, ideally earlier rather than later. However, patients and families need to understand that the therapeutic plan can be flexible as patients’ needs change.

Comprehensive Geriatric Oncology

1250

Care of breast cancer survivors As more women with treated breast cancer survive into old age, new questions arise for clinicians caring for them. One question that has received considerable attention in recent years concerns the kind and duration of follow-up care that breast cancer survivors should receive. Post-therapy surveillance is important for detecting local recurrence or new contralateral primary tumors, identifying side-effects of treatment and their consequences, and providing reassurance and counseling to patients.55 Breast cancer surveillance guidelines were published in 1998 and 1999.56,57 These guidelines recommend annual physical examinations and mammograms for breast cancer survivors. We have found that the risk of cancer-related emotional distress and all-cause mortality are reduced by half among women who receive guideline surveillance compared with women who receive less-than-guideline surveillance (T Lash, personal communication). Other questions are especially germane to older women, and should be addressed by carefully conducted follow-up studies of older long-term survivors. These include, but are not limited to: (i) How long should surveillance mammography be continued? (ii) What are the long-term musculoskeletal complications of mastectomy and axillary dissection? (iii) What are the long-term pulmonary complications of postoperative radiation therapy? (iv) What are the long-term psychosocial issues that influence older women’s quality of life? Summary and conclusions Breast cancer is the second most prevalent cancer in the world, following lung cancer, and the most common malignant disease in women.58 It is also becoming an increasingly important disease in older women. Although the knowledge base on which to develop therapeutic recommendations is incomplete, most older women with early-stage disease should be given the same options as younger postmenopausal women. American Cancer Society statistics for 2001 indicate that while 13% (n= 25000) of incident breast cancer cases occurred in women aged 80 or older, this age group accounted for 27.2% (n =10900) of all breast cancer deaths.59 Clearly, the oldest old are disproportionately more likely to die of breast cancer than any other age group. This is of concern, because age alone has not been shown to modify treatment effectiveness.60 The risk of dying of breast cancer, as well as patient preferences, comorbidity, functional status, life-expectancy, and family support, are all important considerations when developing a treatment plan. In addition, older women should be encouraged to participate in clinical trials and outcome studies specifically designed to expand the scientific knowledge on which to base recommendations for their care.

Breast cancer: A geriatric perspective

1251

References 1. Yancik R, Ries LB, Yates JW. Breast cancer in aging women: a population-based study of contrasts in stage, surgery, and survival. Cancer 1989; 63:164–9. 2. Muss HB. The role of chemotherapy and adjuvant therapy in the management of breast cancer in older women. Cancer 1994; 74: 2165–71. 3. Walter L, Covinsky K. Cancer screening in elderly patients: a frame-work for individualized decision making. JAMA 2001; 285:2750–6. 4. Gilford DM (ed). The Aging Population in the Twenty-First Century. Washington, DC: National Academy Press, 1988. 5. Walter L, Eng C, Covinsky K. Screening mammography for frail older women. What are the burdens? J Gen Intern Med 2001; 16: 779–84. 6. Early Breast Cancer Trialists’ Collaborative Group. Effects of radiotherapy and surgery in early breast cancer—An overview of the randomized trials. N Engl J Med 1995; 333:1444–55. 7. Jacobson JA, Danforth DN, Cowan KH et al. Ten-year results of a comparison of conservation with mastectomy in the treatment of stage I and II breast cancer. N Engl J Med 1995; 332:907– 11. 8. Fisher B, Anderson S, Redmond CK et al. Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1995; 333:1456–61. 9. van Dongen JA, Voogd AC, Fentiman IS et al. Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial. J Natl Cancer Inst 2000; 92:1143–50. 10. NIH Consensus Conference. Treatment of early stage breast cancer. JAMA 1991; 265:391–5. 11. NIH Consensus Development Conference Statement: adjuvant therapy for breast cancer. J Natl Cancer Inst 2001; 93:979–89. 12. Silliman RA, Troyan SL, Guadagnoli E et al. The impact of age, marital status, and physicianpatient interactions on the care of older women with breast carcinoma. Cancer 1997; 80:1326– 34. 13. Clark RM, Whelan T, Levine M et al. Randomized clinical trial of breast irradiation following lumpectomy and axillary dissection for node-negative breast cancer: an update. J Natl Cancer Inst 1996; 88: 1659–64. 14. Early Breast Cancer Trialists’ Collaborative Group. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomized trials. Lancet 2000; 355: 1757–70. 15. Joslyn SA. Radiation therapy and patient age in the survival from early-stage breast cancer. Int J Radiat Oncol Biol Phys 1999; 44: 821–26. 16. Goldhirsch A, Glick JH, Gelber RD et al. Meeting Highlights: International Consensus Panel on the Treatment of Primary Breast Cancer. J Clin Oncol 2001; 19:3817–27. 17. Allen C, Cox ED, Manton KG, Cohen HJ. Breast cancer in the elderly: current patterns of care. J Am Geriatr Soc 1986; 34:637–42. 18. Bland KI, Scott-Conner CEH, Menck H, Winchester DP. Axillary dissection in breastconserving surgery for stage I and II breast cancer: a National Cancer Data Base study of patterns of omission and implications for survival. J Am Coll Surg 1999; 188:586–96. 19. Maunsell E, Brisson J, Deschenes L. Arm problems and psychological distress after surgery for breast cancer. Can J Surg 1993; 36: 315–20. 20. Recht A, Houlihan MJ. Axillary lymph nodes and breast cancer: a review. Cancer 1995; 76:1491–512.

Comprehensive Geriatric Oncology

1252

21. Borgstein PJ, Pijpers R, Comans EF et al. Sentinel lymph node biopsy in breast cancer. Guidelines and pitfalls of lymphoscintography and gamma probe detection. J Am Coll Surg 1998; 186:275–83. 22. Krag D, Weaver D, Ashikaga T et al. The sentinel node in breast cancer: a multicenter validation study. N Engl J Med 1998; 339: 941–6. 23. Lichter AS. Conservative treatment of primary breast cancer: How much is required? J Natl Cancer Inst 1992; 84:659–60. 24. Robertson IF, Ellis IO, Elston CW, Blamey RW. Mastectomy or tamoxifen as initial therapy for operable breast cancer in elderly patients: 5-year follow-up. Eur J Cancer 1992; 28A: 908–10. 25. Gazet JC, Markopoulos C, Ford HT et al. Prospective randomized trial of tamoxifen versus surgery in elderly patients with breast cancer. Lancet 1988; i: 679–81. 26. Bates T, Riley DL, Houghton J et al. Breast cancer in elderly women: a Cancer Research Campaign trial comparing treatment with tamoxifen and optimal surgery with tamoxifen alone. The Elderly Breast Cancer Working Party. Br J Surg 1991; 78:591–4. 27. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet 1998; 351:1451–67. 28. Stewart HJ, Prescott RJ, Forrest PM. Scottish Adjuvant Tamoxifen Trial: a randomized study updated to 15 years. J Natl Cancer Inst 2001; 93:456–62. 29. Love RR, Mazess RB, Barden HS et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 1992; 326:852–6. 30. Fisher B, Constantino JP, Wickerham DL et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 1998; 90: 1371–88. 31. Benshushan A, Brzezinski A. Tamoxifen effects on menopause-associated risk factors and symptoms. Obstet Gynecol Surv 1999; 54: 272–8. 32. McDonald CC, Stewart HJ. Fatal myocardial infarction in the Scottish Adjuvant Tamoxifen Trial. BMJ 1991; 303:435–7. 33. Rutqvist LE, Mattsson A. Cardiac and thromboembolic morbidity among postmenopausal women with early-stage breast cancer in a randomized trial of adjuvant tamoxifen. J Natl Cancer Inst 1993; 85: 1398–406. 34. Fisher B, Brown A, Wolmark N et al. Prolonging tamoxifen therapy for primary breast cancer. Ann Intern Med 1987; 106:649–54. 35. Shapiro CL, Recht A. Side effects of adjuvant treatment of breast cancer. N Engl J Med 2001; 344:1997–2008. 36. Pritchard KI, Paterson AH, Paul NA et al. Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. National Cancer Institute of Canada Clinical Trials Group Breast Cancer Site Group. J Clin Oncol 1996; 14:2731–7. 37. Fornander T, Cedermark B, Mattson A et al. Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1989; i: 117–20. 38. Fisher B, Costantino JP, Redmond CK et al. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 1994; 86:527–37. 39. Fritsch M, Wolf DM. Symptomatic side effects of tamoxifen therapy. In: Long-Term Tamoxifen Treatment for Breast Cancer (Jordan VC, ed). Madison: University of Wisconsin Press, 1994:235–55. 40. American College of Obstetrics and Gynecology Committee on Gynecologic Practice. Tamoxifen and endometrial cancer. Committee Opin 1996; 169:231–3. 41. Eltabbakh GH, Mount SL. Tamoxifen and the female reproductive tract. Expert Opin Pharmacother 2001; 2:1399–413. 42. Ragaz J, Goldman A. Age-matched survival impact (SI) of adjuvant tamoxifen in long term breast cancer survivors (LTBCS) taking into analysis contralateral breast cancer (CBC),

Breast cancer: A geriatric perspective

1253

cardiovascular events (CVS), uterine cancer (UC) and pulmonary emboli (PE). Proc Am Soc Clin Oncol 1995; 14:112. 43. Manson JE, Martin KA. Postmenopausal hormone-replacement therapy. N Engl J Med 2001; 345:34–40. 44. Viscoli CM, Brass LM, Kernan WN et al. A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 2001; 345: 1243–9. 45. Hulley S, Grady D, Bush T et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280:605–12. 46. Collaborative Group on Hormonal factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 411 women without breast cancer. Lancet 1997; 350: 1047– 59. 47. Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998; 352:930–42. 48. Gelman RS, Taylor SG. Cyclophosphamide, methotrexate and 5-fluorouracil chemotherapy in women more than 65 years old with advanced breast cancer: the elimination of age trends in toxicity by using doses based on creatinine clearance. J Clin Oncol 1984; 2:1404–13. 49. Christman K, Muss HB, Case LD et al. Chemotherapy of metastatic breast cancer in the elderly. The Piedmont Oncology Association experience. JAMA 1992; 268:57–62. 50. SEER*Stat Software, version 2.0. (SEER Cancer Incidence Public-Use Database, 1973–1996, August 1998 Submission.) National Cancer Institute, 1999. 51. Pritchard RI, Sutherland DJA. The use of endocrine therapy. Hematol Oncol Clin North Am 1989; 3:765–806. 52. Ziegler LD, Buzdar AU. Recent advances in the treatment of breast cancer. Am J Med Sci 1991; 301:337–49. 53. Dhodapkar MV, Ingle JN, Cha SS et al. Prognostic factors in elderly women with metastatic breast cancer treated with tamoxifen. Cancer 1996; 77:683–90. 54. Hainsworth JD, Burris HA, Yardley DA et al. Weekly docetaxel in the treatment of elderly patients with advanced breast cancer: a Minnie Pearl Cancer Research Network phase II trial. J Clin Oncol 2001; 19:3500–35. 55. Lash TL, Silliman RA. Medical surveillance after breast cancer diagnosis. Med Care 2001; 39:945–55. 56. Smith TJ, David NE, Schapira DV et al. American Society of Clinical Oncology 1998 Update of Recommended Breast Cancer Surveillance Guidelines. J Clin Oncol 1999; 47:1080–2. 57. Murphy KC, Coppin CML, Kader HEHA et al. Follow-up after treatment for breast cancer. Can Med Assoc J 1998; 158(Suppl 3): S65–70. 58. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001; 2:533–43. 59. Breast Cancer Facts and Figures 2001–2002. Atlanta: American Cancer Society, 2001. http:\\www.cancer.org/downloads/STT/BrCaFF2001.pdf 60. Silliman RA, Balducci L, Goodwin IS et al. Breast cancer care in old age: What we know, don’t know, and do. J Natl Cancer Inst 1993; 85:190–9.

53 Colorectal cancer Barbara A Neilan Epidemiology and etiology Incidence Colorectal cancer (CRC) is a disease of epidemic proportions. It is the third most commonly diagnosed malignancy and the second leading cause of cancer death in the USA. There are approximately 135000 new cases of CRC and 56000 deaths per year.1 CRC is of special interest to geriatricians, since it occurs primarily in older persons. More than 90% of cases of CRC occur in people aged over 50, and about 75% in people older than 65. Moreover, in women and men over 75, this carcinoma represents the first and the third site for cancer mortality, respectively.2 With respect to sex, CRC occurs slightly more often in women than in men.1 Risk factors Several definite and possible risk factors have been identified for CRC (Table 53.1). Age is a leading risk factor for CRC. Risk begins at 40 years of age, but it increases sharply at 50 years of age, doubling each decade until age 80.3 There is considerable evidence that most colorectal cancers develop from adenomas. The chance of an adenoma becoming malignant depends on its size and histology. About 5% of adenomas that reach 5 mm will

Table 53.1 Risk factors for colorectal cancer • Age:

>40 years old

• Adenomas:

villous > tubular

• Previous colon cancer:

metachronous > synchronous

• Inflammatory bowel ulcerative > granulomatous disease: • Hereditary:

familial adenomatous polyposis (FAP, familial polyposis coli), Gardner syndrome, and hereditary non-polyposis colorectal cancer (HNPCC)

become malignant.4 On average, a 1cm adenoma will become an invasive cancer within 7 years (range 0–14 years).4 Patients who have had polyps of 1cm or greater in size

Colorectal cancer

1255

removed are at increased risk for cancer in other areas of the bowel.5 Villous adenomas have a higher frequency of developing invasive carcinoma than tubular adenomas. In addition to histology and size, it appears that the greater the number of polyps, the higher the risk of cancer.5 Another major risk factor is a history of CRC. Persons with colon cancer are at increased risk for having a second colon cancer either at initial presentation (synchronous) or at a later date (metachronous). Synchronous lesions occur with a frequency of 1.5–2.5%.6 The frequency of metachronous lesions is even higher, at 5– 10%.3 Inflammatory bowel disease is associated with an increased risk of colorectal carcinoma. In ulcerative colitis, the risk increases with duration of the disease and extent of bowel involvement. Patients with granulomatous colitis are also at increased risk, although this risk is less than with ulcerative colitis. There are also hereditary conditions associated with colorectal cancer. The role of inheritance is evident in two syndromes: familial adenomatous polyposis (FAP, familial polyposis coli) and hereditary non-polyposis colorectal cancer (HNPCC). FAP is characterized by hundreds of adenomas. Prophylactic colectomy is recommended for such patients, since a small number of these adenomas progress to carcinoma in the fourth decade. HNPCC consists of the Lynch I syndrome (which only includes inherited colorectal cancer) and the Lynch II syndrome (which includes other tumors, such as pancreatic, gastric, endometrial, and ovarian). A family history of one or two close relatives with cancer increases the risk of CRC. The risk of CRC is increased twofold in people who have a first-degree relative with either an adenomatous polyp or CRC. Etiology The cause of CRC is not known; however, it has been suggested that genetic, environmental, and diet-related factors may all play a role. The hereditary nature of CRC has suggested a genetic basis for this disease. The identification of specific genetic mutations in hereditary CRC syndromes gives further support to this. Epidemiologic studies suggest that environmental factors, especially diet, are causative. The incidence of colon cancer is lower in African countries than in Western nations. When Africans migrate to developed countries, the incidence of CRC rises, which may be related to dietary change. The diets of African populations contain more fiber and less refined carbohydrates and fats. High-fiber diets may be protective by causing a faster intestinal transit time, resulting in less exposure to potential carcinogens. In addition, it has been suggested that the high fat content of Western diets may change the activity of intestinal microflora and the concentration of bile acids, leading to production of tumor-promoting substances in the colon. A variety of lifestyles may be associated with development of CRC. Beer consumption has been labeled a risk factor.3,7 Substantial consumption of alcohol (>2 drinks daily), when combined with inadequate intakes of folate and methionine, may increase the risk of colon cancer.8 Physical inactivity may predispose to colon cancer.9,10 In addition, abdominal adiposity has been associated with an increased risk of CRC.10 Cigarette smoking may be responsible for a significant percentage of CRC cases.11 CRC death rates were found to be lowest among people who had never smoked, intermediate among ex-

Comprehensive Geriatric Oncology

1256

smokers, and highest among current smokers. The risks of dying of CRC increased with the number of cigarettes smoked daily and the number of years of smoking. The risk of CRC increased when a person had smoked for 20 years, but decreased with each year after quitting smoking. Prevention Studies suggest that the risk of CRC can be reduced by various dietary measures. Risk can be reduced by a low intake of animal-derived fat and high intakes of vegetables and fiber. The World Health Organization (WHO) Collaborating Center for the Prevention of Colorectal Cancer at the Memorial Sloan-Kettering Cancer Center, in conjunction with an International Advisory Committee, has published guidelines for primary prevention of colorectal cancer (Table 53.2).12 Dietary factors may account for the different mortality rates from colon cancer in Florida and in the northeast-ern USA.13 The mortality rate of people who lived in the northeast but retired to Florida is lower than the mortality rate of the population still living in the northeast. This decrease in mortality may be due to a change in lifestyle in Florida—possibly diet. Since the decrease happens in a relatively short time, dietary change may be able to lower the incidence of CRC, even in elderly individuals such as reside in Florida.

Table 53.2 WHO guidelines for the prevention of colorectal cancer 1. Fat consumption should be low, not exceeding 20% of total calories. Both animal and vegetable fat should be reduced to achieve this goal 2. A balanced diet should be consumed. It should include at least 5–8 servings daily of fruits and vegetables, legumes, and wholegrain cereals and breads in order to provide adequate fiber, vitamins, and other components with potential anticarcinogenic effects 3. Dietary fiber from all sources should be at least 25g/day 4. Consumption of excess calories and being overweight should be avoided 5. Tobacco use should be avoided 6. Physical activities should be incorporated into daily routine (walk rather than drive short distances; climb the stalrs rather than take the lift or elevator)

Calcium may be beneficial because of binding to fatty and bile acids in the gut, forming insoluble soaps that may then prevent potential carcinogens from contacting the bowel.14 Although two studies have shown an inverse relationship between calcium intake and CRC mortality,15,16 four of five case-control studies have not shown a beneficial effect.7 Regular use of aspirin appears to decrease the risk of CRC. One study involving 47900 male health professionals who responded to a mailed questionnaire showed that regular intake of aspirin (>2 times per week) decreased the risk of CRC.17 In the Nurses’ Health Study, the rates of CRC were determined according to the number of consecutive years of regular aspirin use.18 This study showed that regular aspirin use substantially reduced the

Colorectal cancer

1257

risk of CRC in women also, but the benefit may not be evident until after a decade of aspirin consumption. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely studied agents for the chemoprevention of CRC. Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, resulted in a significant reduction in the number of colorectal polyps in patients with FAP.19 Postmenopausal use of estrogens may result in a decreased risk of CRC. A large prospective study of women taking estrogen replacement therapy found that estrogen therapy, particularly recent and long-term use, was associated with a decreased risk of fatal colon cancer.20 Detection and diagnosis Screening CRC is highly preventable. The purpose of colorectum screening is first to find and remove colorectal adenomas, thus preventing cancer, and second to detect CRC in its

Table 53.3 Screening for colorectal cancer (ACS guidelines, update 2001) Five options for average-risk men and women aged 50 and older: • Fecal occult blood test (FOBT) annually and flexible sigmoidoscopy every 5 years • Flexible sigmoidoscopy every 5 years • FOBT annually • Colonoscopy every 10 years • Double-contrast barium enema every 5 years

early stage. Screening of asymptomatic persons is one of the primary ways to reduce mortality from CRC. It is estimated that early detection can save the lives of 75% of patients with CRC. As the population of the USA grows older and more people are at risk for CRC, the number of lives saved can be increased. Screening for CRC is feasible since it is a common disorder, screening tests are readily available, and early detection decreases mortality. Guidelines for CRC screening have been published by a number of medical associations. The American Cancer Society (ACS) guidelines (update 2001) for screening of average-risk individuals start at age 50. The incidence of invasive disease is low at age 50; however, adenomatous polyps occur in about 25% of 50-year-old adults. Therefore, screening at age 50 has the potential to detect and remove precursor lesions, thus preventing the development of cancer. The ACS guidelines give five options for screening average-risk individuals (Table 53.3). Annual fecal occult blood testing (FOBT) alone has been demonstrated to decrease the risk of death from CRC by one-third.21 The use of annual FOBT also significantly decreases the incidence of CRC.22 A positive FOBT should be followed by a colonoscopy so that an important lesion can be biopsied.

Comprehensive Geriatric Oncology

1258

Two interesting observations have been made with respect to age and FOBT.23 One was that the number of positive test results increased with age. Secondly, the percentage of adenomas and cancer found in persons with positive FOBT increased with advancing age. Thus, this test may be more sensitive in asymptomatic geriatric patients. Flexible sigmoidoscopy every 5 years is another screening option. Case-control studies have shown a significant decrease in mortality from cancers within reach of the sigmoidoscope, and a reduced incidence of cancer in patients who have had screening sigmoidoscopies.24–26 The ACS regards an annual FOBT combined with flexible sigmoidoscopy as a better choice than either alone.26 FOBT can detect occult blood from a lesion anywhere in the colorectum. On the other hand, flexible sigmoidoscopy is better at detecting distal polyps, and can also detect non-bleeding cancers. Other options include colonoscopy every 10 years, or double-contrast barium enema (DCBE) every 5 years. DCBE can image the entire colon, but does not allow biopsy or polypectomy. There is increasing interest in colonoscopy as the initial screening test for average-risk individuals. It is the only procedure that can identify and remove both premalignant and malignant lesions from the entire colorectum. In a comparison of colonoscopy with FOBT and sigmoidoscopy, more malignant lesions were found by colonoscopy.27 In July 2001, Medicare reimbursement for screening colonoscopy was initiated. Screening rates for CRC are low. Presently, 60% of Americans aged over 50 do not get screened for CRC. However, when the importance of early diagnosis is emphasized by physicians, patient compliance with screening studies is generally good. Elderly patients are equally cooperative. When evaluating FOBT, no difference in compliance was found between younger and older individuals.28 Clinical presentation It is important to recognize the presenting symptoms of CRC. One-half of patients present with bleeding, abdominal pain, change in bowel habits, anorexia, or weight loss. Symptoms may differ, depending on the location of the cancer. Cancer of the right side of the colon may present with abdominal pain or fatigue secondary to iron deficiency anemia. Left-sided colon cancers are associated with crampy abdominal pain, signs of obstruction, or bleeding. Rectal cancers most often present with bleeding, a sense of incomplete evacuation and urgency, or constipation. In the elderly, the presenting symptoms may be more vague. Weight loss, change in bowel habits, increased bearing down during evacuation, or fatigue may be the only symptoms. These symptoms must be fully evaluated and not attributed simply to age. It is unclear whether the distribution of colon cancers is affected by age. In one study, the location of cancers in the right or left colon was not affected by age. However, a retrospective review of 922 patients with CRC showed that female patients with rightsided colon cancer are significantly older.29 Therefore, the increasing incidence of proximal CRC may be related in part to an aging population, especially in women.

Colorectal cancer

1259

Diagnostic studies When CRC is suspected from the above symptoms, or from a positive result from one of the screening tests, further diagnostic studies are indicated. Sigmoidoscopic examination can be performed using either the rigid or flexible sigmoidoscope. The rigid sigmoidoscope can be passed through 25cm of the colon, although the average length visualized is about 17cm. The flexible scope has improved visualization (up to 60cm) and patient comfort. Barium enemas can be done with or without air contrast. Polyps can be detected better with air contrast studies. The lower sigmoid is not well visualized by barium enema, and sigmoidoscopy may be done in addition to evaluate this segment of colon. Colonoscopy allows for direct visualization of the entire colon, and may be done in place of sigmoidoscopy and barium enema. Colonoscopy is also indicated preoperatively to rule out synchronous lesions. Carcinoembryonic antigen (CEA) has been studied to evaluate its role in screening for CRC. However, CEA testing is not sensitive or specific enough to be useful in screening. CEA levels are useful in predicting the presence of liver metastases in the preoperative setting, or can be used to monitor for recurrent cancer postoperatively. When CRC is suspected in geriatric patients, the possible risks of these diagnostic procedures must be considered. One study indicated that these tests could be done without major complications in patients aged over 60 as well as in patients below 60.28 Another consideration is whether geriatric patients will be less cooperative with diagnostic workups. No difference was found in the compliance with testing, including both radiographic studies and colonoscopy, between patients aged over 60 and those under 60.28 In fact, the percentage of patients who refused studies decreased with age, even though these patients had more medical problems. Classification Pathology Adenocarcinomas account for more than 90% of colorectal cancers. Other histologic variants include mucinous (colloid) carcinoma, signet-ring carcinoma, adenosquamous carcinoma, and undifferentiated carcinoma. Adeno-carcinomas are graded by their degree of differentiation, nuclear pleomorphism, and number of mitoses. Grade 1 tumors have the most developed glandular structures and the least number of mitoses. Staging Staging of cancers of the large bowel is important to determine prognosis and potential treatment options. These cancers are staged according to whether the cancer has remained within the intestine or has spread to another organ. Commonly used staging systems are the TNM (‘tumor, lymph node, distant metastasis’) and Dukes stagings (Table 53.4).

Comprehensive Geriatric Oncology

1260

Table 53.4 Staging of colorectal cancer: TNM and Dukes stagings T

N

M

Dukes

0

Tis

N0

M0

—

I

T1

N0

M0

A

T2

N0

M0

A

T3

N0

M0

B

T4

N0

M0

B

Any T

N1

M0

C

Any T

N2

M0

C

Any T

Any N

M1

D

II

III

IV

Prognosis The prognosis for CRC is based primarily on the stage of disease. The two most important predictors of prognosis are depth of invasion and the presence or absence of regional lymph node involvement. Early-stage lesions are readily cured by surgery. Dukes stage A cancer is curable in 80–90% of patients. However, in later-stage disease, the prognosis decreases markedly. The 5-year survival rate for Dukes stage C cancer is 35–50%. The degree of histologic differentiation has also been shown to have prognostic significance. Other factors influencing prognosis include the presence of obstruction, perforation, and rectal bleeding.30 Geriatric patients do not appear to have an adverse prognosis on the basis of age. In one report, older patients fared as well as younger patients when matched by stage, with the exception of a small fraction of patients less than 45 or over 75 with localized disease.31 Management Although few studies have specifically evaluated the treatment of older patients, no biologic difference has been found between younger and older patients with CRC.32 Therefore, treatment decisions should not be based on age, but rather on the stage of disease and the medical condition of the patient. Surgery Surgery is the primary and most important initial treatment for most patients. The goal of curative surgery is to remove the cancer in the bowel, draining lymph nodes, and contiguous organs. In colon cancer, procedures entailing wide surgical resection and

Colorectal cancer

1261

anastomosis are done. In rectal cancer, the standard surgical treatment has been an abdominal-perineal resection that requires a permanent sigmoid colostomy. Recent advances have led to the use of sphincter-preserving surgery for mid and some distal rectal cancers. Age in itself does not appear to increase surgical risk. The Cancer Collaborative Group in the UK analyzed the effects of age on surgical outcomes by review of published reports.33 This report presents a detailed analysis of most of the data presently available with respect to CRC surgery in the elderly. It includes 28 independent studies and a total of 34194 patients. Within each study, operative morbidity, mortality, and survival were looked at for patients aged 65–74, 75–84, and 85+, and were compared with those for patients younger than 65. Older patients had more comorbid conditions. Older persons presented with more advanced disease—which is not completely understood, but is not different than older persons with other common cancers. The incidence of postoperative morbidity and mortality increased progressively with advancing age, and overall survival was decreased in the older age groups. However, these differences were not striking. Moreover, if the patients undergoing emergency surgery were excluded, complication rates and survival were comparable to younger patients. Adjuvant therapy Adjuvant therapy has been studied in patients at high risk for relapse after surgery, Dukes stage B2 or C disease. These recurrences may result from the presence of micrometastases or from tumor cell dissemination at surgery. For these reasons, adjuvant therapy has been tried before, during, and immediately after surgery. Radiotherapy, chemotherapy, and immunotherapy, either alone or in combination, have been evaluated. Colon cancer Is age a factor in benefit or toxicity of adjuvant chemotherapy? In adjuvant clinical trials with 5-fluorouracil (5-FU) and the immunomodulatory drug levamisole, age was not an exclusion criterion.34,35 Patients as old as 84 were entered. Age did not affect treatment outcome. Similar disease-free survivals and overall survivals were found in patients aged over 60 and under 60. Likewise, age does not appear to affect tolerance of adjuvant chemotherapy. Preliminary results of a study done on 1014 patients with Dukes stage B2, B3, or C colon cancer who were randomized to receive 5-FU plus levamisole or 5-FU plus leucovorin (folinic acid) and levamisole suggest that patients aged over 70 do not have greater toxicity than younger patients.36 However, the percentage of patients who had their treatment discontinued was higher in the elderly. This lower adherence to treatment plans in the older patients may have been due to a bias that geriatric patients are more likely to experience toxicity. Further support for the elderly receiving the same adjuvant chemotherapy as younger patients comes from a pooled analysis of data from seven phase III trials involving 3351 patients with stage II or III colon cancer.37 Five clinical studies using 5-FU and leucovorin and two trials using 5-FU and levamisole adjuvant therapy versus surgery

Comprehensive Geriatric Oncology

1262

alone were reviewed. The data were analyzed according to four age groups (<50, 51–60, 61–70, and >70 years). The 5-year overall survival rate was 71% for those receiving adjuvant therapy versus 64% for those untreated. No significant interaction was observed between age and efficacy of treatment. The incidence of toxic effects was not increased among the elderly (age >70), except for leukopenia in one study. Despite the efficacy of 5-FU-based adjuvant chemotherapy in decreasing colon cancer mortality, adjuvant chemotherapy is not widely used among elderly patients.38 Efforts are needed to ensure that elderly patients receive appropriate treatment. Rectal cancer Unlike colon cancer, when rectal cancer recurs, the failures are more often local. The principal reasons for local recurrence appear to be anatomic constraints in obtaining wide radial margins at surgery, and the lack of an adequate serosa in the rectum. Radiotherapy has been shown to reduce the risk of locoregional failure, but does not improve overall survival.39 Available evidence suggests that adjuvant radiation is well tolerated among the elderly.40,41 However, special attention to limiting small-bowel exposure is important in older patients, since they may be at higher risk of radiation-induced small-bowel complications.42 Treatment decisions regarding adjuvant radiotherapy in older patients should be made on the basis of available data and not age alone. The addition of 5-FU to radiotherapy has been shown to significantly reduce recurrence and improve survival in rectal cancer.43 The best method of administering 5FU for radiosensitization is still being investigated. An Inter-group trial comparing 5-FU by protracted venous infusion with bolus 5-FU found that infusional 5-FU was associated with improved relapse-free and overall survival.44 Should elderly patients with stage III rectal cancer receive standard-of-care combinedmodality treatment? The use of this treatment and its effectiveness was studied in elderly patients with stage II or III rectal cancer.45 The linked Surveillance, Epidemiology, and End Results (SEER)/Medicare database was used to identify 1807 patients aged over 65 with surgically resected stage II or III rectal cancer. It was found that 37% of patients received both adjuvant 5-FU and radiation, 11% 5-FU alone, and 14% radiation alone. Combined chemoradiation was associated with improved survival for stage III but not for stage II rectal cancer. This association of combined therapy with improved survival in stage III disease was similar to that observed in other studies. These findings suggest that age does not diminish the benefits of standard-of-care combined-modality therapy for stage III rectal cancer. Surveillance One of the first principles of follow-up is to ensure that the entire large bowel is clear of adenomas or synchronous cancers. Therefore, if colonoscopy was not done prior to surgery, a postoperative colonoscopy is performed. After the clearing colonoscopy, the first follow-up colonoscopy is done at 3 years. If the colonoscopy is normal, then repeat colonoscopies are done every 5 years. After surgery, patients should be followed closely for the possibility of recurrent disease. Eighty-five percent of recurrent disease is manifested during the first 2.5 years

Colorectal cancer

1263

after surgery, while the remaining 15% of cases recur during the subsequent 2.5 years. Therefore, patients require close monitoring for possible recurrence. Patients should be seen every 3 months for the first 3 years and have FOBT and blood tests (liver function tests, complete blood count, and CEA) done. Chest X-rays should be obtained every 6 months for 2 years, and then yearly. A baseline computed tomography (CT) scan of the abdomen and pelvis should be obtained about 3 months after surgery, but the value of routine follow-up CT scans has not been demonstrated. CEA levels may be followed to detect recurrent disease prior to clinical manifestations. After complete surgical resection, the CEA level returns to normal in 4–6 weeks. If the CEA level does not normalize, all of the cancer may not have been removed. If a normal postoperative CEA level subsequently rises, the possibility of recurrent disease should be further investigated. If diagnostic studies do not reveal the site of recurrent disease, second-look surgery may be indicated. Recurrent and metastatic disease Metastatic CRC is not considered a curable disease. Therefore, the goals of treatment are to relieve symptoms. Palliative therapy may include surgery, radiotherapy, chemotherapy, or a combination of these modalities. Age Until recently, older patients were excluded from treatment protocols or given dose reductions of chemotherapy based on age alone. This age-related treatment bias was based primarily on anecdotal experience, and has not been substantiated. A retrospective analysis of patients with CRC enrolled in Eastern Cooperative Oncology Group (ECOG) trials showed that patients aged 70 or older tolerated chemotherapy as well as younger patients.46 Therefore, it appears that the same principles for prescribing chemotherapy should be used for younger and older patients. Chemotherapy Palliative chemotherapy consists mainly of 5-FU-based regimens in advanced CRC. The combination of irinotecan and 5-FU/leucovorin has been shown to have superior efficacy to 5-FU/leucovorin in two large randomized phase III trials.47 The first oral chemotherapy, capecitabine, has now received US Food and Drug Administration (FDA) approval as a first-line therapy for metastatic CRC. Hepatic resection Since metastatic disease from colorectal cancer occurs primarily in the liver, resection of liver metastases has been evaluated. Resection of a solitary metastatic lesion has given 5year survival rates of 37%.48 Although there are no randomized studies evaluating the role of hepatic resection, two studies with matched controls showed no survivors at 3 years in the unresected group.49,50

Comprehensive Geriatric Oncology

1264

Is complicated surgery such as hepatic resection contraindicated in the elderly? Although this may have been true in the past, age alone should not deter a potentially life-prolonging operation. In a retrospective analysis of liver resection for colorectal metastases performed between 1985 and 1994, there were no significant differences in morbidity and mortality in patients aged over 70 compared with younger patients.51 This study suggests that properly selected geriatric patients can tolerate major surgical procedures for cancer. Summary Colorectal cancer is one of the leading causes of death in older individuals. It is the most prevalent lethal cancer in geriatric populations. Although its etiology is unknown, it has been suggested that CRC results from genetic, environmental, and diet-related factors. Modifications of diet and lifestyle may be helpful in preventing the development and progression of CRC. Screening asymptomatic older persons is the most important method for preventing CRC and decreasing mortality. Since age is the leading risk factor for CRC, the ACS has developed screening guidelines for older patients. When CRC is detected, patients require staging studies to determine prognosis and potential treatment options. Surgery can provide years of added life if CRC is diagnosed early and surgical resection is elective. Depending on the pathologic stage, surgical resection may be followed by standard-of-care adjuvant therapy. In advanced disease, palliative treatment may include the use of surgery, radiotherapy, chemotherapy, or a combination of these modalities. Available studies suggest that age alone should not be used to deny potentially beneficial therapy to older patients. Principles of CRC management should be applied similarly in geriatric and younger patients. References 1. Parker SL, Tong T, Holden S et al. Cancer statistics. CA Cancer J Clin 1996; 46:5–27. 2. Ziegler RG, Devesa SS, Fraumeni JF et al. Epidemiologic patterns of colorectal cancer. In: Important Advances in Oncology (DeVita VT, Hellman S, Rosenberg SA, eds). Philadelphia: JB Lippincott, 1986: 209–32. 3. Winawer SJ, Miller DG, Sherlock P. Risk and screening for colorectal cancer. Adv Intern Med 1984; 30:471–96. 4. Morson BC. Genesis of colorectal cancer. Clin Gastroenterol 1976; 5: 505–25. 5. Lotfi AM, Spencer RJ, Ilstrup DM et al. Colorectal polyps and the risk of subsequent carcinoma. Mayo Clin Proc 1986; 61:337–43. 6. Cutler SJ, Young JL Jr (eds). Third national cancer survey incidence data. Monogr Natl Cancer Inst 1975; 41:1–454. 7. Faivre I, Wilpart M, Boutron MC. Primary prevention of large bowel cancer. Recent results. Cancer Res 1991; 122:85–99. 8. Giovannucci D, Rirnrn EB, Ascherio A et al. Alcohol, low-methionine-Iow-folate diets, and risk of colon cancer in men. J Natl Cancer Inst 1995; 87:265–73.

Colorectal cancer

1265

9. Garabrant DH, Petero JM, Mack TM, Bernstein L. Job activity and colon cancer risks. Am J Epidemiol 1984; 199:1005–14. 10. Giovannucci E, Ascherio A, Rimm EB et al. Physical activity, obesity, and risk for colon cancer and adenoma in men. Ann Intern Med 1995; 122:327–34. 11. Chao A, Thun MJ, Jacobs EJ et al. Cigarette smoking and colorectal cancer mortality in the cancer prevention study II. J Natl Cancer Inst 2000; 92:1888–96. 12. Winawer SJ, St. John Dl, Bond JH et al. Prevention of colorectal cancer: guidelines based on new data. Bull WHO 1995; 73:7–10. 13. DeVita VT. Opening remarks. In: Perspectives on Prevention and Treatment of Cancer in the Elderly (Yancik R, Carbone PP, eds). New York: Raven, 1983:1–3. 14. Slattery ML, Sorenson AW, Fora MH. Dietary calcium intake as a mitigating factor in colon cancer. Am J Epidemiol 1988; 128:504–14. 15. Garland C, Shekelle RB, Barrett-Connore E et al. Dietary vitamin D and calcium and risk of colorectal cancer a 19-year prospective study in men. Lancet 1985; i: 307–9. 16. Garland C, Garland F. Do sunlight and vitamin D reduce the risk of colon cancer? Int J Epidemiol 1980; 9:227–31. 17. Giovannucci E, Rimm EB, Stampfer MJ et al. Aspirin use and the risk for colorectal cancer and adenoma in male health professionals. Ann Intern Med 1994; 121:241–6. 18. Giovannucci E, Egan KM, Hunter DJ et al. Aspirin and the risk of colorectal cancer in women. N Engl J Med 1995; 333:609–14. 19. Steinbach G, Lynch PM, Phillips RKS et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000; 342:1946–52. 20. Calle EE, Miracle-McMahill, HL, Thun MJ et al. Estrogen replacement therapy and risk of fatal colon cancer in a prospective cohort of postmenopausal women. J Natl Cancer Inst 1995; 87:517–23. 21. Mandel JS, Bond JH, Church TR et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med 1993; 328:1365– 71 [Erratum 329:672]. 22. Mandel JS, Church TR, Bond JH et al. The effect of fecal occult-blood screening on the incidence of colorectal cancer. N Engl J Med 2000; 343:1603–7. 23. Winawer SI, Andrews M, Flehinger B et al. Progress report on controlled trial of fecal occult blood testing for the detection of colorectal neoplasia. Cancer 1980; 45:2959–64. 24. Selby N, Friedman GD, Quesenberry CPJ et al. A case-control study of screening sigmoidoscopy and mortality from colorectal cancer. N Engl J Med 1992; 326:653–7. 25. Muller, AD, Sonnenberg A. Prevention of colorectal cancer by flexible endoscopy and polypectomy. A case-control study of 32,702 veterans. Ann Intern Med 1995; 123:904–10. 26. Kavanagh AM, Giovannucci EL, Fuchs CS, Colditz GA. Screening endoscopy and risk of colorectal cancer in United States men. Cancer Causes Control 1998; 9:455–62. 27. Leiberman DA, Weiss DG. One-time screening for colorectal cancer with combined FOBT and examination of the distal colon. N Engl J Med 2001; 345:555–60. 28. Winawer SI, Baldwin M, Herbert E et al. Screening experience with fecal occult blood testing as a function of age. In: Perspectives on Prevention and Treatment of Cancer in the Elderly (Yancik R, Carbone PP, eds). New York, Raven Press, 1983:265–74. 29. Fleshner P, Later G, Aufes A Jr. Age and sex distribution of patients with colorectal cancer. Dis Colon Rectum 1989; 32:107–11. 30. Steinberg SM, Barkin IS, Kaplan RS et al. Prognostic indicators of colon tumors: the Gastrointestinal Tumor Study Group experience. Cancer 1986; 57:1966–70. 31. Five-year relative survival rates. White patients, both sexes 1967–73. Cancer Patient Survival, Report No.5, DREW Pub NIII:77–992. 32. Patterson W. Oncology perspective on colorectal cancer in the geriatric patient. In: Perspectives on Prevention and Treatment of Cancer in the Elderly (Yancik R, Carbone PP, eds). New York, Raven Press, 1983:105–12.

Comprehensive Geriatric Oncology

1266

33. Colorectal Cancer Collaborative Group. Adjuvant radiotherapy for rectal cancer: a systematic overview of 8,507 patients from 22 randomised trials. Lancet 2001; 358:1291–304. 34. Laurie IA, Moertel CG, Fleming TR et al. Surgical adjuvant therapy of large bowel carcinoma: an evaluation of levamisole and the combination of levarnisole and fluorouracil. J Clin Oncol 1989; 7: 1447–56. 35. Moertel CG, Fleming TR, Macdonald IS et al. Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report. Ann Intern Med 1995; 122:321–6. 36. Aschele C, Guglielmi A, Tixi LM et al. Adjuvant treatment of colorectal cancer in the elderly. Cancer Control 1995; 26–38. 37. Sargent DJ, Goldberg RM, Jacobson SD et al. A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med 2001; 345:1091–7. 38. Sundararajan V, Grann VR, Jacobson JS et al. Variations in the use of adjuvant chemotherapy for node-positive colon cancer in the elderly: a population-based study. Cancer J 2001; 7:213– 18. 39. Rosenthal SA, Trock BJ, Coia LR. Randomized trials of adjuvant radiation therapy for rectal carcinoma: a review. Dis Colon Rectum 1990; 33:335–43. 40. Ramsey SD, Andersen MR, Etzioni R et al. Quality of life in survivors of colorectal carcinoma. Cancer 2000; 88:1294–303. 41. Pignon T, Horiot JC, Bolla M et al. Age is not a limiting factor for radical radiotherapy in pelvic malignancies. Radiother Oncol 1997; 42:107–20. 42. Parniak KE, Levitt SH. The role of radiation therapy in the treatment of colorectal cancer. Implications for the older patient. Cancer 1994; 74:2154–59. 43. Krook JE, Moertel CG, Gunderson LL et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 1991; 324:709–15. 44. O’Connell MJ, Martenson JA, Wieand HS et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 1994; 331:502–7. 45. Neugut AK, Fleischauer AT, Sundararajan V et al. Use of adjuvant chemotherapy and radiation therapy for rectal cancer among the elderly: a population-based study. J Clin Oncol 2002; 20: 2643–50. 46. Begg CB, Carbone PP. Clinical trials and drug toxicity in the elderly: the experience of the Eastern Cooperative Oncology Group. Cancer 1983; 52:1986–92. 47. Vanhoefer U, Harstrick A, Achterrath W et al. Irinotecan in the treatment of colorectal cancer: clinical overview. J Clin Oncol 2001; 19: 1501–18. 48. Hughes K, Simon R, Songhorabodi S et al. Resection of the liver for colorectal carcinoma metastases: a multi-institutional study of indications for resection. Registry of hepatic metastases. Surgery 1988; 103:278–88. 49. Wilson SM, Adson MA. Surgical treatment of hepatic metastases from colorectal cancers. Arch Surg 1976; 111:330–4. 50. Scheele J, Stangl R, Altendorf-Hofmann A. Hepatic metastases from colorectal carcinoma: Impact of surgical resection on the natural history. Br J Surg 1990; 77:1241–6. 51. Pong Y, Blumgart LH, Portner JG et al. Pancreatic or liver resection for malignancy is safe and effective for the elderly. Ann Surg 1995; 222:426–37.

54 Head and neck oncology in the aging patient James N Endicott, Lodovico Balducci Introduction There are approximately 95140 cases of cancer of the head and neck each year in the USA, with the average age at 59.1 A 5-year analytic review of cases of head and neck cancer over age 65 ending in December 1994 at the H Lee Moffitt Cancer Center in Tampa, Florida found that 114 (30%) of patients were in their 70s and that 32 (10%) were aged over 80. Eighty percent of these cancers are of the squamous cell type and occur primarily in the upper aerodigestive system. The remaining 20% of cancers are adenocarcinomas and sarcomas and occur primarily in the glandular tissue or mesodermal elements of the head and neck. The majority of the patients surviving treatment have residual morbidity as a result of their therapy. Although head and neck cancer comprises only 7% of all cancers, the resulting cosmetic deformity and functional, economic, and psychosocial consequences that affect quality of life warrant special attention.2 The overall survival rate with standard therapy using surgery or radiation for localized disease is approximately 67% (stage I) and 30% for those with regional metastasis (stages III and IV). The cure rate for stage IV patients with distant metastasis is negligible.3 Pathogenesis The induction and progression of head and neck cancer are probably part of a multistep process that occurs after long-term exposure to carcinogens and promoters. The process is associated with a concomitant failure of natural immunologic homeostasis that is directly related to the aging process. Cytogenetic disruption is another factor in the initial event of carcinogenesis. The mechanisms of exposure to carcinogens include natural and man-made radiation, direct contact by respiration and alimentation, and iatrogenic causes.4 Exposure to radiation in the form of ultraviolet rays from the Sun may result in basal cell carcinomas, squamous cell carcinomas, malignant melanomas, and Merkel cell carcinomas in decreasing order of frequency. Melanoma accounts for 75% of deaths from all varieties of skin cancer. The risk of an individual developing malignant melanoma during their lifetime is estimated to be 1 in 75 at present.5 Skin cancers are increasing in frequency,6 and may be attributed to genetic factors and to the decrease in the ultraviolet filtering ozone layer of the atmosphere caused by air pollution. Protective clothing and sunscreen lotions can diminish the incidence of skin cancers. X-ray treatment for adenoids (as was

Comprehensive Geriatric Oncology

1268

performed in the first part of the 20th century in the Baltimore area) or for acne or other head and neck lesions, before the hazards of radiation were known, has left an older generation of aging patients at risk for head and neck cancer development. These sites include skin, thyroid, and upper aerodigestive mucosal and glandular sites. Some assert that perhaps all cancers are caused by environmental factors.7 A single exposure to some carcinogens is enough to induce a cancer under laboratory conditions. However, there is usually a long time between exposure and the appearance of cancer, and even if a single exposure causes cancer in humans, carcinogen identification may not be possible. It is generally felt that few cancers occur in humans after a single exposure to a carcinogen. A primary reason why cancer is an affliction of older people is their repeated exposure to carcinogens over time. As we eradicate infections, disease, and trauma that kill younger members of society, allowing the population to live longer, we see a relative increase in degenerative diseases that accompany aging, such as heart disease, stroke, and cancer.7 The largest single irrefutable causative factor in head and neck carcinogenesis today is tobacco use. Cigarette smoking accounts for 360000 premature deaths annually, which could be avoided by eliminating this unnecessary social habit. One-half of these patients die of cancer; 25% of cancer victims succumb to lung cancer.8 Genetic factors may play a role in cancer. Nasopharyngeal cancer (NPC) has a high prevalence in Chinese living in southern China, as well as in Eskimos, North Africans in the Mediterranean area, and East Africans.9 Epstein-Barr virus (EBV) is present in many cases of NPC and is also implicated in Burkitt lymphoma and mononucleosis, and is an example of an infectious agent that may play a role in the induction of some cancers. Human retroviruses, such as human immunodeficiency virus (HIV), which is responsible for AIDS, may also play a role in carcinogenesis. Kaposi sarcoma, which is found in many patients afflicted with AIDS, may be virally induced. Human papillomavirus (HPV) can induce wart-like surface lesions, including laryngeal papillomatosis. In 1986, HPV capsid antigens were identified in tissue taken by biopsy from 14 of 20 patients with carcinoma in situ of the larynx.10 Problems in identifying infectious agents as a cause of cancer lie in individual resistance or susceptibility to infection by viruses, as well as synergism with other carcinogens. The increased incidence of cancer with age indicates that factors other than viruses are the major etiologic agents. Heavy alcohol consumption when combined with cigarette smoking seems to be synergistic in causing an increased incidence of cancer of the upper aerodigestive tract, usually involving the oral cavity, esophagus, and pharynx.11,12 Theories explaining the carcinogenic effects of alcohol emphasize (i) the role of carcinogens other than ethanol as risk factors, (ii) nutritional deficiency caused by the impaired absorption of nutrients and vitamins such as vitamin A, which is important in the regulation of epithelial cell differentiation,11,12 (iii) alcohol as a solvent for tobacco-related carcinogens, thereby permitting their easier passage through the gastrointestinal cellular membrane, and (iv) decreased liver metabolism in severely cirrhotic patients, resulting in a decreased ability to detoxify carcinogens. Another possible cause involving ethanol is the diminution of the hepatic contribution to the immune system. A prospective study of 462 head and neck cancer patients had only 34 non-drinkers and eight non-smokers.13

Head and neck oncology in the aging patient

1269

A major component of the aging process is a gradual senescence of the immune system, which has been associated with an increased incidence of neoplasia, autoimmune disorders, and infectious diseases.14,15 New knowledge about immune mechanisms has been achieved through advances in biochemistry, molecular biology, and hybridoma technology. The function of T lymphocytes as mediators of tumor rejection and the role of regulatory cytokines (e.g. interleukins) as important cofactors in the maintenance and amplification of the immune response have been recognized.16 Many changes in the cellular immune system that are associated with aging are attributed to the gradual loss of a cell’s ability to proliferate, for example a decrease in antigen-specific T-cell cytotoxic function (e.g. of CD8+ cytotoxic suppressor cells) and a decline in interleukin-2 production with increasing age.17,18 These deficits are similar to immune deficits in patients with head and neck cancer, and may be related to senescence of the thymus.19 Strategies of immunorestorative treatment that are used as an adjuvant to conventional treatment and might benefit the older patient with cancer include adaptive replacement of affected cell populations and cytokines or stimulation of appropriate cytokine production and lymphocyte proliferation in vitro. These techniques have been used in preliminary studies with advanced renal cell carcinoma and melanoma, but were associated with severe toxicities.20 Immunorestorative measures that employ bettertolerated natural products, such as thymic hormones (thymosin α1, retinoids, or essential trace elements, may be used for older tumor-free or cancer patients. Chromosomal mutations of specific genes that affect cell growth (oncogenes) or genes involved in immunologic regulation are now thought to play a role in the development of cancer.21 Aging may play an important role in chromosomal fragility or mutagenic capability. Gene splicing using retrovirus technology may be a useful potential therapeutic strategy. Management In the past, advanced age was considered a relative contraindication to major surgery, and these patients were treated with alternative, less effective modes of therapy.22 The prospect of locally and regionally uncontrolled head and neck cancer with its slow progression resulting in a gradual increase in pain, disfigurement, and loss of function should be weighed against the surgical and anesthetic risks in the elderly patient. Studies of surgery in aging patients have demonstrated acceptable morbidity and mortality in the geriatric population. Physiologic age and concurrent illness are more closely associated with mortality and complication rates than is chronologic age alone. Surgery of the head and neck, in general, is better tolerated than surgery of the body cavities. Mortality usually occurs when there are one or more pre-existing complications—i.e. the domino effect. Cardiac and pulmonary problems are the leading causes of postoperative death in older patients. Therefore, close attention to all details of preoperative, intraoperative, and postoperative management is critical. Head and neck surgery is equally tolerated in patients both above and below the age of 65.23 The older head and neck cancer patient requires more specific preoperative considerations than the younger patient. The etiologic risk factors for head and neck cancer—smoking and alcohol use—are also causes of major systemic and organ diseases.

Comprehensive Geriatric Oncology

1270

Aging may result in variable degrees of renal impairment, decreased cardiac and pulmonary reserve, atherosclerosis, and diminished wound healing.24 Therefore, medical and specialty preoperative consultations are often necessary when intercurrent disease is present or a lengthy surgical case is anticipated. A metastatic workup is necessary, including chest X-ray, liver enzyme analysis, and computed tomography (CT) scans, with selected CT-guided needle biopsy for remote disease. Frequently, the head and neck cancer patient is malnourished. Caloric, protein, vitamin, and mineral depletion result from alcoholism and from pain, dysphagia, and metabolic derangements secondary to cancer. Malnutrition results in poor wound healing and secondary surgical complications.25,26 Nutritional evaluation and aggressive enteral feeding by PEG tube or G tube are essential in the dysphagic patient, particularly when an ablative surgical procedure is necessary that would result in a severe postoperative swallowing impairment with an unpredictable functional recovery or when radiation therapy may be interrupted due to dysphagia. Patients with extreme visceral protein loss may have inefficient gastrointestinal absorption and require parenteral nutrition. Advances in technology, pharmacology, and anesthesia methods now allow major surgery to be performed routinely in the older patient. The elderly patient has, with careful attention and timely physiologic support, as good a chance of surviving as a similarly ill younger patient, although his or her course may be more prolonged.27 Intraoperatively, volume status and cardiac and pulmonary function can be monitored precisely using pulmonary artery and radial artery catheters and SaO2, SVO2, and PaCO2 measurements. Optimal management of the cardiac and pulmonary systems is possible. Studies of the risk of reinfarction after myocardial infarction show that the time from the infarction to anesthesia is the most critical factor determining the reinfarction rate.28 Similarly, advances in the postoperative management of major head and neck surgery patients enable the successful management of the older patient. Intensive care facilities can monitor cardiac rhythm and hemodynamics, oxygen saturation, bronchial hygiene, airway and fluid status, and the suction drainage apparatus in the immediate postoperative recovery phase. Postoperative broad-spectrum antibiotics and the rapid resumption of nutritional therapy are now routine. Ambulation can begin within 48 hours in most head and neck surgery patients, thus diminishing the risk of pulmonary embolism and postoperative pneumonia. Medical support for intercurrent disease management is useful. Rehabilitative surgical reconstructive techniques for communication and improved function have been developed to further improve the quality of life of older patients. The most simple yet effective means of reconstruction are favored for rehabilitation. Complications are largely related to intercurrent disease and previous radiation.29 For limited defects of the oral cavity and oropharynx, split-thickness skin grafts, local mucosal flaps, and primary closure are the best reconstructive methods. More extensive reconstructive methods may be necessary when there is limited tongue, palate, or upper pharynx function. Skin or skin muscle flap reconstruction uses local or regional soft tissue flaps nourished by a specific arterial supply to replace the surgically ablated anatomic site. Local flaps, such as tongue and nasolabial flaps, are useful for limited defects. However, for larger defects, or in some heavily irradiated patients, regional flaps are indicated. The popular pectoralis musculocutaneous flap, based on the thoracoacromial artery, was developed in the 1970s and has revolutionized head and neck

Head and neck oncology in the aging patient

1271

reconstruction. Microvascular free flaps add versatility to head and neck reconstruction, allowing the selection of different thicknesses of skin and muscle and enabling vascularized bone to be used for reconstruction. Limitations of this technique include flap reliability, the need for suitable recipient vessels, technical demands and length of the procedure, and the variable donor site morbidity. In the elderly, conservative surgery of the larynx is available for early lesions at specific glottic and supraglottic sites, thereby allowing preservation of the physiologically functional voice. Supraglottic laryngectomy requires adequate pulmonary reserve with a good cough so that postoperative aspiration pneumonia can be avoided. Total laryngectomy is traditionally necessary to effect a cure in cases of radiation failure of most patients with small lesions (T1 and T2) and for more advanced cancers of the larynx. Total loss of voice has a profound impact on quality of life. Speech rehabilitation can be accomplished in one or more of three ways. Only 20% of patients can successfully acquire the traditional esophageal speech, a technique of releasing air from the esophagus in a controlled manner.30 The hand-held, battery-operated mechanical ‘artificial larynx’ produces an electronic voice and may be used successfully by most patients. Sound is directed into the vocal tract either by placement of the device against the side of the neck or through a small plastic tube directly into the mouth. Speech is produced when the sound is articulated by the lips and tongue. In 1980, Singer and Blom described the tracheoesophageal puncture procedure for patients who do not develop acceptable esophageal speech or are unable to use the electro-larynx.23 Voice is produced when exhaled air is directed through a stoma Silastic prosthesis during momentary tracheostoma occlusion, with expulsion through the mouth giving the patient lungpowered speech. Successful prosthesis use requires good manual dexterity and sufficient visual acuity to enable the patient to learn how to remove, clean, and reinsert a small device in the stomal airway. Some geriatric patients may not meet these criteria. A speech therapist plays an important rehabilitative role in the alaryngeal patient’s future functional recovery. Ninety-five percent of all cases of oral cancer occur in individuals over 40. Although early cancers of the oral cavity may be managed solely by surgery or radiation therapy with similar outcomes, surgery is the treatment of choice, because radiation will leave permanent significant dryness as a sequela. This side-effect in an older patient contributes to dysphagia and poor appetite.31 Good nutritional status has prognostic and therapeutic importance in oncology.32 Screening for oral cancer is a simple, non-invasive procedure that can be easily incorporated into the comprehensive assessment of older patients. Oral cancer screening can detect early, localized lesions, which are associated with an improved prognosis. Five-year survival rates are more than four times greater in individuals with localized lesions than those with distant metastases. Since older Americans visit their physician more often than their dentist, the physician’s medical examination provides an excellent opportunity to screen for oral cancers.33 Older patients with locoregional oropharyngeal cancer (or at least a subset of them) appear to be able to tolerate radical courses of radiotherapy, and have similar outcomes as do younger patients.22 When partial or total pharyngectomy is necessary for primary hypopharyngeal, oropharyngeal, and some laryngeal tumors and for most peristomal recurrences, rehabilitation by the pectoralis myocutaneous flap or jejunal microvascular

Comprehensive Geriatric Oncology

1272

free flap34 is favored when primary closure cannot be effected. Gastric transposition has an 11% mortality rate36 as a reconstructive procedure, and may not be suitable for the older patient. Thyroid nodules in the elderly are more frequent and more frequently malignant. Fineneedle aspiration is the first step in the diagnosis of this type of nodule, and thyroid scans and ultrasound may be obtained in special cases. Thyroid suppression is frequently not effective in decreasing the size of the nodule, and may cause subclinical or clinical thyrotoxicosis. Between 2% and 10% of thyroid nodules are noted to be carcinomatous.36 Patients with a maxillectomy, rhinectomy, and/or orbital exenteration may be rehabilitated successfully by an intraoral or extraoral prosthesis made by a skilled maxillofacial prosthodontist. The unusually good cosmetic result and subsequent patient self-acceptance are important in the older patient, thereby allowing aggressive surgical management of cancers of the nose and paranasal sinuses, and large facial carcinomas. However, these patients should be observed for several years for early recurrence before facial reconstruction is performed.37 Radiation therapy plays an important role in management of malignancy in the head and neck cancer patient. Radiation used as an optional single modality of treatment in the range of 7000 rad for attempted cure in stage I or II carcinomas has a higher rate of success depending upon the site of the lesion. Early glottic larynx lesions can have a cure rate as high as 97% (stage I) and 85% (stage II), using surgery for salvage.38 However, a T1 lesion (stage I) of the hypopharynx (pyriform sinus) has a cure rate of 80%, and this rate is lower for a stage II lesion treated solely by radiation. More advanced carcinomas—stage III and stage IV—often require planned surgery, as well as postoperative radiation in the range of 5000 rad, for the best cure rates. Preoperative radiation is generally avoided because of the high incidence of postoperative complications and loss of visible original tumor margins at most sites. Newer developments in radiation include hyperfractionation techniques, the use of radiation sensitizers, and oxygen radical enhancement for unresectable advanced or recurrent disease. Investigations are ongoing of concomitant chemotherapy and radiation and various fractionation radiation schedules for advanced disease. With the aid of new imaging techniques and preradiation dosimetry planning by radiation physicists, cure rates can be improved. Recent advances in the management of cancer of the head and neck and relevance to older patients During the past decade, two major advances in the management of cancer of the head and neck have occurred, and are related to the use of combinations of radiation therapy and chemotherapy. These include organ preservation and more prolonged control of locally advanced tumors.39 The feasibility of organ preservation for the larynx with three induction courses of cisplatin and 5-fluorouracil (5-FU) followed by radiation therapy in 64% of patients with resectable cancer of the larynx (stages III and IV) had been demonstrated already in 1991.40 More recently, Forestiere et al41 reported that the simultaneous combination of daily radiation therapy and cisplatin 3-weekly was superior to the sequential treatment. A number of studies demonstrated that this approach may

Head and neck oncology in the aging patient

1273

also be applied to other head and neck areas.42 A yet-unsolved issue is whether hyperfractionated radiation therapy may produce comparable results to chemoradiation.43 Several studies have demonstrated that the combination of chemotherapy and radiation therapy is superior to radiation alone in terms of complete response rate, time to progression, disease-free survival, and overall survival in unresectable locally advanced disease.39,44 Concomitant treatment is probably superior to sequential treatment, and is preferred by the majority of practitioners. Combined-modality treatment is associated with an increased risk of mucositis and strictures than radiation alone; furthermore, chemotherapy may cause myelosuppression, and cisplatin is associated with increased risk of peripheral neuropathy in older individuals (see Chapter 39 of this volume45). Despite these risks, the majority of older individuals seem to tolerate combined-modality treatment. If the patient appears to be at high nutritional risk, the prophylactic positioning of a PEG tube may substantially improve the tolerance of treatment.46 Another important advance in the management of head and neck cancer is the introduction of new drugs that may be better tolerated by older individuals. These include carboplatin, for which the risk of nausea and vomiting, neuropathy, and renal insufficiency is substantially lower than for cisplatin, taxanes at low weekly doses, and gemcitabine.41 The advantages of weekly taxanes include a reduced risk of myelotoxicity and mucositis with concomitant chemotherapy and a reduced risk of post-radiation strictures; the main drawback is the risk of neuropathy with paclitaxel and of fluid retention with docetaxel. Gemcitabine is well tolerated, but is a powerful radiosensitizer, and concomitant treatment with radiation and gemcitabine is not well standardized. At present, its main use in older individuals is for palliation of metastatic disease. It can be used alone or in combination with a taxane or a platinum derivative. Finally, in palliating metastatic head and neck cancer in older and frail individuals, it should not be forgotten that methotrexate at low oral doses (15mg daily for 3 days every 3 weeks) still represents an effective and non-toxic option. Case reports Aging patients with head and neck cancer usually have complex problems that affect their function and self-image after treatment. Equally important in determining outcome are the functional and social situations of the patient. The needs and abilities of a selfsufficient patient who lives alone are different from those of an institutionalized patient suffering from senile dementia. Other factors of importance are the patient’s psychologic state, communicative abilities and disabilities, available social resources, and the perception of quality of life issues. It should be apparent that each case must be thoughtfully individualized to ensure the best possible outcome.23 Doing so requires several health professionals, working as a team in a comprehensive systematic fashion, to effect the treatment and rehabilitation of the patient.

Comprehensive Geriatric Oncology

1274

Case 1 (Figure 54.1) An 84-year-old White male with arthritic knees and hypertension developed intranasal squamous cell carcinoma. He received radiation therapy for the primary disease, which recurred and required midline maxillectomy. Over 6 years, he recurred locally in three midface sites, requiring three more operative procedures. He then

Figure 54.1 (a) Patient with right midface and palatal resection. (b) Intraoral prosthesis.

Head and neck oncology in the aging patient

1275

developed right neck metastasis (N2B levels II and III) and received 7000cGy to his neck, but disease persisted, requiring a right selective neck dissection. At age 92, he had been disease-free for 2 years. He is very alert, vigorous, and enjoys his life with his family, especially his 8-year-old grandson. He wears a prosthesis allowing him to talk and to eat a normal diet. He chooses not to wear his external prosthesis. Case 2 A vigorous 88-year-old White male developed a T1 squamous cell carcinoma of one left true vocal cord. Two years later (after a recent marriage), he developed a subglottic recurrence. A total laryngectomy was performed, and required a return to surgery later the same day because of a large hematoma thought to be secondary to a hypertensive episode in the recovery room. The hematoma was evacuated under local anesthesia and the patient recovered uneventfully. He is speaking with an electro-larynx and will soon receive a Blom-Singer prosthesis for improved speech. Case 3 An 84-year-old White male received radiation therapy to a T1 spindle cell carcinoma of the left true vocal cord. He was in good health, played 18 holes of golf 3 days a week and carried his own clubs using no golf cart and did pushups every morning and evening. He developed a recurrence of his cancer, and had a hemilaryngectomy with a resulting hoarseness no worse that his preoperative symptom. He is again playing golf over 1 year from his surgery. All patients were cleared for major surgery by the medicine service and all were physiologically much younger than their stated age. They felt that their psychosocial quality of life was impaired in only a minor way, because of the strong support from close family members and that their resulting functional impairments have been corrected by prosthetic rehabilitation. Conclusions Current therapeutic research protocol strategies using neoadjuvant chemotherapy are now prevalent throughout the USA. Carboplatin can be given safely in elderly patients or patients with renal impairment.39 Organ preservation is now a major goal in many of these multidisciplinary protocols, which are designed to improve the quality of life in the older patient by avoiding the standard treatment of ablative surgery plus radiation for advanced head and neck cancer. The Veterans Administration VA 268 Cooperative Study for cancer of the larynx demonstrated the efficacy of this approach in 266 prospectively randomized patients using triple-cycle chemotherapy (cisplatin/5-FU) and postoperative radiation therapy, with surgery used for salvage on the study arm.13 Multidisciplinary research into new treatment strategies for advanced and relapsed disease, such as adjuvant immunotherapy and other newer modalities of treatment, is not as prevalent. Rehabilitative interdisciplinary research in speech pathology, swallowing, prosthetics, physical therapy, and psychosocial and dietary disciplines is extremely

Comprehensive Geriatric Oncology

1276

important for the advancement of our knowledge and ability to improve the quality of life of the post-treatment head and neck cancer patient. Both basic science and clinical research should be supported. A series of scientifically rigorous, carefully executed clinical trials, performed in a multi-institutional framework, could provide reasonably rapid answers to important scientific questions.2 From such research, we would learn how the aging immune system affects the development of head and neck cancer and where interventions could be applied to correct age-related defects. We would better understand the pathophysiology of these disorders; develop new cytologic, diagnostic, and prognostic tests; establish better-defined hypotheses for future studies, and thus enhance our ability to prevent and treat head and neck cancer.23 References 1. American Cancer Society. Estimated new cancer cases and deaths by sex for all sites. In: Cancer Facts and Figures. Atlanta: American Cancer Society, 1996. 2. Endicott JN, Cantrell R, Kelly J et al. Head and neck surgery and cancer in aging patients. Otolaryngol Head Neck Surg 1989; 100: 290–1. 3. Conley J. Oncology and aging: introduction. In: Geriatric Otorhinolaryngology (Goldstein JC, Kashima HK, Koopman CF, eds). Philadelphia: BC Decker, 1989:146–7. 4. Cantrell RW. Etiologic factors in the development of cancer. In: Geriatric Otorhinolaryngology (Goldstein JC, Kashima HK, Koopman CF, eds). Philadelphia: BC Decker, 1989:148–57. 5. Brozena SJ, Fenske NA, Perez IR. Epidemiology of malignant melanoma, world wide incidence, and etiologic factors. Semin Surg Oncol 1993; 9:165–67 6. Cantrell RW. Malignant neoplasms of the skin of the head. In: Otolaryngology, Vol 5 (English GM, ed). Philadelphia: Harper & Row, 1982: Chap 59.1. 7. Cairns J. The cancer problem. Sci Am 1975; 233:64–72, 77–8. 8. Warner KE. Health and economic implications of a tobacco-free society. JAMA 1987; 258:2080– 6. 9. de The G. Role of Epstein-Barr virus in human diseases: infectious mononucleosis, Burkitt’s lymphoma, and nasopharyngeal carcinoma. In: Viral Oncology (Klein G, ed). New York: Raven Press, 1980:769. 10. Kashima H, Mounts P, Kuhajda F et al. Demonstration of human papillomavirus capsid antigen in carcinoma in situ of the larynx. Ann Otol Rhinol Laryngol 1986; 95:603–7. 11. Kabat GC, Chang CJ, Wynder EL. The role of tobacco, alcohol use, and body mass index in oral and pharyngeal cancer. Int J Epidemiol 1994; 23:1137–44. 12. Baron AE, Franceschi S, Barra S et al. A comparison of the joint effects of alcolol and smoking on the risk of cancer across sites in the upper aerodigestive tract. Cancer Epidemiol Biomark Prev 1993; 2: 519–23. 13. Endicott JN, Jensen R, Lyman G et al. Adjuvant chemotherapy for advanced head and neck squamous carcinoma. Final Report of the Head and Neck Contracts Program. Cancer 1987; 60:301–11. 14. Weksler ME. Senescence of the immune system. Med Clin North Am 1983; 67:263–72. 15. Ford PM. The immunology of ageing. Clin Rheum Dis 1986; 12: 1–10. 16. Gillis J. Interleukin-2: biology and biochemistry. J Clin Immunol 1983; 3:1–15. 17. Wolf GT, Schmaltz S, Hudson J et al. Alterations in T-lymphocyte subpopulations in patients with head and neck cancer: correlations with prognosis. Arch Otolaryngol Head Neck Surg 1987; 113:1200–6. 18. Wu W, Pahlavani M, Cheung HT, Richardson A. The effect of aging on the expression of interleukin-2 messenger ribonucleic acid. Cell Immunol 1986; 100:224–31.

Head and neck oncology in the aging patient

1277

19. Wolf GT. Aging, the immune system, and head and neck cancer. In: Geriatric Otorhinolaryngology (Goldstein JC, Kashima AK, Koopman CT, eds). Philadelphia: BC Decker, 1989:161. 20. Rosenberg SA, Lotze MT, Muul LM et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high dose interleukin-2 alone. N Engl J Med 1987; 316:889–97. 21. Lester EP, Tharapel SA. Chromosome abnormalities in squamous carcinoma cell lines of head and neck origin. In: Proceedings of the 3rd International Head and Neck Oncology Research Conference, September 1990 (abst). 22. Chin R, Fisher RJ, Smee Rl, Barton MB. Oropharyngeal cancer in the elderly. Int J Radiat Oncol Biol Phys 1995; 32:1007–16. 23. Sanders A, Blom E, Singer M, Hamaker R. Reconstructive and rehabilitative aspects of head and neck cancer in the elderly. Otolaryngol Clin North Am 1990; 23:1159–68. 24. Robinson DS. Head and neck considerations in the elderly patient. Surg Clin North Am 1994; 74:431–9. 25. Daly JM, Dudrick SJ, Copeland EM. Parenteral nutrition in patients with head and neck cancer: techniques and results. Otolaryngol Head Neck Surg 1980; 88:707. 26. Hooley RD, Levine H, Toribio CF et al. Predicting postoperative head and neck complications using nutritional assessment. Arch Otolaryngol 1983; 109:83. 27. Watters JM, Bessey PQ. Critical care for the elderly patient. Surg Clin North Am 1994; 74:187– 97. 28. Steen PA, Tinker JH, Tarhan S. Myocardial reinfarction after anesthesia and surgery. JAMA 1978; 239:2566. 29. Johnson JT, Rabuzzi DD, Tucker HM. Composite resection in the elderly: a well tolerated procedure. Laryngoscope 1977; 87:1509. 30. Gates GA, Ryan W, Cooper JC et al. Current status of laryngectomee rehabilitation: Results of therapy. Am J Otolaryngol 1982; 3:1. 31. Silverman S Jr. Precancerous lesions and oral cancer in the elderly. Clin Geriatr Med 1992; 8:529–41. 32. Tchekmedyian NS, Zahyna D, Halpert C et al. Clinical staging or nutrional status of cancer patients. Proc Am Soc Clin Oncol 1992; 11: A1388. 33. Fedele DJ, Jones JA, Niessen LC. Oral cancer screening in the elderly. J Am Geriatr Soc 1991; 39:920–5. 34. Robinson DW, MacLeon AM. Microvascular free jejunal transfer. Br J Plast Surg 1982; 35:258. 35. Harrison DFN. Surgical management of hypopharyngeal cancer: particular reference to the gastric ‘pull-up’ operation. Arch Otolaryngol 1979; 105:149. 36. Rolla AR. Thyroid nodules in the elderly. Clin Geriatr Med 1995; 11: 259–69. 37. Teichgraber JF, Goepfert H. Rhinectomy: timing and reconstruction. Otolaryngol Head Neck Surg 1990; 102:362–9. 38. Wang CC. Radiation therapy of laryngeal tumors. In: Comprehensive Management of Head and Neck Tumors, 2nd edn (Lindberg RD, Thawley SE, Panje WR, Batsakis JG, eds). Philadelphia: WB Saunders, 1998. 39. Al-Sarraf M. Treatment of locally advanced head and neck cancer: historical and critical review. Cancer Control 2002; 9:387–99. 40. The department of Veterans Affairs Laryngeal Study Group. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 1991; 324:1685–90. 41. Forestiere AA, Berkey B, Maor M et al. Phase III trial to preserve the larynx: induction chemotherapy plus radiotherapy vs concomitant chemoradiotherapy vs radiotherapy alone. Intergroup trial R 91–11. Proc Am Soc Clin Oncol 2001; 20:4.

Comprehensive Geriatric Oncology

1278

42. Pignon JP, Bourhis J, Domenge C et al. Chemotherapy added to locoregional treatment for head and neck squamous carcinoma: three meta-analysis of updated individual data. Lancet 2000; 355:949–55. 43. Brizel DM, Albers ME, Fisher SL et al. Hyperfractionated irradiation with and without concurrent chemotherapy forlocally advanced head and neck cancer. N Engl J Med 1998; 338:1798–804. 44. Browman GP, Hudson DI, Mackenzie RJ et al. Choosing a concomitant radiation therapy and chemotherapy regimen for squamous cell carcinoma of the head and neck: a systematic review of the published literature with subgroup analysis. Head Neck 2001; 23:579–89. 45. Cova D, Balducci L. Cancer chemotherapy in the older patient. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004: 463–88. 46. Zachariah B, Balducci L, Venkattaramabalajii GV. Radiotherapy for cancer patients aged 80 and older: a study of effectiveness and sideeffects. Int J Oncol Biol Phys 1997; 39:1125–9.

55 Prostate cancer in the elderly Timothy D Moon Introduction Adenocarcinoma of the prostate has, for several years now, had the dubious distinction of being the most commonly diagnosed non-skin cancer in men.1 In 2001, the American Cancer Society estimated that 198100 men would be diagnosed with prostate cancer and 31500 would die from their disease.1 Indeed, these numbers reflect part of the problem in that the diagnosis rate has risen from 56000 per year in 19752 to 198100 at present. During the same period, the mortality rate has increased from 18700 to 31500. Thus, in the past quater of a century, the diagnosis of prostate cancer has risen fourfold while the mortality rate has doubled. Confusing the data further was the spike in diagnosis rates between 1988 and 1992.1 The hypothesized reason for this was the introduction of prostate-specific antigen (PSA) testing during the 1980s. This led to a stage migration in the diagnosis of prostate cancer, with cancers being diagnosed earlier than previously. Overall, several hypotheses might be developed from these data. The first is that prostate cancer is being successfully treated—as evidenced by the more slowly rising mortality rate. Another contrarian hypothesis is that most cancers are indolent, with the patients dying of causes other than from prostate cancer. Implied in this latter hypothesis is a lack of relevance of treatment to these statistics. As stated above, the major factor in this increasing diagnosis rate has been the introduction of serum PSA measurement for screening, or at least case-finding.3 In addition, we have a rapidly expanding aged population, who form the primary cohort for the diagnosis of prostate cancer. Thus, while it is clear that for most patients, the disease runs an indolent course, prostate cancer is the second most common cause of cancer death in men. At a time when society’s resources are diminishing, while the aged population expands, it is important to define the efficacy of therapy, especially in the context of quality of life. Surprisingly, surgical treatments for prostate cancer were first performed nearly a century ago,4 yet without any scientific demonstration of their efficacy. This position is no longer tenable, and the US National Cancer Institute (NCI) recognized the importance of economics in patient treatment when they held their first Economic Conference on the integration of economic outcome measures into NCIsponsored therapeutic trials.5 Finally, in a discussion of treatment for the gerontologic patient, we must also recognize that neither the approach of the physician nor the wishes of the patient are necessarily the same as they might be for a younger person.

Comprehensive Geriatric Oncology

1280

Etiology An increasing number of influences upon the development of prostate cancer are being described, and advances in molecular biology have greatly expanded our knowledge (Table 55.1). Hereditary prostate cancer The concept of genetic influences upon the development of prostate cancer has been around for many years. A computerized database of the Mormon population has defined clustering within families.6 Additional studies using case-control methods have shown significant increases in the cancer risk for first-degree relatives.7,8 This risk increases from 2-fold with one relative involved or affected to 11-fold with three affected probands.9 Segregation analysis suggested an autosomal dominant model affecting 0.36% of the population but accounting for 43% of cancers occurring in men younger than 55.10

Table 55.1 Factors influencing the development of prostate cancer • Heredity • Chromosomal alterations • Oncogenes • Tumor suppressor genes • Apoptosis • Growth factors • Androgens/androgen receptors

In 1996, the first prostate cancer susceptibility gene (HPC1) was located to chromosome 1q24–25.11 It appears to be more prevalent in large families with early-onset prostate cancer.12 Since then, three other prostate cancer susceptibility genes have been identified: at chromosome 1q42.2–43,13 on the long arm of the X chromosome (Xq27– 28),14 and, most recently, at chromosome 1p36.15 Finally, several studies have linked the breast cancer-associated genes BRCA1 and BRCA2 with prostate cancer.16–19 Overall, these genes seem to increase the risk of prostate cancer threefold.19 Cytogenetic data Multiple chromosomal aberrations have been defined in prostate cancer. Loss of chromosomes 1, 2, 5, and Y, together with gains in chromosomes 7, 14, 20, and 22, have been described.20 Multiple rearrangements have also been described, including chromosomes 2p, 7q, and 10q.20

Prostate cancer in the elderly

1281

Molecular analysis of alleles using restriction fragment length polymorphism (RFLP) and tumor-associated loss of heterozygosity (LOH) has been used to demonstrate LOH at 11 sites, namely 3p, 7q, 9q, 10p, 10q, 11p, 13q, 16p, 16q, 17p, and 18q. The highest frequency of losses are found at 10q and 16q. Of interest is the finding of decreased expression of the cell adhesion molecule E-cadherin in high-grade prostate tumors.21,22 Ecadherin is located on chromosome 16q. Oncogenes A proto-oncogene is a normal gene sequence coding for a normal cellular protein required for normal cell growth and proliferation.23 The altered form of gene sequence is the oncogene. The alterations may be point mutations, replications (extra copies of the gene resulting in amplification), or translocations on the gene such that gene promoters or regulators do not act correctly. Several oncogenes have been studied. Studies of c-myc and c-fos have not been fruitful.24–26 Mutations in ras family genes have been studied by many investigators. American studies have rarely shown aberrations,27–30 while Japanese studies have shown alterations in about 25% of cases.31,32 Tumor suppressor genes The p53 gene is currently the gene of preeminence for study in prostate cancer. Located at chromosome 17p13, it encodes for a nuclear phosphoprotein that arrests the cell from entering S phase of the cell cycle.23,33 It may also be involved with the regulation of apoptosis.34 Mutations in p53 may therefore permit DNA-damaged cells in G: to enter S phase, resulting in genetically unstable cells more likely to be associated with the development of malignancy.35 Additionally, mutated p53 protein exhibits an increased half-life, giving the appearance of increased expression.23 Most studies have shown alterations in p53 expression in prostate cancer, with the greatest expression in highergrade tumors.36 A study using tissue from hormonally untreated patients demonstrated no abnormal p53 staining in patients with cancers confined to the gland, while 10% of locally advanced tumors showed abnormal p53 accumulation and 20% of patients with metastatic disease demonstrated abnormal p53 concentration.37 Interestingly, in the majority of these patients, the p53 abnormality was only detected at the metastatic site and not in the primary tissue.37 Other tumor suppressor genes associated with prostate cancer that have been identified are the retinoblastoma (Rb) gene, BRCA2, and the KAI1 gene.19 Programmed cell death (apoptosis) Apoptosis is the programmed cell death that occurs for all cells. Loss of apoptotic potential leads to uncontrolled growth and the development of a tumor. Various factors have been identified that either increase or decrease the apoptotic mechanisms. The first gene identified that inhibits apoptosis was Bcl-2.38 Subsequently, a whole family of genes was identified, with both blocking and promoting activity.39,40 More recently, a new family of inhibitors of apoptosis (IAPs) has been identified.41 Insulin-like growth factor I (IGF-I) has also been identified as an antiapoptotic modulator.42 The final common

Comprehensive Geriatric Oncology

1282

pathway to apoptosis is through a family of proteolytic cysteine proteases known as caspases.43–45 As well as IAPs, there are several factors that increase apoptosis. The p53, c-myc, and Rb genes have been associated with this process.46–48 Intracellular calcium has also been associated with apoptosis. Cell death occurs as a result of many signals, including DNA fragmentation secondary to activation of Ca2+/Mg2+ -dependent nuclear endonuclease.49 Castration causes androgen levels to fall, with a simultaneous reduction in androgen receptors.50 These changes in hormonal milieu allow for the expression of normally repressed genes such as TPRM-2 and TGF-β (transforming growth factor β).51,52 TGF-β1 has been associated with increased intracellular calcium levels and an increase in expression of the calcium-binding protein calmodulin. Calmodulin levels have also been found to be increased in other tumors.53 Although the caspase proteases are the final common pathway for apoptosis, earlier central events suggest the mitochondria as the locus for the initiation.43 Mitochondrial disruption precedes nuclear fragmentation. Permeabilization of the mitochondrial membrane leads to the release of cytochrome c, which activates the caspase family.54 Growth factors One of the earlier growth factors to be studied was epidermal growth factor (EGF). EGF receptors (EGFR) are located on the basement membrane side of the glandular epithelial cells.55 While the receptor is present in 90% of benign prostatic hyperplasia (BPH) tissue, it is absent from prostatic adenocarcinoma tissue.56,57 However, TGF-a, which is structurally and functionally related to EGF and which reacts with EGFR, has been demonstrated in prostate cancer tissue.58 TGF-β is expressed in most prostate cells, but primarily in the mesenchyme.59 TGF-β on its own appears to have inhibitory growth effects, yet when co-cultured with EGF is stimulatory in action.49 TGF-β has also been found to regulate fibroblast growth factor (FGF).60 Acidic FGF may be required to support the growth of malignant epithelium through a paracrine mechanism.61 Androgens and androgen receptors Androgens are essential for the normal growth and function of prostatic tissue.62 Both testosterone and dihydrotestosterone mediate their effects through the same androgen receptor protein and function as nuclear transcriptional activators. Dihydrotestosterone is 10 times more powerful than testosterone as a receptor transcriptional activator. This difference results from the much higher binding affinity of dihydrotestosterone to the androgen receptor. This receptor is encoded by the X chromosome between the centromere and 13q.63 Mutation of the androgen receptor has been shown to inactivate antiandrogens.64,65 While the androgen receptor cannot be viewed as a proto-oncogene, the importance of its presence and its transcriptional regulation of a host of gene products that have proven to be more important in cellular transformation cannot be overlooked. However, although androgens and androgen receptors are obviously required for normal prostatic growth, the place of androgens as carcinogens is less clear. In an attempt to define a carcinogenic role for hormones in the induction of prostate cancer, Noble66 treated rats with testosterone and markedly increased the incidence of

Prostate cancer in the elderly

1283

tumors from 0.45% to 18%. Further, he found that if the testosterone was administered concurrently with estrone, the tumors developed after a shorter lag time, suggesting a more complex hormonal inter-relationship than androgen stimulation alone. Additionally, the work demonstrated that, with one exception, transplants from these tumors were hormone-independent.67 Synergism between androgens and estrogens has been noted in BPH,68 and leads to the question of whether BPH increases the risk of developing prostate cancer. The evidence is unclear, and opposing viewpoints are available in the literature.69,70 Preventlon A variety of nutritional factors associated with an altered risk for prostate cancer have been evaluated and have been reviewed.71 A diet high in animal fat has been associated with an increased risk of prostate cancer.71 Unfortunately, for the geriatric population described in this book, it is no doubt far too late for the beneficial effects of dietary changes. β-Carotene has also been associated with an increased risk of cancer,72 although this may be because, in a Western diet, most β-carotene is ingested through animal fat sources. Potential dietary sources for prostatic cancer prevention are selenium,73 vitamins D and E,71,74,75 soy,76 and even green tea.77 Screening for prostate cancer The basic requirement for any screening program is that it results in a reduction of the mortality and/or morbidity of the disease. It has yet to be conclusively demonstrated that active (with curative intent) intervention alters patient outcome. It is a rather sad commentary that despite the fact that the first radical prostatectomy was performed nearly a century ago,4 it was only in 1994 that the National PIVOT (Prostate Intervention Versus Observation Trial) study was started78 The PIVOT study randomizes men with clinically localized disease to radical prostatectomy versus watchful waiting (no active treatment). Results from this study will not be available until the year 2010. In addition to the medical requirements of a screening program, economics have clearly begun to impact how we treat disease. With healthcare costs in the USA reaching 12.1% of GNP in 1990,79 it is clear that we are reaching our fiscal limits as a society. Discussions about how limited resources will be allocated will eventually be made, and will be termed ‘rationing’ by politicians. For comparison, European countries spent 6.2– 8.8% of GNP on healthcare during the same period.79 The NCI first formally addressed this issue in 1994 at their Economic Conference mentioned above.5 Not surprisingly, the following discussion does not provide clear-cut recommendations for screening. If anything, they are confused for the pregeriatric population but perhaps less so for the elderly, whose interests tend more toward quality of life than quantity of life. One paper that indirectly addressed the issue of screening, but directly confronted the issue of diagnosis and screening in the elderly, is that by Albertsen et al.80 This paper reviewed the outcome of 767 men diagnosed in the 1970s and 1980s who were initially followed expectantly. What it showed was that even for

Comprehensive Geriatric Oncology

1284

men in their 70s, high-grade cancers (Gleason 7–10) were still associated with a cancer death. Thus, while treatments may not work well for poorly

Table 55.2 Screening for prostate cancer: recommendations of the American Cancer Society/American Urologic Association • Annual: – Digital rectal examination (DRE) – Prostate-specific antigen (PSA) determination starting at age 50 (or age 40 for men at high risk (e.g. African-Americans) • Men with a life-expectancy of ≥10 years may benefit

differentiated cancers, these patients in their 70s will still die from prostate cancer and not from competing causes of death. Current recommendations In 1992, the American Cancer Society recommended as part of health screening that every man aged 50 years and older should undergo an annual PSA determination and digital rectal examination (DRE), with men at high risk (e.g. African-Americans or those with a strong family history) starting at a younger age, and that men with a lifeexpectancy of at least 10 years may benefit from examination (Table 55.2). According to the life tables, a man will have a 10-year life-expectancy at age 74. The American Urologic Association has also endorsed these recommendations. This position is not held universally, however—the US Preventive Services Task Force does not recommend for or against screening for prostate cancer.81 Additionally, the Canadian Task Force on the Periodic Health Examination has recommended against use of PSA in prostate cancer screening, as has the Canadian Urological Association.82 The controversy over screening is summarized in Table 55.3. Screening tests At the present time, screening for prostate cancer consists of DRE and PSA determination.83 Prostatic ultrasound has been tested and rejected as a screening tool. The DRE is a time-honored examination not only for prostate cancer but also for the detection of rectal cancer. It is limited in its effectiveness, however. One can only palpate the posterior surface of the prostate, and while the majority of cancers are located in this region, they will only be palpable when quite large. About half of the cancers detected in this manner have already spread beyond the capsule when diagnosed. In a study of men aged over 50, 15% had an abnormal DRE.84,85 Of these men, 21% were diagnosed with cancer, for a detection rate of 3.2%. The real detection rate, however, was only 1.3%, since the remainder were diagnosed from biopsies taken elsewhere in the gland. A review of the studies evaluating DRE as diagnostic tool has shown detection rates varying from 0.1% to 2.5%.83

Prostate cancer in the elderly

1285

PSA is a 34 kDa serine kinase produced by normal as well as malignant prostatic epithelium.86 Its function is the liquefaction of semen. PSA levels in semen are in milligram amounts, while in serum they are in nanogram amounts. There is thus a million-fold difference between these concentrations. Any cellular changes that allow PSA to ‘leak’ into the blood will cause increased levels. Inflammatory changes,87,88 together with those associated with malignancy (such as the abnormal blood vessels associated with malignant neovascularity), are associated with such leaks. Prostatic biopsy may also cause an increase in PSA levels, such that repeat serum measurements within several weeks of biopsy may reveal artifactually elevated levels. Several assays are clinically available. Abbott’s IMx assay and the Hybritech Tandem assay utilize monoclonal antibodies and have normal levels at 0–4 ng/ml, while the Yang Pros-check assay utilizes a polyclonal antibody and has values about 1.6-fold higher than the other two assays.83 It is therefore important to know which assay one’s laboratory uses and any changes that are made. Overall, PSA levels in the normal range of 0–4 ng/ml in the absence of rectal abnormality will have a very low yield. PSA levels between 4 and 10 ng/ml will have a 25% likelihood of being associated with prostate cancer. Above

Table 55.3 Controversy over prostate cancer screening Pro

Con

• Prostate cancer is the most common cancer in men

• Most men die with cancer rather than of cancer

• Prostate cancer is the second most common cause of cancer death in men

• Patients with well-differentiated cancers do just as well without treatment

• Screening allows the detection of cancer while it is still localized (and asymptomatic)

• Patients with poorly differentiated cancers do poorly with or without treatment

• Screening allows curative treatment while the tumor is still localized

• Competing causes of death overwhelm deaths from prostate cancer • Curative treatments are not proven over expectant therapy in controlled trials

10ng/ml, the positive predictive value is about 67%.89 BPH is probably the most common cause of benign elevations in this range, although values up to 80ng/ml have been seen in patients with acute prostatitis.87 Of recent interest have been the studies demonstrating PSA in free and complex forms. PSA may complex with α1-chymotrypsin and also β2-macroglobulin, the latter of which completely envelops the PSA molecule, making it undetectable.90 It has been suggested that measuring free PSA is a more sensitive method for detecting prostate cancer.91

Comprehensive Geriatric Oncology

1286

PSA density As an aid to cancer detection, PSA has been calculated in various ways. PSA density (PSAD) is PSA per unit volume of prostate, and values greater than 0.15 have been suggested to indicate cancer.92 This, of course, requires prostatic ultrasound determination, raising the financial cost of patient evaluation. The value of PSAD has, however, more recently been brought into question.93 PSA velocity Another method of evaluating PSA is PSA velocity (i.e. changes in PSA with time). It is suggested that increases greater than 0.5ng/ml/year are important.94 Other studies have shown that in periods of less than 1 year, changes greater than 30% are common, making PSA velocity of very limited clinical value.95 However, as men collect PSA data about themselves over 5- to 10-year periods, PSA changes may become of more importance. PSA age-specific ranges Finally, PSA age-specific reference ranges have been proposed and even utilized by some clinical laboratories. These suggest normal ranges up to 5.4ng/ml for men in their 60s and 6.5ng/ml for men in their 70s.96,97 Others have questioned the utility of these ranges, suggesting that they would result in detection of fewer organ-confined cancers.98 Studies utilizing PSA for cancer detection have yielded higher detection rates than DRE studies. The PSA cut-off value for the studies has been 4ng/ml. All US studies have been invitational in nature, immediately rendering them non-population-based.83 However, two large US studies both detected prostate cancer in 2.6% and 3.1% of their population groups.99,100 This compares favorably with a population-based Swedish study, where the detection rate was 2.9%.101 A review of PSA-based screening studies has been published, with detection rates varying from 1.5% to 4.1%.83 The final issue that should be addressed concerns the effects of repeated screening of the same population. Relatively few data exist, and suggest a decreasing yield, but with a higher likelihood of diagnosing organ-confined disease.83 Combination testing Patients are routinely evaluated with both PSA and DRE. Studies clearly demonstrate that PSA testing will identify more cancers than will DRE.84,85 However, of patients diagnosed with prostate cancer, up to 20% will have a normal PSA value, indicating that unique patients may be identifiable by each method. This last comment has been qualified by a study evaluating the likelihood of a positive prostate biopsy in the face of an abnormal DRE but normal PSA.102 For a PSA <1ng/ml, the cancer diagnosis rate was 0.3%, while for the 2.0–2.9 ng/ml range, the diagnosis rate was only 2.5%.

Prostate cancer in the elderly

1287

The need for treatment Arguably, the greatest debate in urology at the present time concerns the need, or lack thereof, for treatment of prostate cancer. While it has long been the case that European urologists have taken a more passive line toward therapy, their US counterparts have taken a much more active approach. The debate over treatment heated up following the publication by Johanson et al103 in 1992. In this study, men with prostate cancer were merely followed, with the resultant mortality rate from prostate cancer of 10% at 10 years. More recently, Chodak et al104 performed a meta-analysis of watchful waiting series, with the conclusion that low-grade cancers may be watched, while high-grade cancers will have a poor outcome with such management. The prostate Patient Outcome Research Team (PORT) utilized published treatment result data in a Markov computer decision analysis model to measure the effects of radiation therapy or radical prostatectomy versus outcomes with watchful waiting.105 The results for 65-year-old men revealed a quality of life adjusted benefit of −0.34 year for well-differentiated cancer, with 0.33 year and 1.0 years, respectively for moderately and poorly differentiated cancers. The Baylor group has recently revised these outcomes, inputting more recent clinical data into the model. Their results now show quality of life adjusted benefits of radical prostatectomy of 1.01, 2.41, and 2.18 years for well, moderately, and poorly differentiated cancers, respectively.106 Again, these figures represent benefits for 65-year-old men. As men get older, these benefits will shrink accordingly. The reasons are threefold: (i) carcinoma of the prostate is generally slowly growing; (ii) life-expectancy is shrinking; (iii) competing causes of death are becoming more prominent. However, Albertsen et al,80 reviewing the natural history of prostate cancer, found that even for men in their 70s, prostate cancer deaths for high-grade cancers overwhelmed the already high mortality rates from other causes.80 Diagnosis and staging Prostate biopsy The diagnosis of prostate cancer is usually made by biopsying the prostate. This is normally performed by transrectal ultrasound-guided biopsies. Several years ago, the Stanford group calculated that by taking sextant biopsies, one had less than a 5% chance of missing a significant cancer.107 More recent data have suggested that eight or more biopsies may be needed to reasonably sample the prostate.108,109 Additionally, it is usual practice for most urologists to biopsy the whole gland, even if the decision to biopsy was driven by a palpable nodule with a normal PSA level. Previous work suggests that at least 16% of cancers would have been missed if only the nodule had been biopsied. Prostate biopsy is usually indicated because of a prostate nodule or elevated PSA level. Occasionally, the finding of metastatic adenocarcinoma requires prostate biopsy in the search for the primary tumor. Ten percent of patients undergoing transurethral

Comprehensive Geriatric Oncology

1288

prostatectomy for presumptively benign disease are found, after histologic analysis, to have adenocarcinoma in the prostate. Staging The current staging system for prostate cancer was published in 1992, and is summarized in Table 55.4.110 Essentially, T1 tumors are incidentally found subsequent to surgery for benign disease or because of an elevated PSA. T2 tumors are localized to the prostate, T3 tumors have clinically spread beyond the prostatic capsule, and T4 tumors involve the organs or the pelvic sidewall. Grading Numerous grading systems have been proposed for prostate cancer. The most common of these is the Gleason grading system.111 The basis for this system is low-power microscopic evaluation of the prostatic glands. The glands are graded from 1, where there is an increase in the number of glands that are slightly smaller than normal, to 5, where only sheets of anaplastic cells exist. Gleason also noted that prostatic tumors are heterogeneous in nature, with areas of different degrees of differentiation. For that reason, the Gleason system has two numbers attached to it. The first represents the primary tumor grade while the second represents the secondary pattern (which must represent more than 5% of the total area). Generally, tumors with a combined score of 2–4 are considered well differentiated, 5–6/7 moderately differen

Table 55.4 Prostate cancer staging T1

Tumors

T1a Clinically benign prostate found incidentally at surgery (usually transurethral prostatectomy). Well-differentiated tumor involving less than 5% of resected tissue T1b Incidentally found tumor. Poorly differentiated tumor or involving more than 5% of resected tissue T1c Clinically benign prostate with tumor diagnosed because of elevated PSA level T2

Palpable tumor clinically localized to the prostate

T2a Involves less than half of one prostatic lobe T2b Involves more than half of one prostatic lobe T2c Involves both lobes of the prostate T3

Tumor extends beyond the capsule of the prostate

T3a Unilateral extension beyond the prostate T3b Bilateral extension beyond the prostate T3c Tumor invades one or both seminal vesicles T4

Tumor involves other organs or pelvic sidewalls

Prostate cancer in the elderly

1289

T4a Tumor involves bladder neck plus external sphincter plus rectum T4b Tumor involves additional adjacent organs N

Nodal metastases

N0

No nodal metastases

N1

Metastases in a single node <2cm in diameter

N2

Metastases in one or more nodes 2–5 cm in diameter

N3

Metastases in one or more nodes >5cm in diameter

M

Metastases

M0 No distant metastases present M1 Distant metastases present

tiated, and 7/8–10 poorly differentiated. The other, less commonly utilized, grading systems use the more common cytologic abnormalities such as mitotic figures, nuclearto-cytoplasmic ratios, and nucleoli, Approximately 10%–20% of tumors will be well differentiated, 70–80% moderately differentiated, and 10% poorly differentiated. Treatment The treatment of prostate cancer has generated more heated debate in the urologic community and from a position of less certainty than the average debate in the US Congress. The treatment spectrum runs the gamut from no treatment (watchful waiting) to radical prostatectomy, with radiation therapy in between (Table 55.5). Watchful waiting To rationalize this disparity, one must recognize that most cancers run a protracted course such that competing causes of death overwhelm the likelihood of the cancer

Table 55.5 Treatment options for prostate cancer • No treatment (watchful waiting) • Radical prostatectomy: Retropubic Perineal • Radiation therapy: External-beam Conformational external-beam Interstitial radiation

Comprehensive Geriatric Oncology

1290

• Hormonal therapy • Other therapies: Cryotherapy Proton therapy • Alternative therapy

actually being the cause of death.112,113 The hazard ratio for progression (and presumably clinical problems) continues to increase, such that US standards have defined a 10-year life-expectancy as the threshold for treatment. Thus, treatments with intent to cure will have limited benefit for men over the age of 70. The meta-analysis performed by Chodak et al104 from six watchful waiting studies gave 10-year disease-specific survival rates of 87%, 87%, and 34% for grade 1, 2, and 3 tumors, respectively. The non-metastatic rates at 10 years were 81%, 58%, and 26% for grade 1, 2, and 3 tumors, respectively. These data do not separate by stage at diagnosis, and higher-stage disease not surprisingly is associated with higher progression rates. The above data demonstrate that, even with grade 1 disease, about 20% of patients will have metastases by 10 years. For grade 2 tumors, the progression rate is 52% over 10 years, making active intervention a much more attractive proposition. From a patient decision-making process, this should be balanced by the upfront morbidity associated with active intervention. A complex subjective evaluative process is necessary for the patient to make the right choice of treatment for him as opposed to the right choice for the physician (Table 55.6). It is also apparent that many patients are poorly informed of these choices, but many are also unable to grasp complex issues for themselves, making it important for the physician to try and interpret the patient’s wishes and help him toward those goals. In many respects, watchful waiting trades lack of morbidity now for possible morbidity later (if the patient lives that long). When a patient makes that choice, there appears to be little benefit (in terms of reduction of quality of life) from focusing on tumor progression (whether by DRE or PSA) in the absence of symptomatic change. Despite this, current practice advises routine follow-up, which may vary from quarterly to annually, where changes in DRE and PSA will be measured. As part of the natural history, one might anticipate that nodules will enlarge and PSA will rise over time, inevitably having a negative impact upon the patient’s quality of life yet not benefiting the patient in any way. An extreme example of the unrealistic expectations instilled in many patients was an octogenarian who was unable to walk because of severe cardiac disease but who, along with his relatives, obsessed about his PSA and/or changes in DRE despite an absence of change in urinary symptoms. Interestingly, such patients become conditioned by practice of care such that they are offended by the notion that specific urologic follow-up is not helpful in the absence of a change in symptoms.

Prostate cancer in the elderly

1291

Radical prostatectomy (Table 55.7) Radical prostatectomy was first performed in 1904, yet it is only in the last two decades or so that it has seen an explosive growth in popularity. During the 1980s, the primary approach was radical retropubic prostatectomy. This technique was championed by Walsh and colleagues, who demonstrated that with anatomic dissection of the prostate, the penile nerves could be preserved and with them potency.114 Complete surgical descriptions will not be given here, but may be found in many surgical textbooks.114 Briefly, the retroperitoneum is exposed through a lower midline incision. The peritoneum is swept cephalad such that the lymph nodes surrounding

Table 55.6 Watchful waiting Pro

Con

• No side-effects of treatment

• The patient’s quality of life is negatively impacted by worrying over untreated cancer

• The disease may not impact the patient’s quality of life

• Treatment is unlikely to affect survival • The disease has a high likelihood of spreading given in less than 10 years long enough time • PSA will rise • The tumor will enlarge • Local symptoms may develop

Table 55.7 Radical prostatectomy Pro

Con

• Cancer is removed

• Major surgery is involved • There is a 90% impotence rate (but 50% of the population aged over 70 are impotent) • 30% will have some alteration in continence

the external iliac vessels are exposed and may be dissected along with the obturator nodes (Figure 55.1). If the nodes are negative, then the prostate is removed. The neurovascular bundles lie posterolateral to the prostate. The technique for preserving the nerves has been refmed over the last two decades.115 Previously, the nerves were preserved based upon where they were presumed to lie, whereas now they are identified and specifically dissected off the prostate. Blood loss during the procedure seems to have generally declined, such that autologous blood donation, commonplace during the 1980s, has come under fire as not being effective.116 Autologous blood donation at our institution costs $300 per unit, but is variably covered by insurance companies. Hospitalizations have also shrunk from a week

Comprehensive Geriatric Oncology

1292

or more a decade ago to about 2–3 days today, with the patient being admitted to the hospital postoperatively. The patient is discharged with a Foley catheter indwelling, to be removed 1–2 weeks after surgery depending upon the surgeon’s preference. Recovery time is about 2 months, although continence (if

Figure 55.1 Operative view of pelvis during exposure for radical retropubic prostatectomy. Note the neurovascular bundles posterolateral to the prostate, which is deep in the pelvis below the pubic symphysis. Table 55.8 Complications of radical prostatectomy and radiation therapy126,178 Rate (%) Complication Death

Radical prostatectomy

Radiation therapy 1

0.2

Any incontinence

27

6

Total incontinence

6

1

Any bowel injury

3

11

Bowel injury requiring long-term treatment

1

2

12

5

Stricture

Prostate cancer in the elderly

1293

Impotence

85

42

Diarrhea

—

4

Rectal bleeding

—

1

a problem) may continue to improve for up to 6 months following surgery. The main complications of this procedure are shown in Table 55.8. Urinary incontinence117 has been reviewed and found to be much more prevalent than previously published.118,119 However, a study at the University of Wisconsin-Madison demonstrated significant incontinence prior to treatment.119 It is important that patients understand that their continence mechanism will be different and that, while one-third of patients will lose some urine during stress, for most this will have a trivial impact upon their quality of life. A major problem with urinary control should occur in less than 5% of patients. Indeed, of the one-third of patients reported to have incontinence,117 many place a pad in their underwear merely for self-confidence rather than because they have any significant leakage. Interestingly, data evaluating Medicare claims for 1991 show that incontinence claims were only 8%.120 The other major issue with radical retropubic prostatectomy concerns potency. The early work from Walsh and his group suggested that about three-quarters of patients with localized disease would maintain potency. A review of Medicare patients found that about 90% were functionally impotent.117 Thus, while potency preservation is age- and stage-dependent, and while penile engorgement is different from rigidity, and with it the ability for vaginal penetration, when one looks at the overall patient population the majority will be impotent following surgery. Indeed, in a patient group aged over 70, it would only be the rare patient potent before surgery who would maintain this following surgery. For perspective, we have found that in general, for men in their 60s, about 25% were impotent and by their 70s 50% were impotent.121 Further, a recent study has evaluated the decline in potency for men treated

Comprehensive Geriatric Oncology

1294

Figure 55.2 Patient position for radical perineal prostatectomy. The enlargement shows the incision line

Prostate cancer in the elderly

1295

with the position of the prostate relatively superficial to the skin. by watchful waiting. This study demonstrated that even for men receiving no active treatment, there was a 17% decrease in potency during follow-up.122 Radical perineal prostatectomy Early in the 20th century, perineal prostatectomy was the approach of choice for prostatic surgery (Figure 55.2). In the early 1990s, the procedure underwent a revival, based upon this being a surgical procedure with less morbidity and with a shorter hospital stay and quicker recovery. In the last few years, however, the technical advances with radical retropubic prostatectomy have reduced hospital stay to an equivalent 2 days. Postoperative recovery times also approach each other. Finally, data have been presented suggesting a greater problem with rectal incontinence when the perineal approach is used.123 Laparoscopic radical prastatectomy The most recent development for radical prostatectomy has been the use of the laparoscopic approach. The first report was only in 1997.124 Unfortunately, the first attempts were hindered by very long operative times and less than stellar outcomes. However, in the last few years, several groups have revisited the laparoscopic approach, most notably a French team.125 This group has now reported 120 procedures, with operative times approaching 4 hours. Likewise, their continence and potency rates are similar to those of radical retropubic prostatectomy reports. The technique, however, requires five port sites and very advanced laparoscopic skills. Robotic camera control is usual, and the use of hand-controlled robots for the actual surgery will further the development of this technique. As yet, however, this approach is applicable in only a few very experienced centers. Radiation therapy (Table 55.9) Radiation therapy is the other main type of therapy for prostate cancer. The radiation may be delivered in several forms (Table 55.10): conventional external-beam, conformational external-beam, and interstitial radiation therapy. The most commonly utilized method of delivery is conventional external-beam. Modern therapy units utilize

Table 55.9 Radiation therapy for prostate cancer Pro

Con • Not surgery

• Efficacy debated • Impotence • Incontinence

Comprehensive Geriatric Oncology

1296

Table 55.10 Methods of radiation therapy for prostate cancer • Conventional external-beam radiotherapy: Four fields or rotational fields delivered using pelvic X-rays (pubic symphysis) to define the treatment fields • Conformational external-beam radiotherapy: Computer-guided using computed tomography (CT) reconstructed images for more precise localization to the prostate • Interstitial radiation: Radioactive pellets placed permanently or temporarily in the prostate for radiation delivery. Seeds are placed using ultrasound or CT guidance • Neoadjuvant hormonal therapy

linear accelerators. With increasing energy, side-effects from radiation therapy have decreased. The primary acute side-effects (Table 55.8) are radiation proctitis and cystitis.126 Chronic radiation cystitis and proctitis are much less common, but may be debilitating. Incontinence and impotence, while less than with radical prostatectomy, are still significant. Good studies comparing efficacy between radical prostatectomy and radiation therapy do not exist, but an evaluation of Radiation Therapy Oncology Group (RTOG) studies suggests that external-beam radiation therapy is 50% effective for T2 disease when viewed from 15-year follow-up data.127 Patients with T1 disease show 15-year survivals in keeping with life-table expectant survivals, although this is also true for the watchfiil waiting group. In an attempt to improve on survival data (especially for stage T2 patients), the idea of conformational radiation therapy was developed.127 In order to increase the delivered radiation dose, in excess of 7000 cGy, the scientific disciplines of medical physics, radiation dosimetry, computer science, statistics and probability, radiology, and radiation oncology have been combined to deliver increased doses of radiation precisely (conforming) to the prostate.128 Three-dimensional images of the prostate are obtained using computed tomography (CT), from which pseudo-three-dimensional images are developed. With these models, it is now possible to deliver radiation precisely to the prostate and therefore at greater doses. Standard techniques use 7cm×7cm to 8cm×8cm boxes centered 1 cm superior to the symphysis in the anteroposterior dimension and over the femoral neck for the lateral projection. Using such techniques, there is a 25% geographic miss of part of the prostate.129 Preliminary reports suggest that dose escalations to 7400–8040 cGy are possible using conformational radiation without an increase in normal-tissue side-effects. However, long-term studies will be required to define improvements in efficacy. Attempts to improve outcomes for patients treated with external-beam radiation led to protocols involving neoadjuvant hormonal therapy.130,131 At 3–5 years, the diseasefree rates were approximately double in favor of the neoadjuvant groups (36% versus 15%, and 85% versus 48%)

Prostate cancer in the elderly

1297

Prostate brachytherapy The insertion of radioactive seeds into the prostate now has a long history. A variety of isotopes have been inserted, with iodine-125 (125I) being the most common. One of the largest series utilizing manually placed seeds came from the Memorial Sloan-Kettering Cancer Center, New York.132 In this series, a formal retropubic dissection was performed and the seeds were placed manually with a trocar. Dosimetry reconstructions have suggested significant problems with underdosing, such that long-term results have been poor (70% progression at 10 years). In an attempt to improve on these results, seeds are now placed using ultrasound or CT guidance. The anesthetized patient is placed in the lithotomy position. A template is placed against the perineal skin and is used, along with transrectal ultrasound, to place the seeds in the prostate. Some long-term data are now available demonstrating a disease-free survival rate of 66% at 10 years.133 One debate within the radiation oncology community concerns the use of adjuvant external-beam radiation with brachytherapy. The general sentiment is that for patients with low grade, low stage, low volume (<50 cm3), and PSA <10 ng/ml, brachytherapy alone is appropriate.134 For tumors not fitting these parameters, the recommendation is for adjuvant external-beam radiation. A set of guidelines has been published by the American Brachytherapy Society defining these parameters for treatment.135 The one additional group comprises those patients with large glands. They may be acceptable for treatment if the gland is reduced in size by neoadjuvant hormonal therapy.134 Overall, brachytherapy is the most rapidly growing form of treatment for the Medicare population. Cryotherapy The concept of freezing tissue for the purpose of destruction has been around for many years. Consequently, cryotherapy of the prostate has not required Food and Drug Administration (FDA)-controlled trials in the USA. Interestingly, the medical insurance industry has taken a different approach, and generally has not accepted cryotherapy as a covered benefit. Thus, patients have been treated in multiple centers around the USA without even appropriate animal studies being conducted. We have, however, conducted animal studies at the University of Wisconsin-Madison, and have demonstrated a failure to destroy all prostatic tissue. Essentially, the procedure consists of inserting multiple probes perineally into the prostate under transrectal ultrasound guidance. A transurethral warming catheter is placed in order to preserve the prostatic urethral mucosa, and the prostate is frozen by circulating liquid nitrogen through the cryoprobes. The iceball thus created is monitored with transrectal ultrasound. Clinical data from salvage radical prostatectomy after cryotherapy have confirmed the lack of destruction of prostatic tissue despite the obvious ‘iceball’ appearance involving the complete prostate.136 This same investigation found that 59% of treated patients suffered from complications, the most frequent of which were urinary retention (29%), urinary incontinence (27%), tissue slough (19%), and perinealpain (11%).136

Comprehensive Geriatric Oncology

1298

Cryotherapy has also been used for radiation failures. The initial data were not promising,137 but more recent data have been more encouraging, with a biochemical disease-free survival rate of 66% at 1 year.138 Interestingly, these data have satisfied the HCFA to the extent that they will now reimburse for salvage cryotherapy. Alternative therapies The use of alternative medicine is now so widespread that it should be evaluated for all patients.139 The most common of these therapies include herbal medicine, massage, megavitamins, self-help groups, folk remedies, energy healing, and homeopathy.140 The use of alternative medicine in the USA increased from 36.3% in 1990 to 46.3% in 1997.140 Additionally, 60% of the use of alternative medicine is out of pocket, and equated to $12 billion in 1997. Stress has been shown to decrease the body’s immune function, and the use of meditation and Chinese medicine may help to reduce stress and improve the overall outlook for the patient.141,142 In general, the issues of overall health that apply to prevention apply also to treatment. Dietary inclusion of fruits, vegetables, and soy products has generally found to be good, while reducing fat intake is also helpful.71,143 One treatment that has received much publicity is the Chinese herb preparation PCSPES for the treatment of androgen-independent cancers.144 This herb combination has obvious estrogenic effects, but additionally has other beneficial effects, which are as yet poorly characterized. Metastatic disease Once prostate cancer spreads beyond the prostate, cure is not possible. Indeed, even for localized disease, palliative therapy may be used as the primary treatment for older patients (aged 70–75 and older). In 1941, Huggins and Hodges145 noted the hormone sensitivity of prostate cancer. Over the past half-century, newer methods of hormonal manipulation have been developed, but the fundamental outlook of patients with metastatic prostate cancer has not significantly changed. All clinical methods for hormonal therapy of metastatic prostate cancer work by blocking the various steps of androgen production, secretion, or action (Figure 55.3). Orchiectomy is the most basic form of androgen ablation, and is the standard against which all other therapies should be compared. Because the testes produce 95% of serum testosterone, bilateral orchiectomy results in an immediate decrease in androgen blood levels. This fall will sometimes give overnight ‘relief from painful metastases. No chemical methods can provide such an immediate effect. For those patients who refuse orchiectomy, the standard treatment, until recently, was diethylstilbestrol (DES). In the 1960s, studies were conducted by the US Veterans Administration Cooperative Urologic Research Group (VACURG). These studies looked at all stages of

Prostate cancer in the elderly

1299

Figure 55.3 The sites of action for drugs controlling androgen production or activity on the prostate cell: (A) gonadotropin-releasing hormone; (B) estrogens; (C) ketoconazole; (D) megestrol acetate; (E) cyproterone acetate; (F) non-steroidal antiandrogens; R, androgen receptor; DHT, dihydrotestosterone. prostate cancer.146–151 For patients with focal localized disease, they found that the addition of estrogen treatment to radical prostatectomy decreased survival, presumably owing to the side-effects of estrogen.146 Patients who refused participation in this study

Comprehensive Geriatric Oncology

1300

were offered participation in the second study, randomizing placebo, DES, and orchiectomy with and without estrogen.148 No significant differences were seen between the groups or with the radical prostate group in the other study. This study also demonstrated that only 6.8% of patients progressed during the study (mean age 73). More recent studies have shown progression rates for stage A1 or stage T1 disease of 9–16%. Patients with metastatic disease were treated with placebo, orchiectomy with and without DES or DES alone, 5 mg/day.149 No significant differences were seen in patient survival over 5 years. It should be noted that patients who progressed were taken off study and treated individually. Thus, most placebo patients were treated hormonally at progression. This suggests that delayed hormonal treatment is not detrimental to patient survival. One other observation from the first VACURG study was the excess number of deaths from cardiovascular causes in the estrogen-treated patients. This led the investigators to evaluate different doses of DES, namely 0.2, 1, and 5mg/day.149 This study revealed that 0.2mg/day was not sufficient to control the prostate cancer, while 5mg/day caused an excess of cardiovascular deaths.152,153 Subsequent studies demonstrated that 1 mg/day did not reliably suppress testosterone production, while 1 mg three times daily did not cause an increase in cardiovascular deaths. Combined, the data for DES or orchiectomy show that 10% of patients die within 6 months and 50% within 2.5 years, while 10% are alive 10 years later.154 More recently, the morbidity associated with estrogen therapy has been studied further. One non-randomized study evaluated 48 patients treated with DES 1 mg three times daily. Over a 4-year period, 14 cardiovascular complications were seen.155 The control arm of 37 patients who underwent a bilateral orchiectomy suffered only three cardiovascular complications. In an attempt to understand the mechanism of this increased risk, investigators measured serum levels of antithrombin-III. Antithrombin-III is an oc-globulin synthesized in the liver and is the single most important physiologic inhibitor of blood coagulation. In one study, antithrombin-III levels were reduced by 25% in patients on 5 mg/day DES, while no changes were seen with 1 mg/day.156 In another study, no differences were seen between 1 and 3mg/day in the effected antithrombin-III levels, although the numbers in the study were very small.157 Interestingly, when the gonadotropin-releasing hormone (GnRH) agonist goserelin was studied, no change was seen, while the antiandrogen cyproterone acetate increased antithrombin-III levels.158,159 GnRH analogs produce castrate levels of testosterone through their action on the pituitary gland.160 Although 50–100 times more potent than the natural hormone, chronic administration depletes pituitary luteinizing hormone (LH) and downregulates GnRH receptors, making the pituitary refractory to further stimulation. Extrapituitary effects of GnRH analogs include the desensitization of the gonads to LH and direct gonadal steroid enzyme inhibition, further decreasing testosterone production.160 In a multicenter study, leuprolide was compared with DES 3 mg/day. In this study, 98 and 101 patients, respectively, were assigned to each arm.161 In the DES group, testosterone levels fell to anorchic levels within 2 weeks, while in the leuprolide group, testosterone levels rose during the first week and only reached anorchic levels at 4 weeks. No differences in progression rates or survival were seen between the two arms. Nausea, vomiting, and edema were significantly increased in the DES group (16% versus 5%), and, while not significant, thrombosis or phlebitis and pulmonary embolus were also increased in the DES group (7% versus 1%). This study demonstrated that daily

Prostate cancer in the elderly

1301

leuprolide injections were equally as effective as DES in treating prostate cancer, but with fewer side-effects. Current formulations of the available GnRH agonists (leuprolide and goserelin) require monthly injections. One problem with the GnRH analogs concerns their agonistic properties. Prior to blocking testosterone production, they stimulate the testes to increase the output of testosterone. This may be associated with increased pain from metastasis, and anecdotally has resulted in paralysis and even death. This is the so-called ‘flare phenomenon’. In an attempt to control this problem and to block the effects of adrenal androgens, Labrie et al162 pioneered combination treatment with GnRH analogs together with the antiandrogen flutamide. Flutamide is a non-steroidal antiandrogen that acts by blocking the effects of dihydrotestosterone on the cell nucleus. This phenomenon will negate the effects of initial rise in testosterone levels and permanently block the effects of adrenal steroids. This type of combination has been termed complete androgen blockade. A national cooperative study group compared the response to the GnRH analog leuprolide with or without the addition of flutamide.163 This study, with more than 600 patients, demonstrated improved overall survival for patients treated with leuprolide plus flutamide. When the data were analyzed relative to the extent of metastases, those patients with minimal metastatic disease did markedly better with the addition of flutamide. This difference was not seen for patients with large-volume metastatic disease. Flutamide has two major problems. Diarrhea has been a problem for 12% of patients. Much less common, but more serious, is hepatic dysfunction. A report from the FDA demonstrated a mortality rate from flutamide of 3 per 10 000 patients treated.164 It is therefore extremely important that patients have liver function checked for the first few months after starting treatment and also that patients be instructed to report any problems with nausea, vomiting, fatigue, or jaundice. The whole issue of complete androgen blockade has been called into question as a result of a trial comparing orchiectomy with or without the addition of flutamide.165 This study randomized 1387 patients to each arm. The results demonstrated no difference between the arms. While leuprolide is different from orchiectomy, the net result is similar, and as this study was twice the size of the previous study,163 it raises serious doubts about the use of combined androgen blockade. One caveat, however, concerns the potential flare phenomenon during the first 2 weeks of GnRH use, when a non-steroidal antiandrogen may still have some utility. Another non-steroidal antiandrogen, bicalutamide, has been approved by the FDA. This drug has once-a-day dosing (compared with three times a day for flutamide). In an 800-patient study, bicalutamide was compared with flutamide, with both being used in combination with a GnRH agonist.166 Bicalutamide was shown to be at least as effective as flutamide. The severe diarrhea rate for bicalutamide was much less than that for flutamide (0.5% versus 6%). Of note, however, the abnormal liver function test rate was similar for both drugs. Thus, it is extremely important to evaluate liver function when any non-steroidal antiandrogen is being used for therapy. Bicalutamide is also undergoing testing as a single agent for use in metastatic prostate cancer In summary, hormonal manipulation will benefit approximately 75% of patients with newly diagnosed metastatic prostate cancer. The median duration of response is approximately 15 months. Following failure of hormonal therapy to control the disease,

Comprehensive Geriatric Oncology

1302

median survival is less than 1 year. The spectrum of survival from diagnosis of metastatic disease is wide. In the Veterans Administration study conducted during the 1960s, 10% of patients survived for less than 6 months and 10% for longer than 10 years, while the median survival was about 2.5 years. Furthermore, when ‘off-study’ patient data were analyzed, those initially treated with placebo fared no worse than those actively treated at the beginning of the study.167 Since the publication of the orchiectomy with/without flutamide study,164 the use of combined androgen blockade has waned. Current research studies are continuing to evaluating the effect of intermittent hormone therapy. Essentially, patients are treated for about 9 months with a GnRH agonist. If the PSA returns to normal and the patient becomes essentially asymptomatic, the GnRH agonist is discontinued and the patient is followed off therapy until such time as the PSA starts rising again, when the cycle is repeated. There have been anecdotal reports that patients failing complete androgen blockade have had a symptomatic, and PSA, response to the withdrawal of flutamide.168 The precise mechanism is not clear, but this is now the subject of clinical cancer group investigations. One complication common to the various hormonal manipulations is the phenomenon of hot flashes. After orchiectomy, this problem is rarely reported, yet when patients are specifically questioned, its prevalence appears much higher. Studies of GnRH agonists and DES have shown incidences of 51% and 11%, respectively. The etiologic mechanism remains obscure. The only event common to the described treatments is a rapid reduction in androgen levels. Orchiectomy causes an increase in GnRH and LH as a consequence of loss of feedback inhibition. GnRH agonists exogenously increases GnRH while decreasing LH and testosterone levels. Estrogen suppresses GnRH, LH, and testosterone production. The treatment for men (and women) is estrogen therapy. It has been suggested that after orchiectomy this works by suppression of GnRH and LH production. For some patients, estrogens are contraindicated for cardiovascular reasons. For these patients, the antiandrogen cyproterone acetate has been used successfully.169 As a progestational agent, cyproterone acetate inhibits GnRH production, and it is probably this mechanism that is active rather than its antiandrogenic activities at the cellular level. More recently, clonidine and megestrol acetate have been reported to be successful in the treatment of hot flashes.170,171 Clinically, they are rarely a problem, although their prevalence is much greater if patients are questioned about them than if they are not. Again, the severity of the hot flashes tends to diminish with time. Chemotherapy Active chemotherapeutic agents are urgently needed for prostate cancer. To date, no drug has achieved a standard ‘therapy’ status. Over the years, many drugs have been utilized without success. The drugs that have been utilized have been reviewed.172,173 Because no drugs have defined themselves to be extremely effective, they will not be discussed further, since the information would already be out of date by the time of publication.

Prostate cancer in the elderly

1303

Quality of life Earlier in this chapter, we touched upon the fact that as patients get older—frequently with multiple comorbidities—their quality of life becomes as important as, and frequently surpasses, the issue of quantity of life. In a study of patient outcomes from radical prostatectomy or radiation therapy, surgical patients suffered more incontinence and impotence, while the radiation patients had more bowel problems.174 Interestingly, patients aged over 70 had less bother with impotence than those who were younger. The logical explanation for this is a change in the importance of such issues to patients’ quality of life. Another study of psychosocial issues found that patients attached more importance to this issue of impotence than their partners (wives).175 Conversely, this same study found that partners were more concerned about pain and physical limitation issues than patients. Overall, there was general cancer distress in 47% of patients and 76% of partners. As might be expected, quality of life decreased inexorably during the last year of life.176 Physical function deteriorated more rapidly for men with prostate cancer than for those dying from other cancers or benign disease. Areas for research The fundamental problem with carcinoma of the prostate is that most people with histologic prostate cancer die with and not from their disease. Conversely, adenocarcinoma of the prostate is the second leading cause of cancer death in men. The challenge, therefore, is to diagnose those cancers destined to have a malignant course early in the disease process so that interventions with curative intent will be successful. Compounding the problem is molecular heterogeneity between multiple cancers within the same prostate. Genetic studies of multiple foci of cancer within the prostate have demonstrated multiple different abnormalities. The problem is thus that a metastasis may have a genetic abnormality that cannot be seen on a biopsy of only one area of tumor. Thus, even with the development of relevant molecular probes, there will still remain many hurdles to overcome in being able to prognosticate from the diagnosis of prostate cancer to its outcome. However, as we come to understand the genetic biology of prostate cancer more thoroughly, it seems more plausible that some form of gene therapy may be developed in the relatively near future.177 References 1. Cancer statistics, 2001. CA Cancer J Clin 2001; 51:15–36. 2. Cancer statistics, 1975. CA Cancer J Clin 1975; 25:8–26. 3. Mettlin C, Jones G, Averette H et al. Defining and updating the American Cancer Society guidelines for the cancer-related checkup: prostate and endometrial cancers. CA Cancer J Clin 1993; 43:42–6. 4. Young H. A Surgeons Autobiography. New York: Harcourt, Brace, 1940.

Comprehensive Geriatric Oncology

1304

5. National Cancer Institute Economic Conference: The integration of economic outcome measures into NCI-sponsored therapeutic trials. Monogr J Natl Cancer Inst 1995; 19. 6. Cannon L, Bishop DT, Skolnick M et al. Genetic epidemiology of prostate cancer in the Utah Mormon genealogy. Cancer Surv 1982; 1:47. 7. Steinberg GD, Carter BS, Beaty TH et al. Family history and the risk of prostate cancer. Prostate 1990; 17:337–47. 8. Spitz MR, Currier RD, Fueger JJ et al. Familiar patterns of prostate cancer: a case-control analysis. J Urol 1991; 146:1305–7. 9. Carter BS, Beaty TH, Steinberg GD et al. Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci USA 1992; 89:3367–71. 10. Carter BS, Bova GS, Beaty TH et al. Hereditary prostate cancer: epidemiologic and clinical features. J Urol 1993; 150:797–802. 11. Smith JR, Freije D, Carpten JD et al. Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Science 1996; 274:1371–4. 12. Gronberg H, Xu J, Smith J et al. Early age at diagnosis in families providing evidence of linkage to the hereditary prostate cancer locus (HPC1) on chromosome 1. Cancer Res 1997; 57:4707–9. 13. Berthon P, Valeri A, Cohen-Akenine A et al. Predisposing gene for early-onset prostate cancer, located on chromosome 1q42.2–43. Am J Hum Genet 1998; 62:1416–24. 14. Xu J, Meyers D, Freije D et al. Evidence for a prostate cancer susceptibility locus on the X chromosome. Nat Genet 1998; 20: 175–9. 15. Gibbs M, Stanford J, Mclndoe R et al. Evidence for a rare prostate cancer susceptibility locus at chromosome 1p36. Am J Hum Genet 1999; 64:776–87. 16. Ford D, Easton DF, Bishop DT et al. Risk of cancer in BRCAl-mutation carriers. Lancet 1994; 343:692–5. 17. Thorlacius S, Struewing J, Hartge P et al. Population-based study of risk of breast cancer in carriers of BRCA2 mutation. Lancet 1998; 352:1337–9. 18. Easton D, Steele L, Fields P et al. Cancer risks in two large breast cancer families linked to BRCA2 on chromosome 13q12–13. Am J Hum Genet 1997; 61:120–8. 19. Foster CS, Cornford P, Forsyth L et al. The cellular and molecular basis of prostate cancer. BJU Int 1999; 83:171–94. 20. Brothman AR, Peehl DM, Patel AM, McNeal JE. Frequency and pattern of karyotypic abnormalities in human prostate cancer. Cancer Res 1990; 50:3795–803. 21. Carter BS, Ewing CM, Ward WS, Treiger BF. Allelic loss of chromosomes 16q and 10q in human prostate cancer. Proc Natl Acad Sci USA 1990; 87:8751–5. 22. Bergerheim USR, Kunimi K, Collins VP, Ekman P. Deletion mapping of chromosomes 8, 10 and 16 in human prostate carcinoma. Genes Chromosomes Cancer 1991; 3:215–20. 23. Moul JM, Gaddipati J, Srivastava S. Molecular biology of prostate cancer: oncogenes and tumor suppressor genes. In: Prostate Cancer (Dawson NA, Vogelzang NJ, eds). New York: Wiley-Liss, 1994: 19–46. 24. Peehl DM, Wehner N, Stamey TA. Activated Ki-ras oncogene in human prostatic adenocarcinoma. Prostate 1987; 10:281–9. 25. Buttyan R, Sawczuk IS, Benson MC, Siegal JD, Olsson CA. Enhanced expression of the c-myc proto-oncogene in high-grade human prostate cancer. Prostate 1987; 11:327–37. 26. Habib FK, Chisholm GD. The role of growth factors in the human prostate. Scand J Urol Nephrol Suppl 1991; 126:53–58. 27. Pergolizzi RG, Kreis W, Rottach C et al. Mutational status of codons 12 and 13 of the N and K ras genes in tissue and cell lines derived from primary and metastatic prostate carcinomas. Cancer Invest 1993; 11:25–32. 28. Carter BS, Epstein JI, Isaacs WB. ras gene mutations in human prostate cancer. Cancer Res 1990; 50:6830–2.

Prostate cancer in the elderly

1305

29. Gumerlock PH, Poonmallee UR, Meyers FJ, de Vere White RW. Activated ras alleles in human carcinoma of the prostate are rare. Cancer Res 1991; 51:1632–7. 30. Moul JW, Lance RS, Friedrichs PA et al. Infrequent ras oncogene mutations in human prostate cancer. Prostate 1992; 20:327–38. 31. Konishi N, Enomoto T, Buzard G et al. K-ras activation and ras p21 expression in latent prostatic carcinomas in Japanese men. Cancer 1992; 69:2293–9. 32. Anwar K, Nakakuki K, Shiraishi T et al. Presence of ras oncogene mutations and human papillomavirus DNA in human prostate carcinomas. Cancer Res 1992; 52:5991–6. 33. Volgelstein B, Kinzler KW. p53 function and dysfunction. Cell 1992; 70:523–6. 34. Lowe SW, Schmitt EM, Smith SW et al. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 1993; 362: 847–9. 35. Levine AJ, Momand J, Finlay CA. The p53 tumor suppressor gene. Nature 1991; 351:453–6. 36. Hamdy FC, Thurrell W, Lawry J, Anderson JB. p53 mutant expression correlates with hormone sensitivity and prognosis in human prostatic adenocarcinoma. J Urol 1993; 149:377A. 37. Eastham JA, Stapleton AM, Gousse AE et al. Association of p53 mutations with metastatic prostate cancer. Clin Res 1995; 1: 1111–18. 38. McDonnell TJ, Troncoso P, Brisbay SM et al. Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen independent prostate cancer. Cancer Res 1992; 52:6940–4. 39. Vaux DL. Towards an understanding of the molecular mechanisms of physiological cell death. Proc Natl Acad Sci USA 1993; 90: 786–789. 40. White E. Life, death, and the pursuit of apoptosis. Genes Dev 1996; 10:1–15. 41. Clem RJ, Miller LK. Control of programmed cell death by the baculovirus genes p35 and IAP. Mol Cell Biol 1994; 14:5212–22. 42. Pietrzkowski Z, Wernicke D, Porcu P et al. Inhibition of cellular proliferation by peptide analogues of insulin-like growth factor 1. Cancer Res 1992; 52:6447–51. 43. Watson RWG, Fitzpatrick JM. Target sites for manipulating apoptosis in prostate cancer. BJU Int 2000; 85(Suppl 2): 38–44. 44. Henkart PA. ICE family proteases: mediators of all apoptotic cell death. Immunity 1996; 4:195– 201. 45. Armstrong RC, Aja T, Xiang J et al. Fas-induced activation of the cell death-related protease CPP.32 is inhibited by Bcl-2 and by ICE family protease inhibitors. J Biol Chem 1996; 271:16850–5. 46. Kubota Y, Shuin T, Uemura H et al. Tumor suppressor gene p53 mutations in human prostate cancer. Prostate 1995; 27:18–24. 47. Even G, Harrington E, Fanidi A et al. Integrated control of cell proliferation and cell death by the c-myc oncogene. Proc R Soc Lond B Biol Sci 1994; 345:269–75. 48. Phillips SM, Bartin CM, Lee SJ et al. Loss of the retinoblastoma susceptibility gene (RB1) is a frequent and early event in prostatic tumorigenesis. Br J Cancer 1994; 70:1252–7. 49. Habib FK. Thebiology of benign prostatic hyperplasia and prostate cancer. In: Trends in Experimental and Clinical Medicine (Pavone-Macaluso M, Smith PH, eds). Genova: 1995. 50. Kyprianou N, Isaacs JT. Identification of a cellular receptor of transforming growth factor beta in rat ventral prostate and its negative regulation by androgens. Endocrinology 1988; 123: 2124–31. 51. Montpetit ML, Lawless KR, Tenniswood M. Androgen-repressed messages in the rat of ventral prostate. Prostate 1986; 8:25–36. 52. Kyprianou N, Isaacs JT. Expression of transforming growth factor (3 in the rat ventral prostate during castration induced programmed cell death. Mol Endocrinol 1989; 3:1515–22. 53. Moon TD, Morley JE, Levine A et al. The role of calmodulin in human renal cell carcinoma. Biochem Biophys Res Commun 1983; 114:843–9. 54. Li P, Nijhawan D, Budihardjo I et al. Cytochrome c and dATP-dependent formation of Apaf1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997; 91:479–89.

Comprehensive Geriatric Oncology

1306

55. Maddy SQ, Chisholm GD, Hawkins RA, Habib FK. Localization of epidermal growth factor receptors in the human prostate by biochemical and immunocytochemical methods. J Endocrinol 1987; 112:147–53. 56. Mellon K, Thompson S, Chaolton RG. p53, c-erbB-2 and the epidermal growth factor receptor in the benign and malignant prostate. J Urol 1992; 147:496–9. 57. Maddy SQ, Chisholm GD, Busuttil A, Habib FK. Epidermal growth factor receptors in human prostate cancer: correlation with histological differentiation of the tumor. Br J Cancer 1989; 60:41–4. 58. Yang Y et al. Epidermal growth factor and transforming growth factor oc concentrations in BPH and cancer of the prostate: Their relationships with tissue androgen levels. Br J Cancer 1993; 67: 152–5. 59. Timme TL, Truang LD, Merz VW. Mesenchymal/epithelial interaction and transforming growth factor β expression during mouse prostate morphogenesis. Endocrinology 1994; 134:1039–45. 60. Story MT et al. Influence of androgen in transforming growth factor β on basic fibroblast growth factor levels in human prostate derived fibroblast cell cultures. J Urol 1990; 143: A211. 61. Thomson TC. Growth factors and oncogenes in prostate cancer. Cancer Cells 1990; 2:345–54. 62. Moon TD, Sloane BB. Prostatic adenocarcinoma: carcinogenesis and growth. J Am Geriatr Soc 1989; 37:55–64. 63. Lubamn DB, Joseph DR, Sullivan PM et al. Cloning of human androgen receptor complimentary DNA and localization to the X chromosome. Science 1988; 240:327–30. 64. Wilding G, Chen M, Gelmann EP. Aberrant response in vitro of hormone-responsive prostate cancer cells to antiandrogens. Prostate 1989; 14:103–15. 65. Harris S, Harris MA, Rong Z et al. Androgen regulation of HβGFI (αFGF) mRNA and characterization of the androgen-receptor mRNA in the human prostate carcinoma cell lineLNCaP/A-DEP. In: Molecular and Cellular Biology of Prostate Cancer, (Karr JP, Coffey DS, Smith RG, Tindall DJ, eds). New York: Plenum Press, 1991:315–30. 66. Noble RL. The development of prostatic adenocarcinoma in Nb rats following prolonged sex hormone administration. Cancer Res 1977; 37:1929–33. 67. Noble RL, Hoover L. A classification of transplantable tumors in Nb rats controlled by estrogen from dormancy to autonomy. Cancer Res 1975; 35:2935–41. 68. Coffey DS. The biochemistry and physiology of the prostate. In: Campbell’s Urology, 8th edn (Walsh PC, Retik AB, Stamey TA, Vaughan ED, eds). Philadelphia: WB Saunders, 2002. 69. Greenwald P, Vincenne K, Polan AK et al. Cancer of the prostate among men with benign prostatic hyperplasia. J Natl Cancer Inst 1974; 53:335–40. 70. Armenian HK, Lilienfeld AM, Diamond EL, Bross, ID. Relation between benign prostatic hyperplasia and cancer of the prostate: a prospective and retrospective study. Lancet 1974; ii: 115–17. 71. Blumenfeld AJ, Fleshner N, Casselman B, Trachtenberg J. Nutritional aspects of prostate cancer: a review. Can J Urol 2000; 7: 927–35. 72. Heinonen OP, Albanes D, Virtamo J et al. Prostate cancer and supplementation with αtocopherol and β-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst 1998; 90:440–6. 73. Nelson MA, Porterfield BW, Jacobs ET, Clark LC. Selenium and prostate cancer prevention. Semin Urol Oncol 1999; 17:91–6. 74. Konety BR, Johnson CS, Trump DL, Getzenberg RH. Vitamin D in the prevention and treatment of prostate cancer. Semin Urol Oncol 1999; 17:77–84. 75. Moyad MA, Brumfield SK, Pienta K. Vitamin E, α- and γ-tocopherol, and prostate cancer. Semin Urol Oncol 1999; 17:85–90. 76. Moyad MA. Soy, disease prevention, and prostate cancer. Semin Urol Oncol 1999; 17:97–102. 77. Gupta S, Ahmad N, Mukhtar H. Prostate cancer chemoprevention by green tea. Semin Urol Oncol 1999; 17:70–6.

Prostate cancer in the elderly

1307

78. Moon TD, Brawer MK, Wilt TJ. Prostate Intervention Versus Observation Trial (PIVOT): a randomized trial comparing radical prostatectomy with palliative expectant management for treatment of clinically localized prostate cancer. J Natl Cancer Inst 1995; 19:69–71. 79. Holtgrewe HL. The economics of urological care in the 21st century. Urology 1995; 46:1–3. 80. Albertsen PC, Hanley JA, Gleason DF, Barry MJ. Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA 1998; 280: 975–80. 81. The US Preventive Taskforce. Screening for prostate cancer: commentary on the recommendations on the Canadian Task Force on the Periodic Health Examination. Am J Prev Med 1994; 10: 187–93. 82. Feightner JW. The early detection and treatment of prostate cancer: the perspective of the Canadian Task Force on the Periodic Health Examination. J Urol 1994; 152:1682–4. 83. Coley CM, Barry MJ, Fleming C et al. Should medicare provide reimbursement for prostatespecific antigen testing for early detection of prostate cancer? Part II: Early detection strategies. Urology 1995; 46:125–41. 84. Catalona WJ, Richie JP, Ahmann FR et al. Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men. J Urol 1994; 151:1283–90. 85. Richie JP, Ratliff TL, Catalona WJ et al. Effect of patient age on early detection of prostate cancer with serum prostate-specific antigen and digital rectal examination. Urology 1993; 42:365–74. 86. McCormack RT, Rittenhouse HG, Finlay JA et al. Molecular forms of prostate-specific antigen and the human kallikrein gene family: a new era. Urology 1996; 45:729–42. 87. Neal DE, Clejan S, Sarma D, Moon TD. Prostate specific antigen and prostatits I. Effect of prostatitis on serum PSA in the human and nonhuman primate. Prostate 1996; 20:105–12. 88. Moon TD, Clejan S, Neal DE. Prostate specific antigen and prostatitis II. PSA production and release kinetics in vitro. Prostate 1996; 20:113–16. 89. Stamey TA, McNeal JE. Adenocarcinoma of the prostate. In: Campbell’s Urology, 8th edn (Walsh PC, Retik AB, Stamey TA, Vaughan ED, eds). Philadelphia: WB Saunders, 2002. 90. Brawer M. How to use prostate-specific antigen in the early detection or screening for prostatic carcinoma. CA Cancer J Clin 1995; 45:148–64. 91. Stenman UH, Hakama M, Knekt P et al. Serum concentrations of prostate specific antigen and its complex with alpha 1-antichymotrypsin before diagnosis of prostate cancer. Lancet 1994; 344: 1594–8. 92. Benson MC, Whang IS, Pantuck A et al. Prostate specific antigen density: a means of distinguishing benign prostatic hypertrophy and prostate cancer. J Urol 1992; 147:815–16. 93. Brawer MK, Aramburu EA, Chen GL et al. The inability of prostate specific antigen index to enhance the predictive value of prostate specific antigen in the diagnosis of prostatic carcinoma. J Urol 1993; 150:369–73. 94. Carter HB, Pearson JD, Metter EJ et al. Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA 1992; 267:2215–20. 95. Riehmann M, Rhodes PR, Cook TD et al. Analysis of variation in prostate-specific antigen values. Urology 1993; 42:390–7. 96. Oesterling JE, Cooner WH, Jacobsen SJ et al. Influence of patient age on the serum PSA concentration. An important clinical observation. Urol Clin North Am 1993; 20:671–80. 97. Dalkin BL, Ahmann FR, Kopp JB. Prostate specific antigen levels in men older than 50 years without clinical evidence of prostatic carcinoma. J Urol 1993; 150:1837–9. 98. Catalona WJ, Hudson A, Scardino PT et al. Selection of optimal prostate specific antigen cutoffs for early detection of prostate cancer: receiver operating characteristic curves. J Urol 1994; 152:2037–42. 99. Brawer MK, Chetner MP, Beatie J et al. Screening for prostatic carcinoma with prostate specific antigen. Urology 1992; 147:841–5.

Comprehensive Geriatric Oncology

1308

100. Catalona WJ, Smith DS, Ratliff TL, Basler JW. Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA 1993; 270:948–54. 101. Gustafsson O, Norming U, Almgard LE et al. Diagnostic methods in the detection of prostate cancer: a study of a randomly selected population of 2,400 men. J Urol 1992; 148:1827–31. 102. Schroder FH, Roobol-Bouts M, Vis AN et al. Prostate-specific antigen-based early detection of prostate cancer—validation of screening without rectal examination. Urology 2001; 57:83– 90. 103. Johansson JE, Adami HO, Andersson SO et al. High 10-year survival rate in patients with early, untreated prostatic cancer. JAMA 1992; 267:2191–6. 104. Chodak GW, Thisted RA, Gerber GS et al. Results of conservative management of clinically localized prostate cancer. N Engl J Med 1994; 330:242–8. 105. Fleming C, Wasson JH, Albertsen PC et al. A decision analysis of alternative treatment strategies for clinically localized prostate cancer. JAMA 1993; 269:2650–8. 106. Beck JR, Kattan MW, Miles BJ. A critique of the decision analysis for clinically localized prostate cancer. J Urol 1994; 152:1894–9. 107. Hodge KK, McNeal JE, Terris MK, Stamey TA. Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. J Urol 1989; 142:71–4. 108. Presti JC Jr, Chang JJ, Bhargava V, Shinohara K. The optimal systematic prostate biopsy scheme should include 8 rather than 6 biopsies: results of a prospective clinical trial. J Urol 2000; 163:163–7. 109. Babaian RJ, Toi A, Kamoi K et al. A comparative analysis of sextant and an extended 11-core multisite directed biopsy strategy. J Urol 2000; 163:152–7. 110. Montie JE. 1992 Staging system for prostate cancer. Semin Oncol 1992; 11:10–13. 111. Gleason DF. Classification of prostatic carcinomas. Cancer Chemother Rep 1966; 50:125–8. 112. Woolf SH. Public health perspective: the health policy implications of screening for prostate cancer. J Urol 1994; 152:1685–8. 113. Wilt TJ, Brawer MK. The Prostate Cancer Intervention Versus Observation Trial: a randomized trial comparing radical prostatectomy versus expectant management for the treatment of clinically localized prostate cancer. J Urol 1994; 152:1910–14. 114. Walsh PC. Radical retropubic prostatectomy. In: Campbell’s Urology (Walsh PC, Retik AB, Stamey TA, Vaughan ED, eds). Philadelphia: WB Saunders, 1992:2865–86. 115. Steiner MS. Anatomic basis for the continence-preserving radical retropubic prostatectomy. Semin Urol Oncol 2000; 18:9–18. 116. Goad JR, Eastham JA, Fitzgerald KB et al. Radical retropubic prostatectomy: limited benefit of autologous blood donation. Urology 1995; 154:2103–9. 117. Fowler FJ, Barry MJ, Lu-Yao G et al. Patient-reported complications and follow-up treatment after radical prostatectomy. Urology 1993; 42:622–9. 118. Jonler M, Messing EM, Rhodes PR, Bruskewitz RC. Sequelae of radical prostatectomy. Br J Urol 1994; 74:352–8. 119. Jønler M, Madsen FA, Rhodes PR, Bruskewitz RC. Urinary incontinence in patients undergoing radical prostatectomy. Proc Am Urol Assoc 1995; 153: A506. 120. Benoit RM, Naslund MJ, Cohen JK. Complications after radical retropubic prostatectomy in the medicare population. Urology 2000; 56:116–20. 121. Jønler M, Moon TD, Brannan W et al. The effect of age, ethnicity and geographical location on impotence and quality of life. Urology 1995; 75:651–5. 122. Siegel T, Moul JW, Spevak M et al. The development of erectile dysfunction in men treated for prostate cancer. J Urol 2001; 165: 430–5. 123. Bishoff JT, Motley G, Optenberg SA et al. Incidence of fecal and urinary incontinence following radical perineal and retropubic prostatectomy in a national population. J Urol 1998; 160:454–8. 124. Schuessler WW, Schulam PG, Clayman RV et al. Laparoscopic radical prostatectomy: initial short-term experience. Urology 1997; 50:854–7.

Prostate cancer in the elderly

1309

125. Guillonneau B, Vallancien G. Laparoscopic radical prostatectomy: the Montsouris experience. J Urol 2000; 163:418–22. 126. Shipley WU, Zietman AL, Hanks GE et al. Treatment related sequelae following external beam radiation for prostate cancer: a review with an update in patients with stages T1 and T2 tumor. J Urol 1994; 152:1799–805. 127. Hanks GE, Hanlon A, Schultheiss T et al. Early prostate cancer: the national results of radiation treatment from the Patterns of Care and Radiation Therapy Oncology Group studies with prospects for improvement with conformal radiation and adjuvant androgen deprivation. J Urol 1994; 152:1775–80. 128. Russell KJ. Current research directions in the radiation therapy of localized prostate cancer. Prostate 1994; 133–49. 129. Roach M, Pickett B, Holland J et al. The role of the urethrogram during simulation for localized prostate cancer. Int J Radiat Oncol Biol Phys 1993; 25:299–307. 130. Zietman AL, Prince EA, Nakfour BM, Shipley WU. Neoadjuvant androgen suppression with radiation in the management of locally advanced adenocarcinoma of the prostate: experimental and clinical results. Urology 1997; 49(Suppl 3A): 74–83. 131. Bolla M, Gonzalez D, Warde P, Bernard Dubois J. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997; 337:295– 300. 132. Whitmore WF, Hilaris B. Treatment of localized prostate cancer by interstitial 125–1. In: Prostate Cancer: The Second Tokyo Symposium (Karr JP, Yamanaka H, eds). New York: Elsevier Science, 1989. 133. Ragde H, Korb L. Brachytherapy for clinically localised prostate cancer. Semin Surg Oncol 2000; 47:1165–7. 134. Plowman PN. Radical radiation therapy options for organ-confined prostate cancer. BJU Int 2001:87:431–40. 135. Nag S, Beyer D, Friedland J et al. American Brachytherapy Society recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 1999; 44:789–99. 136. Grampsas SA, Miller GJ, Crawford ED. Salvage radical prostatectomy after failed transperineal cryotherapy: histologic findings from prostate whole-mount specimens correlated with intraoperative transrectal ultrasound images. Urology 1995; 45:936–41. 137. Cox RL, Crawford ED. Complications of cryosurgical ablation of the prostate to treat localized adenocarcinoma of the prostate. Urology 1995; 45:932–5. 138. De La Taille A, Hayek O, Benson MC et al. Salvage cryotherapy for recurrent prostate cancer after radiation therapy: the Columbia experience. Urology 2000; 55:79–84. 139. Moyad MA. Nontraditional treatments for localized prostate cancer: ten rules to know before talking to my patients. Semin Urol Oncol 1999; 17:64–9. 140. Eisenberg DM, Davis RB, Ettner SL et al. Trends in alternative medicine use in the United States, 1990–1997: Results of a follow-up national survey. JAMA 1998; 280:1569–75. 141. Hames Coker K. Meditation and prostate cancer: integrating a mind/body intervention with traditional therapies. Semin Urol Oncol 1999; 17:111–18. 142. Moyad MA, Hathaway S, Ni H-S. Traditional Chinese medicine, acupuncture, and other alternative medicines for prostate cancer: an introduction and the need for more research. Semin Urol Oncol 1999; 17:103–10. 143. Moyad MA. Emphasizing and promoting overall health and nontraditional treatments after a prostate cancer diagnosis. Semin Urol Oncol 1999; 17:119–24. 144. Oh WK, George DJ, Hackmann K et al. Activity of the herbal combination, PC-SPES, in the treatment of patients with androgen-independent prostate cancer. Urology 2001; 57:122–6. 145. Huggins C, Hodges CV. Studies on prostatic cancer. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastate carcinoma of the prostate. Cancer Res 1941; 1:293–7.

Comprehensive Geriatric Oncology

1310

146. Arduino LJ, Bailar JC, Becker LE et al. Carcinoma of the prostate: treatment comparisons. J Urol 1967; 98:516–22. 147. Arduino LJ, Bailar JC, Becker LE et al. Factors in the prognosis of carcinoma of the prostate: a cooperative study. J Urol 1968; 100: 59–65. 148. Byar DP. Survival of patients with incidentally found microscopic cancer of the prostate: results of a clinical trial of conservative treatment. J Urol 1972; 108:908–13. 149. Byar DP. The Veterans Administration Cooperative Urological Research Group’s studies of cancer of the prostate. Cancer 1973; 32:1126–30. 150. Lowe BA, Listrom MB. Incidental carcinoma of the prostate: an analysis of the predictors of progression. J Urol 1988; 140:1340–4. 151. Epstein JI, Paull G, Eggleston JC, Walsh PC. Prognosis of untreated stage Aj prostatic carcinoma: a study of 94 cases with extended follow up. J Urol 1986; 136:837–9. 152. Beck PH, McAninch JW, Goebel JL, Stutzman RE. Plasma testosterone in patients receiving diethylstilbestrol. Urology 1978; 11: 157–160. 153. Shearer RJ, Hendry WF, Sommerville JF, Fergusson JD. Plasma testosterone: an accurate monitor of hormone treatment in prostatic cancer. Br J Urol 1973; 45:668–77. 154. Jordan WP, Blackard CE, Byar DP. Reconsideration of orchiec tomy in the treatment of advanced prostatic carcinoma. South Med J 1977; 70:1411–13. 155. Glashan RW, Robinson RG. Cardiovascular complications in the treatment of prostatic carcinoma. Br J Urol 1981; 53:624–7. 156. Buller HR, Boon TA, Henny CP et al. Estrogen-induced deficiency and decrease in antithrombin III activity in patients with prostatic cancer. J Urol 1981; 128:72–4. 157. Dobbs RM, Barber JA, Weigel JW, Bergin JE. Clotting predisposition in carcinoma of the prostate. J Urol 1980; 123:706–9. 158. Varenhorst E, Wallentin L, Risberg B. The effects of orchiectomy, oestrogens and cyproterone-acetate on the antithrombin-III concentration in carcinoma of the prostate. Urol Res 1981; 9:25–8. 159. Blackledge G, Emtage LA, Trethowan C et al. ‘Zoladex’ depot vs DES 3 mg/day in advanced prostate cancer: a randomized trial comparing efficacy and tolerability. J Urol 1989; 141:347. 160. Trachtenberg J. The effect of the chronic administration of a potent luteinizing hormone releasing hormone analogue on the rat prostate. J Urol 1982; 128:1097–100. 161. Leuprolide Study Group. Leuprolide versus diethylstilbestrol for metastatic prostate cancer. N Engl J Med 1984; 311:1281–6. 162. Labrie F, Dupont A, Belanger A et al. New approach in the treatment of prostate cancer: complete instead of partial withdrawal of androgens. Prostate 1983; 4:579–94. 163. Eisenberger M, Crawford ED, Blumenstein B et al. Significance of pre-treatment stratification by extent of disease (ED) in stage D2 prostate cancer (PC) patients treated with leuprolide+flutamide (LF) or leuprolide + placebo (LP). Proc Am Soc Clin Oncol 1989; 8: A515. 164. Wysowsik DK, Fourcroy JL. Flutamide hepatotoxicity. Urology 1996; 155:209–12. 165. Eisenberger MA, Blumenstein BA, Crawford ED et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med 1998; 339:1036–42. 166. Schellhammer P, Sharifi R, Block N et al. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer. Urology 1995; 45:745–52. 167. Hurst KS, Byar DP. An analysis of the effects of changes from the assigned treatment in a clinical trial of treatment for prostatic cancer. J Chronic Dis 1973; 26:311–24. 168. Small EJ, Srinivas S. The antiandrogen withdrawal syndrome. Cancer 1995; 76:1428–34. 169. Moon TD. Letter to the editor: Cyproterone acetate for treatment of hot flashes after orchiectomy. J Urol 1985; 134:155–6. 170. Loprinzi CL, Goldberg RM, O’Fallon J et al. Transdermal clonidine for ameliorating postorchiectomy hot flashes. Urology 1994; 151: 634–6.

Prostate cancer in the elderly

1311

171. Loprinzi CL, Michalak JC, Quella SK et al. Megestrol acetate for the prevention of hot flashes. N Engl J Med 1994; 331:347–52. 172. The role of the urologist in chemotherapy of hormone refractory prostate cancer. Urology 1999; 54(Suppl 6A): 1–52. 173. Hussain M. Highlights from ASCO 2000: Prostate cancer. Federal Forum Suppl 2000; 11–17. 174. Potosky AL, Legler J, Albertsen PC et al. Health outcomes after prostatectomy or radiotherapy for prostate cancer: results from the prostate cancer outcomes study. J Natl Cancer Inst 2000; 92:1582–92. 175. Cliff AM, MacDonagh RP. Psychosocial morbidity in prostate cancer: II. A comparison of patients and partners. BJU Int 2000; 86:834–9. 176. Litwin MS, Lubeck DP, Stoddard ML et al. Quality of life before death for men with prostate cancer: results from the CaPSURE database. J Urol 2001; 165:871–5. 177. Steiner MS, Gingrich JR. Gene therapy for prostate cancer: Where are we now? J Urol 2000; 164:1121–36. 178. Wassan et al. A structured literature review of treatment for localized prostate cancer. Arch Fam Med 1993; 2:487–93.

56 Transitional cell carcinoma of the bladder in the elderly Julio Pow-Sang, Jay Friedland, Albert Einstein Introduction Bladder cancer is the second most common urologic malignancy in the USA.1 Transitional cell carcinoma (TCC) accounts for 75–90% of the cases of bladder cancer.2 The other histologic subtypes (squamous cell and adenocarcinoma) are relatively rare in the USA. The incidence of TCC increases with age, and over 50% of cases occur in persons over 65.1 The most common cause of TCC of the bladder in the USA is tobacco smoke. Over 75% of TCC present as superficial tumors (Ta, Tl, Tis) (Table 56.1), 20% present as invasive cancer, and 5% of cases are metastatic at diagnosis. Eventually 15– 30% of superficial bladder cancer and up to 70% of invasive cancer will give origin to metastases.3 The treatment of bladder cancer is according to stage (Table 56.1). The stage at diagnosis of bladder cancer does not appear to be affected by the age of the patient. Superficial bladder cancer Evaluation The initial presentation is usually gross, painless hematuria. This finding mandates a complete urologic evaluation, including history, physical examination, urinalysis, urine cytology, cystoscopy, and intravenous pyelogram.4 The presence of irritative voiding symptoms,

Table 56.1 Staging of TCC of the bladder: T stages Tis

Carcinoma in situ

Ta

Polypoid lesions, not involving the lamina propria

T1

Lesions involving the lamina propria.

T2

Lesions infiltrating the superficial half of the muscularis

T3a

Lesions involving the deeper half of the muscularis

T3b

Lesions invading the peripheral fat

T4a

Lesions involving adjacent organs

Transitional cell carcinoma of the bladder in the elderly

T4b

1313

Lesions involving the pelvis and the abdominal wall

such as dysuria, frequency, and urgency in the presence of negative urine culture, should alert the practitioner to the presence of carcinoma in situ (CIS).5 Flexible cystoscopes make the evaluation of these patients simple and pain-free. The procedure is well tolerated by patients of advanced ages (even in their 90s). The location, number, size, and configuration of the lesion or lesions have prognostic and therapeutic implications, and should be carefully documented. Treatment The first step in treatment is complete transurethral resection of the lesion or lesions under anesthesia. Selected biopsies of the right and left lateral bladder wall and trigone (and, in males, of the prostate urethra) should be performed to determine the presence of non-obvious lesions. The histopathology should include the grade of the tumor and the depth of invasion. These findings and the configuration, number, and size of lesion(s), the presence or absence of CIS and the number of previous recurrences allow the allocation of patients to groups at high or low risk for recurrence and progression. Patients at low risk undergo surveillance with periodic cystoscopic and cytologic examinations. Approximately 70% of patients experience recurrence within the first 2 years of initial diagnosis.7 Patients at high risk for recurrence and patients whose tumor was incompletely excised are treated with intravesical therapy. The most common agents for intravesical therapy are bacillus Calmette-Guérin (BCG), mitomycin C, and thiotepa. Invasive bladder cancer Evaluation The initial evaluation of these patients is similar to that for superficial bladder cancer. A careful and thorough examination of the bladder under anesthesia is essential to staging, since the presence of a palpable mass after transurethral resection is indicative of deep muscle invasion or perivesical extension. The biopsy indicates the presence of invasive cancer. Initial staging includes a computed tomography (CT) scan of the abdomen and pelvis to assess the presence of lymphadenopathy and liver metastases. Treatment When the cancer invades the bladder muscles, intravesical treatment is no longer effective.8 A selective group of patients may be managed with transurethral resection only.8 These patients are recognized as follows: • presentation of a solitary papillary lesion; • absence of an appreciable mass during bimanual examination under anesthesia after resection of the tumor; • no visible residual tumor after resection.

Comprehensive Geriatric Oncology

1314

A second resection is generally performed in these patients 4–6 weeks after the initial resection. If no tumor is documented at re-resection, these patients can be carefully followed up with surveillance cystoscopies and cytologies. Another group of patients are amenable to partial cystectomy. These patients have a solitary, invasive lesion in non-fixed areas of the bladder away from the trigone. In the majority of cases, management of invasive bladder cancer involves more radical interventions. Radical cystectomy is still the standard treatment for invasive bladder cancer, and radical radiotherapy is the alternative treatment for poor surgical candidates. In recent years, several programs for combined-modality treatment of bladder cancer have been developed, with the aims of improving the cure rate and obtaining organ preservation. These combined-modality treatment programs may be of special interest for older individuals, and will be discussed later in this chapter. Radical cystectomy is the standard treatment for bladder cancer in the USA. With improvements in anesthesia and postoperative care, the mortality rate of this procedure has decreased from 15% to less than 2%.9 Similarly, the morbidity of the procedure has also decreased with improvements in surgical techniques.10 The quality of life of patients is also markedly improved with the use of bladder replacement in the majority of patients undergoing cystectomy. When bladder replacement is contraindicated, a continent urinary diversion or ileal conduit may preserve urinary continence. Radiotherapy is typically administered as external-beam irradiation, although brachytherapy has been utilized in the past.11 Radiotherapy may be administered preoperatively, postoperatively, in conjunction with chemotherapy, or alone. Ongoing clinical trials are evaluating altered radiotherapy fractionation regimens (Eastern Cooperative Oncology Group (ECOG) consortium) and altered chemoradiation fractionation regimens (Radiation Therapy Oncology Group (RTOG) 95–06). In both cases, the goal of therapy is bladder preservation. Using modern techniques with highenergy (greater than megavoltage photons) linear accelerators, multiple fields, custom blocking to spare normal tissues, and appropriate fractionation, the rate of severe complications is quite low (<5%). Complications of radiotherapy include radiation cystitis, radiation proctitis/colitis, impotence, and small-intestinal obstruction. Our unpublished pilot data from the University of South Florida College of Medicine, Tampa indicate that pentoxifylline may ameliorate radiation cystitis and proctitis/colitis in the majority of patients. Approximately 50% of sexually active men will develop impotence. Local-regional tumor control in many published radiotherapy-alone series was not well documented, but was estimated to lie in the range of 10–40% for T2–T4 tumors.12 The complete clinical response rate with conventional radiotherapy alone is about 45%,13 while with accelerated, hyperfractionated radiotherapy alone or chemoradiation, the response rate is about 70%.14–17 Radiotherapy alone is preferred for patients who are unfit for major surgery or chemotherapy, and is well tolerated. However, newer techniques incorporating accelerated and/or hyperfractionated radiotherapy may prove to be both tolerable and more efficacious than conventional radiotherapy, and may become the treatment of choice for older individuals. Response to radiotherapy is affected by several parameters, including clinical stage, presence of ureteral obstruction, tumor morphology (papillary versus solid), tumor grade, completeness of transurethral resection, response to treatment, and dose.11

Transitional cell carcinoma of the bladder in the elderly

1315

Combined therapy for invasive disease and chemotherapy for metastatic disease Invasive TCC of the bladder is a potentially life-threatening problem. The management of invasive disease (stages T2–T4) remains controversial and the subject of multiple clinical trials. Radical cystectomy continues to be the cornerstone for treatment of muscle-invading TCC of the bladder in the USA, whereas full-dose radiotherapy is more commonly employed in the UK and Canada. The best result obtainable with either therapy alone is a 45–50% 5-year survival rate among patients with a lower T-stage tumor having a better prognosis.18–23 Preoperative radiotherapy followed by radical cystectomy does not improve survival rates compared with surgery alone.24–27 Failure of primary therapy has been due to the development of metastases following cystectomy and local bladder failure and/or metastases following radiotherapy. Because of the availability of a number of active chemotherapeutic agents for TCC, current therapeutic strategies involve combining systemic chemotherapy with surgery and/or radiotherapy, with the primary goal of increasing survival by treating micrometastases and in some cases with the secondary goal of preserving the bladder. Systemic chemotherapy may be used as adjuvant therapy after primary tumor treatment or as neoadjuvant therapy prior to treatment of the primary tumor. In either ease, the primary objective is to treat micrometastases that could lead to recurrence and death. In addition, neoadjuvant therapy potentially may downsize the primary tumor and render it more treatable by surgery or radiation therapy as well as providing an in vivo indication of the chemosensitivity of the disease. Adjuvant chemotherapy following radical cystectomy has been difficult for the elderly population to tolerate, and their compliance in clinical trials has been poor. On the other hand, neoadjuvant chemotherapy has been well tolerated, making this approach more appealing in current trials. Clinical trials utilizing single-agent or multiple-agent adjuvant chemotherapy have been inconclusive regarding survival benefit, because most studies were too small, statistically flawed, or stopped too early. The National Bladder Cancer Group phase III trial evaluating cisplatin following preoperative radiotherapy and radical cystectomy had poor compliance with the chemotherapy and failed to demonstrate a survival advantage for patients receiving cisplatin.28 Logothetis et al29 at the MD Anderson Cancer Center did a retrospective analysis of patients receiving CISCA (cisplatin, cyclophosphamide, and doxorubicin) following cystectomy, and reported that the survival of high-risk patients receiving adjuvant chemotherapy was similar to that of low-risk patients and better than that of high-risk patients not receiving chemotherapy.29 Skinner et al30 reported on a randomized trial utilizing CAP (cyclophosphamide, doxorubicin, and cisplatin), and concluded that adjuvant chemotherapy prolonged survival in patients with one positive node, but not in patients with two or more positive nodes. Stoeckle et al31,32 randomized patients post cystectomy to receive adjuvant MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) or MVEC (methotrexate, vinblastine, epirubicin, and carboplatin) versus no chemotherapy even at the time of relapse for stages pN1/2, pT3b, or pT4a, and reported a significant reduction in tumor recurrence and a significant improvement in survival for patients receiving chemotherapy. A trial by the MD Anderson group treated all patients with cystectomy and five cycles of MVAC; half of the patients received two cycles before surgery and three cycles after, and half received

Comprehensive Geriatric Oncology

1316

all five cycles after surgery.33 Fifty-eight percent of all patients remained disease-free with a median follow-up of 6.8 years, with no difference being noted between the two groups. The authors concluded that the 58% survival rate for these high-risk patients, with invasive disease (stages cT3 and cT4a), appeared to be better than what was expected with surgery alone. These trials suggest that adjuvant chemotherapy has value for patients at high risk of recurrence following cystectomy based on adverse pathologic indicators (stage cT3a or cT4 tumors, positive nodes, and lymphatic or vascular invasion), but no trial to date can be considered definitive. Neoadjuvant chemotherapy prior to definitive surgery or radiotherapy remains the most promising approach to positively impact survival of patients with invasive bladder cancer who are at high risk for micrometastases. The theoretical advantages of neoadjuvant therapy are the potential downstaging of the primary tumor, which might increase the cure rate, the ability to determine the chemosensitivity of the tumor, the treatment of micrometastases as early as possible when they are most sensitive to chemotherapy, and the capacity for delivering full-dose therapy when the patient is most likely to tolerate it. Many phase II clinical trials employing cisplatinbased chemotherapy regimens have demonstrated an encouraging local tumor response as well as the difficulties of accurate clinical staging of the disease. Most trials have demonstrated a 20–80% major clinical response rate of the primary tumor and a 25–30% rate of pathologic downstaging to pT0 or pT1 at the time of surgical resection.34 In the Memorial-Sloan Kettering Cancer Center phase II trial, neoadjuvant MVAC (four cycles) followed by cystectomy downstaged the disease in the bladder to endoscopic complete remissions in 48% of patients and pathologically eradicated the disease (pT0) in 23%.35–37 A Southwest Oncology Group (SWOG) phase II study, evaluating extensive transurethral resection and neoadjuvant cisplatin, methotrexate, and vinblastine followed by definitive radiotherapy and concurrent cisplatin in patients who were not candidates for cystectomy, achieved a 56% clinical complete response rate following all treatment, with a median overall survival of 21 months and an 18% 57-month survival rate.38 In this study, aggressive clinically complete resection of a tumor by the initial transurethral resection was associated with prolonged survival. This disparity between the clinical and pathologic results underscores the difficulty in adequately evaluating the tumor prior to surgery or radiotherapy. The ability to achieve pT0 has been found to be greater in T2 and T3a tumors compared with T3b and T4. The optimal number of neoadjuvant courses to achieve maximum tumor response has not been ascertained, but some suggest that more than two courses are necessary.39 A significant response of the primary tumor seems to predict a better survival. Multivariate analyses suggest that pretreatment tumor stage and size and the response to chemotherapy are the most important prognostic factors for survival.40–42 Survival benefit can only be addressed with phase III trials. To date, 10 randomized phase III clinical trials have been reported, demonstrating either a small benefit or no benefit with cisplatin or cisplatin-based combination regimens compared with surgery or radiotherapy alone.43–52 Many of the studies suffer from having too few patients to adequately demonstrate improved survival or from taking many years to complete owing to slow patient accrual. The largest trial, the International Intergroup trial of cisplatin, methotrexate, and vinblastine chemotherapy before cystectomy or radiotherapy, contained almost 1000 patients and demonstrated a small, statistically insignificant

Transitional cell carcinoma of the bladder in the elderly

1317

difference in favor of the chemotherapy-treated group, with only 1% chemotherapyrelated mortality.43 The recently reported US Intergroup trial 0080, randomizing 317 patients to cystectomy with or without three cycles of neoadjuvant MVAC, demonstrated a statistically superior survival for the MVAC arm, with a hazard ratio of 0.74 (95% confidence interval 0.55–0.99, p=0.027) and estimated median survivals of 6.2 and 3.8 years, respectively.46 The Millikan trial, although not randomized to a no-chemotherapy arm, also demonstrated a better-than-anticipated survival utilizing neoadjuvant and adjuvant MVAC in a high-risk population of patients.33 Sternberg and Parmar53 have performed a meta-analysis on seven randomized trials, including the two noted Intergroup trials from which patient-specific data were available, and have concluded that that the value of chemotherapy has not yet been clearly demonstrated. A definitive metaanalysis intending to include all patients from the published studies is currently being conducted, and hopefully will bring greater clarity regarding the benefit of neoadjuvant chemotherapy. The trend in the more recent studies does give credence to neoadjuvant cisplatin-based chemotherapy combinations in the treatment of stage T3b, T4a, and lymph node-positive disease. The use of neoadjuvant chemotherapy also generates some concerns. The first is toxicity, particularly in an elderly population of patients. MVAC and other cisplatin combinations can cause significant grade 4 toxicity and patient death. These regimens need to be administered by experienced oncologists, taking into consideration comorbidities and utilizing supportive care drugs when indicated. Second, some investigators have speculated that neoadjuvant chemotherapy may induce accelerated tumor repopulation within a given individual tumor, thus rendering conventional radiotherapy less effective. Theoretically, this problem could be compensated for by the use of accelerated radiotherapy fractionation schemes. Third, since initial clinical staging is often inaccurate, some patients may be exposed to the treatment unnecessarily and have their primary therapy delayed. Hopefully, future clinical trials with more effective and less toxic drug regimens will better identify the patients at highest risk for micrometastases and produce better survival results. While prolongation of survival remains the primary goal for neoadjuvant trials, a secondary goal for some clinical trials has been bladder preservation. Kaufman et al15 reported on the Massachusetts General Hospital phase II trial employing transurethral resection, two cycles of neoadjuvant CMV (cisplatin, methotrexate, and vinblastine), and 4000 cGy radiation therapy plus concurrent cisplatin followed by reevaluation of the tumor. If no tumor was present, patients completed curative radiotherapy to the tumor site, total dose 6480 cGy, but if a tumor was present, they had a radical cystectomy. The 5-year overall actuarial survival rate was 48%, with 38% surviving with bladder preservation. At 10 years, the overall survival rate was 36% and the disease-specific survival rate 59%, with a pelvic failure rate of only 9.4%.54 Multivariate analyses indicated that the presence or absence of hydronephrosis and tumor stage independently predicted outcome. An RTOG trial utilizing the same protocol in a multi-institutional setting achieved similar results.55 Houssett et al56 at the University of Paris developed a treatment program utilizing concomitant cisplatin, 5-fluorouracil, and twice-daily irradiation of 300 cGy for 3 weeks has yielded a 70% complete response rate confirmed at cystectomy. This program is now being studied as a bladder-sparing treatment by the

Comprehensive Geriatric Oncology

1318

RTOG. All of these multimodality bladder-sparing protocols have been well tolerated by the elderly patients. While combination treatment appears promising for bladder preservation, it is important to mention that bladder preservation has also been accomplished using altered radiotherapy fractionation schemes. Edsmyr et al14 randomized patients with T2-T4 TCC to receive either 84 Gy in 8 weeks (1 Gy thrice daily, on a split course, with 2 weeks’ rest), or 64 Gy in 6.5 weeks (2 Gy once daily, on a continuous course). Local control rates of 24–46% were noticed with conventional fractionation (total dose 64 Gy). In contrast, the complete clinical response rate with hyperfractionated radiotherapy was 62– 67%. The hyperfractionation was associated with improved survival of patients with T3 carcinoma. Another study demonstrating the effectiveness of altered fractionation was reported by Plataniotis et al.17 In a phase II study, patients with T2-T3b bladder cancer received 62–65 Gy in 32–38 days. Local control was achieved in 66.7% of patients, and all T2 patients responded to treatment. The 3-year disease-free survival rate was approximately 60%. The treatment of metastatic TCC of the bladder remains combination chemotherapy (Table 56.2). Phase I and II trials have identified a number of single agents with significant activity, including cisplatin, methotrexate, doxorubicin, vinblastine, gallium, ifosfamide, paclitaxel, docetaxel, trimetrexate, and gemcitabine.57–69 MVAC was the first combination regimen to yield significant results better than single agents, with 39–72% response rates, 13–35% complete response rates, and 12–13 months

Table 56.2 Combination chemotherapy of common use in TCC of the bladder CMV Cisplatin 70mg/m2 every 3 weeks Methotrexate 30mg/m2 Vinblastine 3mg/m2 MVAC Methotrexate 30mg/m2 on days 1, 15, and 21 Vinblastine 3mg/m2 on days 1, 15, and 21 every 4 wccks Doxorubicin 30mg/m2 on day 2 Cisplatin 70mg/m2 on day 2 VIG Etoposide Ifosfamide Gallium nitrate Mesna

Transitional cell carcinoma of the bladder in the elderly

1319

median survival.70–72 Although never directly compared with MVAC, CMV yielded similar results in a phase II trial, and has the advantage of not inducing cardiac toxicity— a potentially significant problem for older patients.73 The combination of vinblastine, ifosfamide, and gallium (VIG) has yielded a 67% response rate and a median survival of 43 weeks, but with formidable hematologic and renal toxicities.74 Phase II trials report that combinations of cisplatin plus paclitaxel or docetaxel produce 62–72% and 60% overall response rates, respectively, similar to MVAC and better tolerated.75–77 The combination of gemcitabine and cisplatin has produced a response rate of 57% overall, with a 21% complete response rate.78 Triplet combinations of the newer active drugs are not yielding significantly better response rates compared with the two-drug regimens. Utilization of these newer combinations of drugs in the neoadjuvant setting provides hope for better survival results for patients with invasive stages of the disease. It is important to underline that many of these patients in these clinical trials were aged 65 or older. Age by itself did not appear to be associated with excessive therapeutic toxicity. Conclusions The two major challenges related to bladder cancer are: • control of systemic disease; • preservation of a functional bladder. Clinical trials indicate that chemotherapy is beneficial in the treatment of localized invasive bladder cancer by downstaging the primary disease and potentially treating micrometastatic disease. However, the best setting in which to use chemotherapy— preoperatively (neoadjuvant), postoperatively (adjuvant), or both—is still not clear. Ongoing clinical trials are exploring these issues. Organ preservation may be achieved by a combination of chemotherapy and radiation or by hyperfractionated radiotherapy. Which of these approaches produces better functional results is not clear at present. As chemotherapy may control systemic disease, a combined approach appears theoretically advantageous. Current clinical trials are addressing this problem. Another issue related to organ preservation is whether this approach is preferable to surgical bladder replacement. Trials randomizing patients to these two primary therapies have not been successful in the past, and probably will not be successful in the future. Of particular note is that age does not seem to alter the clinical presentation or the effectiveness of current therapies. References 1. Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics, 1996. CA Cancer J Clin 1996; 46:5– 27. 2. Murphy WM, Beckwith JB, Farrow GM. Grading system for transitional cell neoplasms. In: Atlas of Tumor Pathology, Vol 11. Washington, DC: Armed Forces Institute of Pathology, 1994:199.

Comprehensive Geriatric Oncology

1320

3. Catalona WJ. Bladder cancer. In: Adult and Pediatric Urology (Gillenwatwer JY, Grayhack JT, Howards SS, Duckett JW, eds). St Louis: Mosby, 1991:1135–83. 4. Cummings KB, Barone JG, Ward WS. Diagnosis and staging of bladder cancer. Urol Clin North Am 1992; 19:455–65. 5. Utz BC, Hanash KA, Farrow DM. The plight of the patient with carcinoma in situ of the bladder. J Urol 1970; 103:160–4. 6. Heney NM, Ahmed S, Flanagan MJ et al. Superficial bladder cancer: progression and recurrence. J Urol 1983; 130:1083–6. 7. Ro JY, Staerkel GA, Ayala AG. Cytologic and histologic features of superficial bladder cancer. Urol Clin North Am 1992; 19:435–53. 8. Herr HW. Conservative management of muscle-infiltrating bladder cancer: prospective experience. J Urol 1987; 138:1162–3. 9. Dreicer R, Cooper CS, Williams RD. Management of prostate cancer and bladder cancer in the elderly. Urol Clin North Am 1996; 23: 87–97. 10. Pow-Sang JM, Lockhart JL. Continent urinary diversion: the Florida pouch. Prob Urol, 1992; 6:581–6. 11. Porter AT. The role of radiotherapy in the treatment of muscle invasive bladder cancer. Prog Clin Biol Res 1990; 353:23–34. 12. Zietman AL, Shipley WM, Kaufman DS. The combination of cisplatin based chemotherapy and radiation in the treatment of muscle-invading transitional cell cancer of the bladder. Int J Radiat Oncol Biol Phys 1993; 27:161–70. 13. Duncan W, Quilty PM. The results of a series of 963 patients with transitional cell carcinoma of the urinary bladder, primarily treated by radical megavoltage X-ray therapy. Radiat Oncol 1986; 7:299–310. 14. Edsmyr F, Anderson L, Esposti PL et al. Irradiation therapy with multiple small fractions per day in urinary bladder cancer. Radiat Oncol 1985; 4:197–203. 15. Kaufman DS, Shipley WM, Griffm PP et al. Selective bladder preservation by combination treatment of invasive bladder cancer. N Engl J Med 1993; 329:1377–82. 16. Russell KJ, Boilean MA, Higano C et al. Combined 5-FU and irradiation for transitional cell carcinoma of the bladder. Int J Radiat Oncol Biol Phys 1990; 19:693–9. 17. Plataniotis G, Michalopoulos E, Kouvaris J et al. A feasibility study of partially accelerated radiotherapy for bladder cancer. Radiat Oncol 1994; 33:84–7. 18. Lerner SP, Skinner E, Skinner DG. Radical cystectomy in regionally advanced bladder cancer. Urol Clin North Am 1992; 19:713–23. 19. Skinner DG, Lieskovsky G. Management of invasive and high-grade bladder cancer. In: Diagnosis and Management of Genitourinary Cancer (Skinner DG, Lieskovsky G, eds). Philadelphia: WB Saunders, 1988:295–312. 20. Blandy JP, England HR, Evans SJ et al. T3 bladder cancer: the ease for salvage cystectomy. Br J Urol 1980; 52:506. 21. Quilty PM, Duncan W, Chishom GD et al. Results of surgery following radical radiotherapy for invasive bladder cancer. Br J Urol 1986; 58:396. 22. Goffmet DR, Schneider NJ, Glastein EJ, et al. Bladder cancer: results of radiation therapy in 334 patients. Radiology 1975; 117:149. 23. Wallace DN, Bloom HJG. The management of deeply infiltrating bladder carcinoma: control trial of radical radiotherapy vs. preoperative radiotherapy and radical cystectomy. Br J Urol 1976; 48:587. 24. Crawford ED, Das S, Smith JA. Preoperative radiation therapy in the treatment of bladder cancer. Urol Clin North Am 1987; 14:781–7. 25. Smith JA, Jr., Crawford ED, Blumenstein B et al. A randomized prospective trial of preoperative irradiation plus radical cystectomy versus surgery alone for transitional cell carcinoma of the bladder. A Southwest Oncology Group study. J Urol 1988; 139:266A.

Transitional cell carcinoma of the bladder in the elderly

1321

26. Blackard CE, Byar DP. Veterans Administration Cooperative Urological Research Group: results of a clinical trial of surgery and radiation in stages II and III carcinoma of the bladder. J Urol 1972; 108: 875–8. 27. Gospodarowicz MK, Warde P. The role of radiation therapy in the management of transitional cell carcinoma of the bladder. Hematol Oncol Clin North Am 1992; 6:147–68. 28. Einstein AB, Shipley WU, Coombs J et al. Cisplatin as adjunctive treatment for invasive bladder carcinoma: tolerance and toxicities. Urology 1984; 23(Suppl): 100–17. 29. Logothetis CJ, Johnsen DE, Chong C et al. Adjuvant cyclophosphamide, doxorubiein, and cisplatin chemotherapy for bladder cancer: an update. J Clin Oncol 1988; 6:1590–6. 30. Skinner G, Daniels JR, Russel CA et al. The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial. J Urol 1991; 145:459– 64. 31. Stoekle M, Meyenburg W, Welleck S et al. Advanced bladder cancer (stages pT3b, pT4a, pN1 and pN2): improved survival after radial cystectomy and 3 adjuvant cycles of chemotherapy. Results of a controlled prospective study. J Urol 1992; 148:302–7. 32. Stoekle M, Meyenburg W, Welleek S et al. Role de la polychimiothérapie M-VAC dans le traitement du carcinome urothelial avancé de la vessie. Ann Urol 1993; 27:51–7. 33. Millikan R, Dinney C, Swanson D et al. Integrated therapy for locally advanced bladder cancer: final report of a randomized trial of cystectomy plus adjuvant M-VAC versus cystectomy with both preoperative and postoperataive M-VAC. J Clin Oncol 2001; 19:4005–13. 34. Splinter TAW, Scher HI. Adjuvant and neoadjuvant chemotherapy for invasive (T3-T4) bladder cancer. In: Comprehensive Textbook of Genitourinary Oncology (Vogelzang N, Miles BJ, eds). 1996:464–71. 35. Seher HI, Norton L. Chemotherapy for urothelial tract malignancies: breaking the deadlock. Semin Surg Oncol 1992; 8:316–41. 36. Schultz PK, Herr HW, Zhang Z-F et al. Neoadjuvant chemotherapy for invasive bladder cancer: prognostic factors for survival of patients treated with M-VAC with 5 year follow up. J Clin Oncol 1994; 12: 1394–401. 37. Scher Hl, Yagoda A, Herr HW et al. Neoadjuvant M-VAC (methotrexate, vinblastine, doxorubiein, and cisplatin) effect on primary bladder lesion. J Urol 1988; 139:470–4. 38. Einstein AB Jr, Wolf M, Hallidya KR et al. Combination transurethral resection, systemic chemotherapy, and pelvic radio therapy for invasive (T2–4) bladder cancer unsuitable for cystectomy: a phase I/II Southwest Oncology Group study. Urology 1996; 47:652–7. 39. Scher HI, Yagoda A, Herr HW et al. Neoadjuvant M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) effect on the primary bladder lesion. J Urol 1988; 139:470–4. 40. Splinter TAW, Scher Hl, Denis L et al. The prognostic value of the pathological response to combination chemotherapy before cystectomy in patients with invasive bladder cancer. J Urol 1992; 147:606–8. 41. Schultz PK, Herr HW, Zhang ZF et al. Neoadjuvant chemotherapy for invasive bladder cancer: prognostic factors for survival of patients treated with M-VAC with 5-year follow-up. J Clin Oncol 1994; 12: 1394–401. 42. Fung CY, Shipley WU, Young RH et al. Prognostic factors in invasive bladder carcinoma in a prospective trial of preoperative adjuvant chemotherapy and radiotherapy. J Clin Oncol 1991; 9:1533–42. 43. International Collaboration of Trialists. Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: a randomized controlled trial. Lancet 1999; 354:533–40. 44. Malmquist PU, Rintala E, Wahlqvist R et al. Five-year follow up of a prospective trial of radical cystectomy and neoadjuvant chemotherapy. J Urol 1996; 155:1903–6. 45. Bassi P, Pagano F, Pappagallo G et al. Neo-adjuvant M-VAC of invasive bladder cancer: the G.U.O.N.E. multicenter phase III trial. Eur Urol 1998; 33(Suppl 1): 142 (Abst 567).

Comprehensive Geriatric Oncology

1322

46. Natale RB, Grossman HB, Blumenstein B et al. SWOG 8710 (INT-0800): randomized phase III trial of neoadjuvant MVAC+cystec-tomy versus cystectomy alone in patients with locally advanced bladder cancer. Proc Am Soc Clin Oncol 2001; 20:2a (Abst 3). 47. Wallace DM, Raghaven D, Kelly KA et al. Neo-adjuvant (preemptive) cisplatin therapy in invasive transitional cell carcinoma of the bladder. Br J Urol 1991; 67:608–15. 48. Coppin CM, Gospodarowicz MK, Jamves K et al. Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation: the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1996; 14:2901–7. 49. Martinez Pineiro JA, Gonzalez Martin M, Arocena F. Neoadjuvant cisplatin chemotherapy before radical cystectomy in invasive transitional cell carcinoma of the bladder: prospective randomized phase III study. J Urol 1995; 153:964–73. 50. Orsatti M, Curotto A, Canobbio L. Alternating chemo-radiotherapy in bladder cancer: a conservative approach. Int J Radiat Oncol Biol Phys 1995; 33:173–8. 51. Malmstrom PU, Rintala E, Wahlqvist R et al. Neoadjuvant cisplatinmethotrexate chemotherapy of invasive bladder cancer: Nordic cystectomy trial 2. Eur Urol 1999; 35(Suppl 2): 60 (Abst 238). 52. Abol-Enein H, El Makresh M, El Baz M et al. Neo-adjuvant chemotherapy in treatment of invasive transitional bladder cancer: A controlled, prospective randomized study. Br J Urol 1979; 80(Suppl 2): 49 (Abst 53). 53. Sternberg CN, Parmar MKB. Neoadjuvant chemotherapy is not (yet) standafd treatment for muscle-invasive bladder cancer. J Clin Oncol 2001; 19:21s–6s. 54. Kaufman DS, Shipley W, Zehr E et al. Combined modality therapy for selective bladder preservation in patients with T2-T4a invasive bladder cancer: the MGH experience 1986–1997. Proc Am Soc Clin Oncol 2001; 20:171a (Abst 683). 55. Tester W, Caplan R, Heaney J et al. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. J Clin Oncol 1996; 14:119–26. 56. Housset M, Maulard C, Chretien YC et al. Combined radiation and chemotherapy for invasive transitional cell carcinoma of the bladder. A prospective study. J Clin Oncol 1983; 1:2150–7. 57. Yagoda A. Chemotherapy of urothelial tract tumors. Cancer 1987; 60: 574–85. 58. Yagoda A, Watson RC, Kemeny H et al. Diammine-dichloride platinum II and cyclophosphamide in the treatment of advanced urothelial cancer. Cancer 1978; 39:279–85. 59. Oliver RJD, England HR, Risdon RN et al. Methotrexate in the treatment of metastatic and recurrent primary transitional cell carcinoma. J Urol 1984; 131:483. 60. Yagoda A, Watson RC, Whitmore WF et al. Adriamycin in advanced urinary tract cancer. Cancer 1977; 39:279–85. 61. Blumenreich MA, Yagoda A, Natale RB et al. Phase II trial of vinblastine sulfate for metastatic urothelial tract tumors. Cancer 1982; 50: 435–8. 62. Crawford ED, Saiers JH, Bakaer LH et al. Gallium nitrate in advanced bladder carcinoma: Southwest Oncology Group study. Urology 1991; 38:355–7. 63. Warrell RP, Coonley CJ, Straus DJ, Young CW. Treatment of patients with advanced malignant lymphoma using gallium nitrate administered as a seven-day continuous infusion. Cancer 1983; 51: 1982–7. 64. Seligman PA, Crawford ED. Treatment of advanced transitional cell carcinoma of the bladder with continuous-infusion gallium nitrate. J Natl Cancer Inst 1991; 83:1582–4. 65. Witte R, Loehrer P, Dreicer R et al. Ifosfamide in advanced urothelial carcinoma: an ECOG trial. Proc Am Soc Clin Oncol 1993; 12:230. 66. Roth BJ, Dreicer R, Einhorn LH et al. Significant activity of paclitaxel in advanced transitional cell carcinoma of the urothelium: a phase II trial of the Eastern Cooperative Oncology Group (E 1892). J Clin Oncol 1994; 12:2264–70.

Transitional cell carcinoma of the bladder in the elderly

1323

67. Sadan S, Bajorin D, Amsterdam A, Scher H. Docetaxel in patients with advanced transitional cell cancer who failed cisplatin-based chemotherapy: a phase II trial. Proc Am Soc Clin Oncol 1994; 13:244. 68. Witte RS, Elson P, Khandaker J, Trump DL. An Eastern Cooperative Oncology Group phase II trial of trimetrexate in the treatment of advanced urothelial carcinoma. Cancer 1994; 73:688–91. 69. Pollera CF, Ceribelli A, Crecco M, Calabresi F. Weekly gemcitabine in advanced bladder cancer: a preliminary report from a phase I study. Ann Oncol 1994; 5:182–4. 70. Sternberg CN, Yagoda A, Scher HL et al. Preliminary results of methotrexate, vinblastine, Adriamycin and cisplatin (M-VAC) in advanced urothelial tumors. J Urol 1985; 133:403–7. 71. Sternberg CN, Yagoda A, Scher HL et al. M-VAC for advanced transitional cell carcinoma of the urothelium: efficacy and patterns of response an relapse. Cancer 1989; 64:2448–58. 72. Conner JP, Olsson CA, Benson MC et al. Long-term follow-up in patients treated with methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) for transitional cell carcinoma of the urinary bladder: cause for concern. Urology 1989; 34:353–6. 73. Harker WG, Meyers FJ, Fuad SF et al. Cisplatin, methotrexate, and vinblastine (CMV); an effective chemotherapy regimen for metastatic transitional cell carcinoma of the urinary tract. A Northern California Oncology Group study. J Clin Oncol 1985; 3:1463–70. 74. Einhorn LH, Roth BJ, Ansari R et al. Phase II trail of vinblastine, ifosfamide and gallium combination chemotherapy in metastatic urothelial carcinoma. J Clin Oncol 1994; 12:2271–6. 75. Burch PA, Richardson RL, Cha SS et al. Combination paclitaxel and cisplatin is active in advanced urothelial carcinoma (UC). Proc Am Soc Clin Oncol 1997; 16:329a. 76. Dreicer R, Roth B, Lipsitz S et al. Cisplatin and paclitaxel in advanced carcinoma of the urothelium: a Phase II trial of the Eastern Cooperative Oncology Group (ECOG). Proc Am Soc Clin Oncol 1998; 17: 320a (Abst 1233). 77. Sengelov L, Kamb C, Lund B et al. Docetaxel and cisplatin in metastatic urothelial cancer: a phase II study. J Clin Oncol 1998; 16:3392. 78. Moore MJ, Winquist EW, Murray N et al. Gemcitabine plus cisplatin, an active regimen in urothelial cancer: a phase II trial of the National Institute of Canada Clinical Trials Group. J Clin Oncol 1999; 17:2876.

57 Brain tumors in the older person Alexandra Flowers Introduction Brain tumors are primary or metastatic malignancies of the central nervous system (CNS), with significant morbidity and mortality. In the spectrum of neurologic disorders, brain tumors are second only to strokes as the leading cause of death. Their treatment requires the cooperative efforts of a multispecialty team, including neurologists, neurosurgeons, radiation therapists, and medical oncologists. The incidence of brain tumors is increasing in the elderly, and their management needs to be adjusted to the specific needs of the older patients. Until recently, these patients were managed with supportive care only, and were not considered eligible for clinical trials.1 The attitude of the medical community is changing, as more elderly patients desire and receive therapy for brain tumors. This change has been made possible by recent advances in basic and clinical research regarding the management of brain tumors, and as treatment modalities are perfected. The overall prognosis remains poor, and there is an ongoing search for new, more effective therapies. This chapter will discuss the epidemiology, clinical aspects and therapy of brain tumors, with emphasis on specific problems in the elderly patient population. Epidemiology Over the last two decades, there has been an increase in the overall incidence of cancer of over 10% as reported in US National Cancer Institute (NCI) statistics, with an average annual percentage change of about 1%. The incidence of brain tumors has increased by an average of 1.2% per year, which is lower than for other cancers, but significant in the context of its personal, social, and economic consequences. Brain tumors account for only 2.2% of all cancers, yet their effect on the patient’s ability to function is dramatic, and their impact is devastating.1–3 In the USA, it is estimated (1993 NCI statistics) that 17 500 new cases of primary brain tumors are diagnosed every year.3 About 12 000 patients are estimated to die every year from brain tumors.3,4 Between 1973 and 1985, there was a dramatic age-specific increase in the incidence of brain tumors.2 The average annual percentage increases in primary brain tumor incidence for ages 75–79, 80–84, and 85 and older were 7%, 20.4%, and 23.4%, respectively.5–8 This trend continues both in the USA and the industrialized European countries.9–16 This increase appears to be independent of diagnostic capabilities, although the introduction of computed tomography (CT) scans in 1973,

Brain tumors in the older person

1325

followed by magnetic resonance imaging (MRI), has allowed for earlier and more accurate diagnosis.17,18 Comparisons between age-related mortality rates suggest that increasing primary brain tumor mortality rates amongst the oldest age groups are directly proportional to the increasing population size of these age groups.19–22 Malignant gliomas, particularly glioblastoma multiforme, are the most common primary brain tumors in the elderly. The epidemiologic factors that have led to the increased incidence of brain tumors in all age groups are not well defined.23–25 There are no clearly established links between environmental factors (e.g. pesticides, electromagnetic fields, and radiation exposure) and the occurrence of brain tumors, except for a higher risk for a meningiomas in patients who had previously received radiation therapy to the head.25,26 The possible causative effect of prolonged use of cellular phones has recently received media attention; however, there is no scientific evidence to support this hypothesis. The incidence of some genetically transmitted diseases associated with brain tumors, such as neurofibromatosis and the familial cancer syndromes such as Li-Fraumeni, has not increased. In some patients with a family history of malignancy, there are abnormalities of tumor suppressor genes and overexpression of oncogenes, which can be identified with molecular biology techniques.27,28 The dramatic increase in incidence of brain tumors in the elderly reflects the overall increase in the general population, improved diagnostic techniques, and changes in the attitude of society and of the medical community towards addressing the healthcare needs of the older population.17,18 Patients as healthcare consumers have

Figure 57.1 Survival of patients with malignant gliomas at 5 years by age (1980–1985 surveys): black bars, glioblastoma multiforme; gray bars, anaplastic astrocytoma).

Comprehensive Geriatric Oncology

1326

become more educated, and there is an increased awareness of the symptoms and signs of brain tumors, which leads to earlier diagnosis.12–17 The number of reported cases will be higher in geographic areas with a higher concentration of senior citizens, such as Florida and Arizona.13 Age is a strong prognostic factor affecting survival.29,30 An analysis based on the NCFs Surveillance, Epidemiology, and End Results (SEER) data shows that for patients aged 65 and older, there was no apparent clinically significant improvement in survival rates for all tumor types, compared with significantly improved survival rates for younger patients with anaplastic gliomas and medulloblastomas.31,32 The 5-year survival rate for patients with glioblastoma multiforme is about 20% in patients younger than 35, 10% for patients aged 35–54, and only 1% for patients aged over 55.29 Similar age-related trends are noted for patients with anaplastic astrocytomas (70%, 22%, and 15%, respectively) (Figure 57.1). The age-based survival data parallel the survival rates based on performance status, as measured by Karnofsky performance score (KPS). Approximately 50% of patients with malignant gliomas over the age of 55 are likely to have a KPS <70 at diagnosis, as compared with only 20% in the younger patient groups (Figure 57.2). The performance status is not the only determinant of survival in the elderly, but a low KPS will influence the type of treatment that these patients will be offered.30 Diagnosis The diagnosis of brain tumors is based on clinical presentation, imaging studies, and histology.33,34 In older patients (in the absence of focal signs), intellectual decline over a short period of time, gait disturbances, and short-term memory deficits are clinical signs that may indicate the presence of a brain tumor, and must be differentiated from the ‘normal’ phenomena of aging.

Brain tumors in the older person

1327

Figure 57.2 Relationship of age and initial Karnofsky performance score (KPS) <70 in patients with malignant gliomas (1980–1985 surveys): black bars, glioblastoma multiforme; gray bars, anaplastic astrocytoma). Symptoms and signs The symptoms and signs are dependent on the tumor location (Table 57.1). Headaches and seizures are the most common symptoms at presentation.35,36 Since in the older age groups, brain tumors are most often located supratentorially, the headaches are caused primarily by local increased pressure. Less commonly, headaches are caused by invasion of the meninges, or hydrocephalus in the case of posterior fossa tumors. The seizures can be generalized or focal; in the latter case, they may have localizing value. The neurologic examination can reveal cognitive and/or behavioral changes seen in patients with frontal, temporal, or parietal lobe tumors, and speech, reading, or writing problems when the tumor involves the dominant hemisphere. The presence of focal neurologic deficits can help to localize the lesion even before neuroimaging

Table 57.1 Symptoms and signs of brain tumors Symptoms and signs Tumor location

Dominant hemisphere

Non-dominant hemisphere

Comprehensive Geriatric Oncology

1328

Frontal lobe

Personality changes; apathy; impaired planning; disinhibition or apathy; expressive aphasia; contralateral motor weakness; motor seizures

Personality changes; motor weakness; motor seizures (the personality changes are most marked with lesions in the right frontal lobe)

Temporal lobe

Loss of verbal memory; short-term memory loss; fluent aphasia; complex partial seizures; contralateral homonymous superior quadrantanopia

Loss of visual spatial memory; complex partial seizures; contralateral homonymous superior quadrantanopia

Parietal lobe

Contralateral sensory deficit; aphasia syndromes; conduction aphasia; Gerstman syndrome); alexia; agraphia; contralateral homonymous inferior quadrantanopia; sensory seizures

Contralateral sensory deficit, contralateral homonymous inferior quadrantanopia; contralateral hemibody neglect; visual neglect; constructional apraxia; dressing apraxia; sensory seizures

Occipital lobe

Contralateral homonymous hemianopia; alexia; prosopagnosia

Contralateral homonymous hemianopia

Posterior fossa

Headache due to obstructive hydrocephalus; focal findings depending on tumor location; vertigo; nystagmus; altered level of consciousness

studies are performed. The degree of neurologic compromise is an important factor in deciding the therapeutic approach. Tumors in the anterior frontal lobes, anterior temporal lobes, or the base of the skull can grow to significantly large size with very few or no symptoms, or non-specific symptoms often ascribed to the aging process, such as memory loss or personality changes, or some gait difficulties. Over 60% of malignant gliomas arise in the frontal and temporal lobes. Brain tumors can also present with stroke-like symptoms and parkinsonism.37,38 Unilateral hearing loss, vertigo, and mild facial weakness are symptoms caused by acoustic neuromas, and imaging studies can help to differentiate these from cerebrobasilar insufficiency. Radiologic diagnosis Neuroimaging studies are valuable tools in determining the location of the lesion(s), and may suggest the diagnosis and the malignant character of a tumor.39 Skull X-rays can reveal abnormalities of the sella turcica, suggesting a pituitary tumor, erosion of the bone as seen in patients with meningiomas, as well as calcifications in low-grade astrocytomas, oligodendrogliomas, or meningiomas. Cerebral angiograms help to differentiate between tumors and vascular malformations or aneurysms, and also define the blood supply of the tumor, and thus can assist with the surgical management. The cerebral angiography technique is used for the Wada test, to establish the dominant areas for speech and memory in left-handed patients with frontotemporal lesions, in preparation for surgery. The most useful neuroimaging techniques are CT scan and MRI of the brain. Nonenhanced CT scan of the brain can reveal the presence of calcifications or hemorrhagic lesions, as well as hydrocephalus. Non-enhanced scans will show hypodense areas at the site of a tumor, but it is necessary to perform a contrast-enhanced scan to visualize the outline of the tumor and differentiate it from surrounding edema. Inferior frontal lobe or

Brain tumors in the older person

1329

anterior temporal lobe lesions, as well as lesions in the posterior fossa, may not be well visualized on CT scans owing to bone artifact. MRI scan of the brain is becoming the imaging modality of choice for brain tumors. It allows visualization of the tumor in axial, coronal, and sagittal planes, giving a three-dimensional view of the tumor and its relationship to the surrounding structures. MRI has greater tissue contrast resolution than CT, and allows visualization of very small lesions, and of lesions in the temporal tip, inferior frontal lobe, or posterior fossa, and at the base of the skull. The paramagnetic substance gadolinium diethylenetriamine pentaacetic acid (Gd-DPTA) is used as a contrast for MRI scan, and helps to define intracranial lesions, to differentiate neoplasms from other lesions, and even to define subtle changes in the appearance of a tumor during treatment. MRI with gadolinium is also useful in diagnosing leptomeningeal metastases, which are seen with increased frequency as brain tumor patients survive longer. Positron emission tomography (PET) and single-photon emission CT (SPECT) scans are less useful at diagnosis, but can help to distinguish tumor necrosis from radiation-induced necrosis in the follow-up of tumors after therapy.40,41 Magnetic resonance spectroscopy (MRS) is still a research tool; however, it has the potential to become a non-invasive diagnostic modality, in differentiating low-grade from anaplastic gliomas and other brain lesions.42 Pathologic diagnosis While imaging techniques can localize a tumor and sometimes suggest the pathologic diagnosis, in order to establish the final diagnosis and course of treatment it is necessary to obtain tumor tissue for histologic characterization. Pathologic examination of the tumor specimen, on frozen section and fixated material, defines the type of tumor and the histologic grade. Brain tumors can be primary or metastatic. Primary brain tumors are classified histologically based on the World Health Organization (WHO) classification.43 The most common primary brain tumors are gliomas, which are classified based on cell type as astrocytic tumors, oligodendroglial tumors, and mixed gliomas. The grade of malignancy is defined based on cellularity, presence of mitoses, vascular endothelial proliferation, and necrosis. For an accurate grading, the pathologist needs to know whether or not the patient received radiation therapy or chemotherapy prior to the surgical procedure. Radiation therapy can cause tissue necrosis, just as some malignant tumors do, particularly glioblastoma multiforme. Several classification schemes have been developed to grade malignant gliomas (Table 57.2). The histologic features are important determinants of prognosis. In 1949, Kernohan et al44 noted the link between the histopathologic features of gliomas and patient survival, and introduced a four-tier grading system, which is still used today, with some modifications. Daumas-Duport determined that the length of postoperative survival is inversely proportional to the number of histologic features of malignancy, such as nuclear atypia, mitoses, vascular endothelial proliferation, and necrosis, found in the tumor.45,46 From a practical standpoint, in older patients, a three-tier grading system is adequate, since even lowanaplastic tumors (grade II) tend to behave more aggressively and need to be treated as anaplastic tumors rather than low grade. Gliomas occurring before the age of 10 and

Comprehensive Geriatric Oncology

1330

Table 57.2 Grading of malignant gliomas Grading system and criteria

Grade 1

Grade 2

Grade 3

Grade 4

• Cellular anaplasia

None

Minimal

In half of cells

Extensive

• Cellularity

Mild

Mild

Increased

Marked

• Mitoses

None

None

Present

Numerous

• Vascular endothelial proliferation

None or minimal

None or minimal

More frequent

Marked

• Necrosis

None

None

Regional

Extensive

• Transition zone to normal brain

Broad

Broad

Narrowed

May be sharply delineated

Pilocytic astrocytoma

Astrocytoma:

Anaplastic astrocytoma:

Glioblastoma:

None of the four criteria

One criterion

Two criteria

Three or four criteria

Kernohan

WHO Based on cell type

Fibrillary, protoplasmic, gemystocytes, giant cell, combinations

Aanaplastic glial tumor with high Astrocytoma with cellularity and areas of anaplastic necrosis transformation

Daumas-Duport • Nuclear abnormalities • Mitoses • Endothelial proliferation • Necrosis Ringertz Astrocytoma:

Anaplastic astrocytoma:

Glioblastoma multiforme:

Tumor showing infiltrative growth pattern and mild to moderate hypercellularity. Cytologic features resemble normal astrocytes, with only mild nuclear

Cellular infiltrative astrocytic tumor containing astrocytes with moderate pleomorphism. Mitoses and moderate vascular proliferation may be seen.

Markedly pleomorphic astrocytic tumor with high cellularity, frequent mitosis, increased

Brain tumors in the older person

abnormalities

No necrosis

1331

vascularity, and necrosis

after the age of 45 tend to be more undifferentiated and associated with more aggressive behavior and shorter postoperative survival.47 Oligodendrogliomas and mked oligoastrocytomas carry a better prognosis.48 Determination of tumor cell proliferation pattern, using mitotic index determination with bromodeoxyuridine (BUdR) or Ki-67 (MIBl) nuclear antigen, or flow cytometry, is being investigated as a way to define prognosis.49–

53

In recent years, research has focused on defining the genetic alterations, and the interactions between tumor suppressor genes, oncogenes and their products, growth factors, and enzyme systems.54,55 The goal of this research is to determine the mechanisms of oncogenesis and of cell resistance and repair mechanisms, and to develop new treatment modalities based on the molecular biology data. The p53 tumor suppressor gene, found on chromosome 17p, is frequently altered in gliomas, as it is in systemic cancers. Tumors with a high percentage of cells with mutated p53 are rapidly growing, and tend to recur faster and be more resistant to therapy. Overexpression of mutated p53 occurs more often in patients under the age of 45.55–57 Alterations on chromosome 17p are the most common seen in gliomas, even in low-grade gliomas. With higher grade of malignancy, other chromosomal alterations are seen on chromosomes 4, 7, 9p, 13 and 19q. Alterations on chromosome 10 are seen in 50% of glioblastomas. The PTEN gene, located on chromosome 10q23, has been identified as a putative tumor suppressor gene.58 Mutations in PTEN are found in high-grade gliomas, and have a tendency to occur in older patients. Loss of chromosome 10 has been directly correlated with amplification of the epidermal growth factor receptor (EGFR), which can be targeted for therapeutic interventions.57,58 Ploidy studies indicate that for astrocytomas, survival is better for patients with aneuploid tumors than for those with euploid tumors. No such correlation has been found for oligodendrogliomas.50,51,56 Meningiomas are more common in older patients (median age 59), with a female predominance. The 5-year survival rate is 92% for patients aged 45–74, and 70% for patients older than 75. From the statistics reviewed, it is not clear whether the drop in survival rate is related to tumor progression or non-neurologic causes. The majority are benign tumors. Only 1% of meningiomas have malignant characteristics, either with brain parenchyma invasion or with an increased number of mitoses and necrosis, indicating a rapid growth pattern and a high rate of local recurrence within a short time after complete resection.4 Pituitary adenomas are also more common in the older age group. In many cases, asymptomatic microadenomas are found on scans of the brain reformed for other reasons, such as head trauma, headaches, or dizziness. Some patients present with galactorrhea, and in such cases an elevated prolactin level will establish the diagnosis of prolactinoma. Treatment with bromocriptine can be curative in patients with small tumors, or may reduce the size of larger tumors to where a trans-sphenoidal resection can be safely performed. The majority of pituitary tumors are non-secreting. Rarely, a growth hormonesecreting adenoma can be suspected based on specific changes in the patient’s appearance (acromegaly). In such cases, somatostatin or bromocriptine could control the

Comprehensive Geriatric Oncology

1332

growth hormone secretion. Surgery or stereotactic radiosurgery may be indicated in some patients. Acoustic neuromas are benign tumors also seen in older patients, and should be suspected in patients with unilateral hearing loss and vertigo that does not resolve with medical treatment. In these patients, unlike the young age group, the acoustic neuromas are unilateral, and usually are isolated, not as part of neurofibromatosis. Depending on the patient’s age, severity of symptoms, and the size of the tumor, the management can be conservative, with symptomatic treatment and follow-up with serial scans, or more definitive, with surgery or stereotactic radiosurgery. Differential diagnosis In older patients presenting with neurologic symptoms, the differential diagnosis is primarily with cerebrovascular disease. Neuroimaging studies can differentiate between tumor and stroke when the lesion does not exhibit a vascular distribution. It can also help to differentiate between hemorrhage due to hypertension and hemorrhage into a tumor. When the scan reveals enhancing lesions, the differential diagnosis is between primary and metastatic tumors. If the chest radiograph is normal, the most yielding procedure will be a biopsy of one of the lesions for tissue diagnosis. In this age group, infectious or vasculitic lesions are less common than in younger patients. Therapy The treatment of brain tumors is determined by histologic type, location in the cranial cavity, patient’s performance status and neurologic status, age, and life-expectancy as defined not only by the neurologic deficits but also by coexisting medical problems.59–80 Benign tumors, such as meningiomas, acoustic neuromas, and pituitary adenomas, can be managed conservatively in older patients, unless the symptoms warrant a more aggressive approach.81 Surgery and/or radiation therapy are indicated for benign tumors extending into the cavernous sinus, compressing cranial nerves or vascular structures, or causing seizures that cannot be well controlled with anticonvulsants. For gliomas, the conventional therapy involves surgery, radiation therapy, and chemotherapy.59–80 New treatment modalities are being developed (Table 57.3). The following sections will detail primarily the management of malignant gliomas, which are the most common (but also the most difficult to treat) primary brain tumors. Age is an impor

Table 57.3 Treatment of brain tumors Therapy

Methods

Surgery

Biopsy: Open Stereotactic; frameless stereotactic Resection:

Brain tumors in the older person

1333

Craniotomy Computer-assisted, minimally invasive Radiation therapy External-beam: Conventional fractionation 180–200 cGy/day Hyperfractionation 120–160 cGy twice a day; 100 cGy three times a day Radiosurgery: Linear accelerator; gamma-knife; particle-beam; conformal Brachytherapy Boron neutron capture therapy Radiosensitizers Chemotherapy

Route of administration: Intravenous Oral Intraarterial, blood-brain barrier modification Interstitial Intracavitary Intraventricular/intrathecal Drugs: Alkylating agents Antimetabolites Polyamine inhibitors Topoisomerase inhibitors Vinca alkaloids Specific enzyme inhibitors Drug combinations

Immunotherapy

Interferons Adoptive immunotherapy (‘tumor vaccine’) Monoclonal antibodies Immunoconjugates

Other agents

Retinoids Tamoxifen

Comprehensive Geriatric Oncology

Gene therapy

1334

Herpesvirus thymidine kinase/ganciclovir Antisense oligonucleotides

Combined

Chemoradiotherapy

modalities

Chemotherapy and tamoxifen Retinoids and interferon Radioimmunotherapy

tant factor influencing the results of brain tumor therapy protocols, and results are often analyzed separately for patients younger than 50 and older. Age 50 is an arbitrary cut-off, and should not be construed as an absolute age limit to good response to therapy. Patients over the age of 50 with good performance status and resectable tumors may respond well to therapy, and have a survival rate better than the average for the age group. Such patients would benefit from aggressive therapeutic approaches. Most primary brain tumors and metastatic tumors have surrounding vasogenic edema, which contributes to the neurologic symptoms. The edema is controlled with corticosteroids, diuretics, or, in some cases, mannitol. The dose of steroids is determined based on the amount of edema and mass effect, and patient’s clinical improvement. The duration of steroid treatment depends on the therapeutic intervention considered. Patients who undergo a wide resection of the tumor can be tapered off steroids relatively quickly. For patients on long-term steroids, the side-effects are gastric irritation, steroid myopathy, cushingoid appearance, and (in some patients) osteoporosis, depression, or steroid psychosis. For patients with diabetes, if they need to be on steroids, blood glucose must be monitored carefully, and they may need to start insulin therapy for control of hyperglycemia. In cases where steroids are contraindicated (e.g. active peptic ulcer, heart failure, or uncontrolled diabetes), diuretics such as acetazolamide or furosemide can decrease the edema. Surgery Surgery is usually the first therapeutic intervention for brain tumors. The decision regarding the extent of resection, considering the morbidity associated with an open resection, should be based on the extent and location of the tumor, the grade of malignancy, the presence of other medical problems, and the subsequent treatment plan.82,89 In patients with rapidly deteriorating neurologic status due to an expanding mass, surgical intervention can bring about significant improvement, while at the same time providing tissue for pathologic diagnosis, and recently for such experimental treatments as gene therapy or adoptive immunotherapy (‘tumor vaccines’). For patients with multifocal lesions, infiltrating tumors, involvement of the corpus callosum, or subependymal or leptomeningeal spread, a stereotactic biopsy for tissue diagnosis will be sufficient. Biopsy is also be indicated in patients with deepseated lesions, or tumors involving the motor or speech areas, even when the tumor is well defined and appears to be localized. Patients with significant neurologic deficits, and

Brain tumors in the older person

1335

serious medical problems such as heart disease or severe lung disease, are at high risk for perioperative complications, and should be offered stereotactic biopsy for diagnosis.82,85 When feasible, complete resection of the tumor has been shown to significantly increase the rate of survival, both by improving the patient’s performance status and by providing cytoreduction, with a better chance of response to subsequent therapy.86,90,91 This survival advantage is particularly significant for anaplastic astrocytomas. The 5-year survival rate is 50% in patients with astrocytomas who had total resection, but only 20% in patients who had biopsy only.90 The perfected neurosurgical techniques, such as computer-assisted minimal access surgery, have reduced the morbidity associated with open craniotomies, and have shortened the length of hospital stay. This has also made such interventions safer, and more acceptable for older patients with resectable tumors.92 Reoperation for recurrent or progressing tumors must be considered on a case-by-case basis, depending on the tumor type, location, expected survival, KPS, age, and plans for further therapy.93–95 Age is a factor that can influence outcome. In one study, survival after reoperation for recurrent gliomas was 57 weeks for patients younger than 40, but only 36 weeks for older patients.93 Other authors found a correlation between age and overall survival from diagnosis, but no difference after reoperation.84,93 For patients with hydrocephalus, shunting procedures are sometimes necessary. Also for cystic tumors, an Ommaya-type reservoir can be inserted, which allows easy access and drainage should the cyst reaccumulate. The rate of complications and operative mortality is reduced when surgery is performed at centers with experience in the management of brain tumors.93 Reported morbidity rates average 10% and mortality rates 6%. Postoperative complications are worsened neurologic deficit due to increased edema, hemorrhage, cerebrospinal fluid (CSF) leak, and infections. In patients with malignant gliomas, there is an increased risk for thromboembolic complications, particularly in the postoperative period, and it is important to screen such patients for deep venous thrombosis and to provide prophylactic measures (early mobilization and elastic stockings). The treating physician needs to maintain a high index of suspicion, and obtain lung ventilation-perfusion scans if a patient complains of fatigue out of proportion with the degree of neurologic deficit, exertional dyspnea, or chest pain. The presence of a brain tumor is not a contraindication to anticoagulation therapy, except in the immediate postoperative period (the first 7–10 days) or if there is recent hemorrhage present within the tumor. In such cases, low-dose subcutaneous heparin, placement of an inferior vena cava filter, and close observation in the hospital may be considered. Radiation therapy Postoperative radiation therapy (RT) is a well-established treatment modality for malignant brain tumors. For malignant gliomas, RT with doses of 50–60 Gy increases survival compared with surgery alone.96 There still seems to be some controversy regarding the usefulness of RT in the treatment of gliomas in the elderly, considering the poor prognosis for long-term survival.97–100 The benefit of RT is dependent on the pathology of the tumor and the patient’s performance status. The role of RT is less well established for the treatment of low-grade gliomas. It is clearly indicated for patients with seizures not controlled with anticonvulsants. When total resection is feasible, RT does not

Comprehensive Geriatric Oncology

1336

add to survival For unresectable tumors, RT has a definite influence on survival rate.101,102 In older patients, low-grade gliomas have a biologic behavior different from that in younger patients, and the progression to anaplastic tumors is more rapid. For this reason, older patients with low-grade gliomas should be offered RT. Oligodendrogliomas also benefit from RT. For malignant gliomas, RT is delivered to the area of tumor as visualized on CT or MRI scan, plus an additional 3 cm margin. Whole-brain RT, which was used in the past, is associated with a high incidence of leukoencephalopathy and long-term cognitive deficits. The total dose of radiation is delivered over 30–33 days, in daily fractions of 160–200 cGy. Age is an important prognostic factor. In one study, the survival rate at 18 months was 64% in patients younger than 40, but only 8% in patients older than 60. The performance status is an independent variable. Patients with an initial KPS ≥70 or greater have a survival rate at 18 months of 34%, as compared with 13% for patients with KPS ≤60. The most important prognostic factor remains the extent of resection. The postoperative residual tumor volume (determined on enhanced CT or MRI scans) correlates inversely with survival.86–88,103 The results of conventional fractionation RT have been disappointing in terms of providing a cure—or at least long-term survival—in patients with malignant gliomas. The reasons for failure are related to tumor cell resistance (particularly in hypoxic areas of the tumor), the presence of repair mechanisms, and also the pattern of spread of these tumors along white matter tracts, outside the radiation field. There are several different methods under investigation to enhance radiosensitivity, provide protection to normal brain tissue, and to deliver higher doses of radiation to the tumor. Hyperfractionation, hypofractionation, and accelerated fractionation schedules In hyperfractionation schedules, RT is delivered in two or three daily treatments. This allows for smaller doses to be delivered at shorter time intervals, with the advantage that larger total doses can be used with less toxicity to the normal brain, since the radiation will preferentially affect the rapidly proliferating tumor cells. Using this approach, in two daily doses, the total dose can be escalated to 72–82 Gy. The survival in a randomized Radiation Therapy Oncology Group (RTOG) study was longer in the 72 Gy group than in the 82 Gy group—probably because of the excessive neurotoxicity of the higher dose. Ongoing hyperfractionation studies with chemotherapeutic agents as radiosensitizers are also in phase III trials. Hypofractionation schedules, where RT is delivered in weekly doses of 500–650 cGy over 6 weeks, to a total dose of 36–39 Gy, together with administration of cisplatin or carboplatin as radiosensitizers, have been used for patients with a poor performance status (KPS ≤60). This approach has been shown to be well tolerated, and has improved both the performance status and survival in some patients.104 In accelerated fractionation schedules, the conventional dose of radiation is delivered in two or three daily fractions. The rationale is that shortened treatment time (2–4 weeks instead of 6 weeks) should improve the therapeutic ratio, with greater tumor control. In an RTOG study with twice-daily doses given over 4 weeks with carmustine (BCNU), there was no survival advantage over conventional fractionation. Clinical trials have been

Brain tumors in the older person

1337

conducted with accelerated fractionation schedules of RT with carboplatin or BUdR as radiosensitizers. The toxicities in these studies are related to the myelosuppressive effect of the cytotoxic agents, and skin rash with BUdR. These schedules are quite well tolerated, even by older patients. Accelerated fractionation has been used for hospitalized patients with poor performance status, to shorten the duration of treatment.105,106 It is not yet known whether such RT schedules will significantly improve survival. Radiosensitizers Hypoxic cell sensitizers such as misonidazole or lonidamine in combination with RT were promising in experimental studies; however, in randomized clinical trials, they showed no benefit in survival. Halogenated pyrimidine analogues such as BUdR or idoxyuridine (IUdR) are incorporated into rapidly dividing cells and act as radiosensitizers. Phase II studies have shown an increase in survival over conventional RT. Other studies have investigated the radiosensitizing effect of some chemotherapeutic agents including hydroxyurea, vincristine, and carmustine. Radiosurgery Stereotactic radiosurgery (RS) is a non-invasive technique that allows the delivery of high-dose single fractions of radiation to small, well-circumscribed tumors. Stereotactic frames establish a coordinate system for the precise definition of tumor location and tumor volume on computerized imaging studies. The radiation is delivered either by stationary multiple coplanar beams centered on the tumor or by similar non-coplanar arc rotations that converge the radiation on the tumor. The most commonly used radiation sources for RS are linear accelerators (linacs) and cobalt-60 (60Co) gamma-ray units (gammaknives). The treatment is safe and effective, and because it is done in one single dose or a few fractionated doses, in an outpatient setting, is very convenient for the patient, as well as being cost-effective. The morbidity associated with RS is primarily related to increased peritumoral edema, and is easily controlled with steroids. To date, no cognitive deficits have been described in patients who have received RS without conventional RT. For treatment of malignant gliomas, RS is used as an adjuvant to external-beam RT, to deliver a high-dose radiation boost to areas of tumor with nodular, well-circumscribed enhancement, usually indicative of more aggressive tumor. These areas have to be smaller than 5 cm. Because of the infiltrative pattern of growth of these tumors, RS cannot be used as the sole radiation modality107,108 Radiosurgery can also be administered in fractionated doses.108,109 On the other hand, brain metastases, which displace rather than invade brain tissue and are usually well circumscribed, are optimal candidates for RS. Radiosurgery is also used for the treatment of small but symptomatic meningiomas when resection is deemed too risky either because of the tumor location or because of the patient’s medical condition. Acoustic neuromas are also treated with RS, especially in elderly patients. Pituitary adenomas, particularly the secreting ones, are successfully treated with RS.

Comprehensive Geriatric Oncology

1338

Brachytherapy Interstitial radiation therapy (brachytherapy) is a more invasive way of delivering highdose radiation to a tumor, while limiting the dose to the surrounding brain. A dose of 60 Gy or more can be delivered even after 60 Gy external-beam RT. Brachytherapy refers to treatment with radiation sources placed directly into the tumor mass or adjacent to tumors (e.g. in the surgical cavity). The most commonly used isotopes for brachytherapy are iridium192 (192Ir) and iodine-125 (125I). The implants can be placed permanently, or the sources can be removed after a few days, once the desired dose has been delivered (temporary implants). Colloidal phosphorus-32 (32P) can also be placed in tumor cavities or tumor cysts. The dose distribution surrounding a radiation source decreases rapidly with distance from the source and as a result of attenuation of radiation as it passes through tissue. The distance between sources and the depth of the implant can thus be calculated to deliver maximal radiation to the tumor tissue, with least damage to the normal brain. Although more invasive than RS, and with significantly greater morbidity, brachytherapy in malignant gliomas has the advantage that it can be used for infiltrating or cavitary tumors and for tumors larger than 3 cm. The implants are placed surgically, under local or general anesthesia, using stereotactic coordinates. The radiation sources are shielded, and during hospitalization medical personnel and visitors need to be protected by wearing a lead apron or by a lead screen. The implant removal can be performed at bedside. Brachytherapy can be done as a boost to external-beam RT, or as salvage therapy at recurrence. Brachytherapy has been shown to improve survival in patients with malignant gliomas.110–113 Serious complications after brachytherapy include wound infections, cerebral edema, abscess into the tumor, hemorrhage, and radiation necrosis, which require surgical intervention. These complications make brachytherapy a less attractive treatment modality for elderly patients, and for patients with poor performance status. Side-effects of radiation therapy Regardless of the radiation modality used, RT does have side-effects of which patients need to be informed, and monitored for. The reactions to RT are more significant when it is administered to a large portion of the brain. The effects can be acute, early delayed, and late delayed.114 The acute effects occur during treatment or shortly after completion of RT. Some patients experience headaches, probably related to edema, or a worsening of the neurologic deficits. Fatigue is another complaint, and, depending on tumor location, patients may experience nausea, sore throat, hearing loss, or blurring of vision. These symptoms are transient, and can be controlled with steroids and reassurance. The early delayed effects appear in the first 3 months after completion of RT, and are marked by somnolence, loss of appetite, and apathy. These effects are self-limiting, and seem to be more severe in older patients. Late delayed radiation injury occurs months or even years after completion of RT. Patients notice loss of short-term memory and cognitive decline. These effects are more significant with whole-brain RT, but are also seen with limitedfield RT, particularly with large fields. CT and MRI scans reveal white matter changes bilaterally, or may show focal radiation necrosis. Areas of necrosis enhance and can have surrounding edema, thus making them difficult to distinguish from recurrent tumor. PET

Brain tumors in the older person

1339

and SPECT scans can be helpful, showing metabolically hypoactive areas of radiation necrosis, as compared with the increased metabolic activity in tumor tissue.40,41 The definitive differential diagnosis is by biopsy.115 Focal radiation necrosis can cause focal neurologic deficits, and may require resection of the necrotic area for control. Corticosteroids may control necrosis, but long-term use has its own complications. The results of treatment with low-dose anticoagulants have been mixed. The risk of radiation necrosis is high with brachytherapy. The degree of cognitive impairment varies, but can be more severe in patients with tumors involving the temporal lobes and in elderly patients with baseline mild dementia. In the latter patient population, the decision regarding RT must be based on type of tumor and life-expectancy. For patients with malignant gliomas, who have a very poor long-term prognosis, conventional fractionation or hypofractionation RT provides palliation and can improve quality of life in the short term. The degree of cognitive impairment can be quantified using neuropsychometric evaluation prior to RT, and at 6-, 12-, and 18-month intervals.116–120 Chemotherapy Chemotherapy (CT) is now established as standard treatment for primary brain tumors.121–123 The addition of chemotherapy to RT has been shown to prolong survival by a further 6–18 months, depending on tumor grade. Longer-term survivals have also been reported. Still, CT is not curative, and the side-effects in some patients can be doselimiting. There are several factors determining CT failure.124–128 Brain tumors are heterogeneous, and glioma cells have been shown to express the multidrug resistance gene (MDR1). Repair enzymes such as glutathione-S-trans-ferase and O6-alkylguanine alkyltransferase counteract the cytotoxic effect of platinum compounds and nitrosoureas, and some tumor cells are in G0 phase and are less susceptible to chemotherapy.126,127 Mismatch-repair enzyme defects also confer tumor resistance both to cytotoxic agents and to radiation therapy.128 The blood-brain barrier limits the brain tissue penetrance of drugs that are not liposoluble or non-ionized. The drugs should attain and maintain in the tumor a cytocidal concentration.124–125 This is dependent on the physical and chemical properties of the drug and its pharmacokinetics. The half-life of the drug, its intracellular binding, and capillary-to-cell diffusion are important factors. The dose, route of administration, and schedule of administration can influence drug concentrations. Most of the drugs used for CT of primary brain tumors are the same drugs as used for systemic cancer. There are very few agents designed for treatment of gliomas, such as diazoquinone and temozolomide. Several classes of drugs have been used for CT of brain tumors: alkylating agents, antimetabolites, natural compounds, urea analogs, methylhydrazine derivatives, and polyamine inhibitors. Nitrosoureas are the most effective drugs for treatment of malignant gliomas.123 These drugs are highly lipophilic, bifunctional alkylating agents that cause DNA crosslinking and inhibit DNA repair and RNA synthesis. The most widely used nitrosoureas are 1, 3-bis-(2-chloroethyl)-1-

Comprehensive Geriatric Oncology

1340

Table 57.4 Response to chemotherapy for malignant gliomas, based on patient age (<50 years and >50 years) Study

Therapya

No. of patients

Response rate (%)

Median duration of response (weeks)

Median survival (weeks)

<50

>50

<50

>50

<50

>50

Grant et al144;b

Carmustine/PCV

146

76

39

23

6

50

24

Sandberg et al138

PCV/RT

171

NA

NA

81

23

124

51

Yung et al129

Carmustine/cisplatin 45

NA

NA

35

31

128

55

a

PCV, procarbazine, lomustine, and vincristine; RT, radiotherapy. Cut-off ages <40, >40 (40–59 and >60). NA, not applicable.

b

nitrosourea (BCNU, carmustine), which is administered intravenously or intraarterially, and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU, lomustine), which is given orally. The clinical activity is similar for the two drugs, with 40% response rates. Resistance to carmustine is determined by the activity of the enzyme O6-alkylguanyl alkyltransferase (AGAT), which is not age-dependent.127–129 Platinum compounds (cisplatin and carboplatin) are also very effective, but their duration of response is shorter than for nitrosoureas.130 Cisplatin can be also administered intraarterially, but the risk of neurotoxicity and optic nerve toxicity is higher.130,131 Dacarbazine (DTIC) is an agent used in combination CT for treatment of malignant meningiomas. Procarbazine, a cellcycle non-specific agent, is used in combination CT, or as a single agent for malignant gliomas. It is an oral agent, related to disulfiram and monoamine oxidase inhibitors, which explains some of its specific dietary restrictions regarding alcohol and foods containing tyramine.132 Temozolomide is an oral analog of DTIC, with good efficacy against malignant gliomas. Its low myelotoxicity and overall low incidence of sideeffects make temozolomide an attractive chemotherapeutic agent. A comparison study between temozolomide and procarbazine showed similar efficacy but much better quality of life for patients taking temozolomide.133 The purine and pyrimidine analogs are used in drug combinations, as are the plant alkaloids vincristine and etoposide. CT is used traditionally after completion of RT as adjuvant treatment, or at the time of tumor recurrence or progression.134–140 Some CT agents, such as carmustine, hydroxyurea, and vincristine, also have a radiosensitizing effect, and there have been clinical trials using CT in conjunction with RT. It has been suggested that there is a benefit in using CT prior to RT, particularly in oligodendrogliomas. Agents such as 9aminocamptothecin, a topoisomerase I inhibitor, are also under investigation as preradiation CT for glioblastomas. Chemotherapy with a combination of procarbazine,

Brain tumors in the older person

1341

lomustine, and vincristine (PCV) is at the present time still considered the most effective for oligodendrogliomas (low-grade or anaplastic) and for anaplastic astrocytomas.137,138 An analysis compar ing survival after adjuvant PCV versus carmustine disputed earlier reports, finding no significant difference in survival.139 In low-grade oligodendrogliomas, CT with PCV was shown to inhibit tumor growth and induce regression of the tumor on imaging studies.141 Preradiation CT can be used for palliation in patients with low performance status.142 Age is an important factor in determining the response of brain tumors to chemotherapy. Patients over the age of 60 have a lower response rate and shorter duration of response than patients under 60.143,144 Rosenblum et al149 demonstrated in vitro that the sensitivity to carmustine of tumor cells obtained from biopsy specimens correlates strongly with patient age. Tumor cells from patients under 50 were sensitive in seven of eight cases, but cells from only one of eight patients over 50 responded to carmustine. The reasons for this observed difference are not known. The outcomes for patients receiving CT are usually analyzed for the whole group. There have only been a few studies evaluating age as a parameter of response (Table 57.4). The differences in duration of response and survival are quite significant when comparing patients under 50 and those over 50.144 The most common side-effect of CT is myelosuppression, in some cases requiring blood transfusions or use of colony-stimulating factors. Myelosuppression from chemotherapy occurs earlier in the course of treatment in older patients. No significant nitrosourea-induced pulmonary toxicity was noted in patients over the age of 60, possibly because their survival rates are low and pulmonary fibrosis occurs after several courses of treatment. Other common side-effects of chemotherapy are nausea, fatigue, and loss of appetite. These respond well to symptomatic treatment and are mild and usually selflimiting. Procarbazine can cause allergic reactions, or, if dietary restrictions are not observed, can cause paroxysmal hypertension. Peripheral neuropathy is a common sideeffect of vincristine, cisplatin, and procarbazine. The symptoms are numbness in the hands and feet, constipation, and occasionally jaw pain or numbness. When the neuropathy affects fine motor skills, the offending agent must be discontinued. Preexisting conditions such as diabetes, hypothyroidism, and vitamin B12 deficiency cause peripheral neuropathy, and patients need to be evaluated neurologically before starting CT with these drugs, to avoid debilitating neuropathy. Cisplatin, cytarabine, 5fluorouracil, and methotrexate have as a potential side-effect central neurotoxicity, manifested by encephalopathy, seizures, or cerebellar dysfunction. Monitoring and correc ting for hyponatremia, hypomagnesemia, and hypokalemia can help prevent some of these serious problems. Patients treated with etoposide are at higher risk of second malignancies, mainly leukemia. In patients with malignant gliomas, the long-term survival is very low, and does not allow enough time for a second malignancy to develop. Hormonal therapy Laboratory studies have shown that protein kinase C (PKC) is an important factor in promoting proliferation of malignant gliomas. Cell replication is inhibited by PKC inhibitors. Tamoxifen, an estrogen receptor (ER)-blocking agent commonly used for the treatment of breast cancer, has been shown to inhibit the proliferation of malignant

Comprehensive Geriatric Oncology

1342

astrocytomas via non-ER-mediated PKC blockade. In clinical studies, the dose of tamoxifen shown to inhibit brain tumor growth is much higher than the dose used for breast cancer (40–100 mg twice daily versus 10 mg twice daily). This effect appears to be dose-dependent, and is cytostatic rather than cytotoxic. Still, in patients with good performance status, tamoxifen has been shown to increase survival. The antimitotic effect is not reversed by estrogen, indicating a non-ER-mediated mechanism of action. Tamoxifen does cross the blood-brain barrier.146,147 The drug is very well tolerated, even at these high doses. Because of its good safety profile and ease of administration, tamoxifen can be offered as an alternative treatment to elderly patients with malignant gliomas who have received RT and do not wish to take chemotherapy, but would consider other forms of treatment. The incidence of thromboembolic complication from tamoxifen is higher in brain tumor patients than in breast cancer patients, but these patients have an overall higher incidence of thromboembolism, even without tamoxifen. Meningiomas are another group of tumors that can benefit from hormonal therapy. These tumors are more common in women, and there is a strong association between meningiomas and breast cancer. Meningiomas express hormone receptors, particularly progesterone receptors, which are present in 70% of meningioma specimens studied. In vitro and clinical studies suggest that progestins can be modulators of meningioma growth.148 Mifepristone (RU 486), an oral non-steroidal anti-progestative agent, has been shown to bring about subjective and objective improvement in meningioma patients.149 Its side-effects are mild, and include fatigue, gynecomastia, thinning of hair, and skin rash. In premenopausal patients, it also causes amenorrhea. In a large randomized study versus placebo, the efficacy of mifepristone for treatment of meningioma was only marginal. Biologic therapy Biologic therapies with differentiating and immunomodulatory agents are under investigation as alternatives to the conventional forms of treatment.150 They can be used alone, or in combination with RT or CT. These agents are cytostatic rather than cytotoxic. Their mechanisms of action are not yet completely elucidated. Retinoids The retinoids 13-cis-retinoic acid (CRA) and all-transretinoic acid (ATRA) are natural and synthetic derivatives of vitamin A, and have proven efficacy in some premalignant and malignant conditions.151 In vitro studies have demonstrated differentiating and growth-inhibitory effects of retinoic acid on glioma cells. The growth inhibition is related to a decrease in EGFR-mediated phosphorylation activity. In clinical studies, CRA showed activity against malignant gliomas.152,153 Its side-effects were relatively mild: dryness of skin and mucosa, and headache. In some patients, the headaches appeared to be due to increased intracranial pressure (pseudotumor cerebritype), and responded to treatment with diuretics and glycerol. Similar problems, somewhat more severe, were noted with ATRA. Another, potentially fatal, complication of treatment with retinoids is pancreatitis, and the enzymes amylase and lipase must be monitored carefully during therapy. Both ATRA and CRA are administered orally in doses of 60–120 mg/m2/day for

Brain tumors in the older person

1343

3 weeks, followed by a 1-week rest. Retinoids are undergoing clinical trials in combination with temozolomide and other agents. Immunomodulators Interferons (IFNs) are naturally produced glycoproteins with antiviral, antiproliferative, and immunomodulatory properties.154 There are three main classes of IFN: α, β, and γ, identified based on their cell of origin and on their antigenic and biological differences. IFNs stimulate immune effector cells in vitro and in vivo, induce expression of major histocompatibility complex (MHC) antigens, and can induce expression of some tumorrelated antigens on the surface of tumor cells. IFN-γ is not effective against brain tumor cells. Both IFN-α and IFN-β have demonstrated activity against malignant gliomas in vitro and in clinical trials.155–159 IFN-α2b modulates the activity of PKC, downregulating it.155 There are reports of enhanced activity of IFNs and other agents in combination against various tumors, as well as an antiangiogenic effect. IFNs may be useful in combination with chemotherapeutic agents.160,161 Known side-effects of IFN therapy are flulike symptoms and hypotension. Some patients develop low-back pain or arthralgias, at times severe enough to warrant discontinuing the treatment. This can make IFNs less well tolerated by elderly patients with arthritis. Other immunomodulators, such as interleukin-2 (IL-α) and lymphokine-activated killer (LAK) cells, alone or in combination, yielded no objective responses when administered intravenously, but have shown promising results with intratumoral administration.162,163 The sideeffects with systemic administration are similar to those seen with IFNs. Capillary leak syndrome and allergic reactions can also occur. Complications of intratumoral administration are mainly related to local edema and necrosis, as well as the inherent potential complications of the surgical procedure. Future directions The management of brain tumors continues to bring new challenges for treating physicians, and there is ongoing research aimed at defining the biologic mechanisms of malignancy and developing new treatment modalities.164 While there has been significant progress in identifying the genes responsible for oncogenesis and drug resistance, progress has been less impressive in finding effective treatments, particularly for malignant gliomas. Some studies are combining conventional therapies with novel approaches, while others are introducing new experimental treatments.

Comprehensive Geriatric Oncology

1344

Modification of conventional therapies Radiation therapy RT is still the most effective cytotoxic agent for brain tumors. Efforts are being made to improve the therapeutic ratio, by increasing the tumoricidal effect and/or reducing the damage done to normal tissues. This is achieved by improving existing RT machines, better tumor localization, and treatment planning. Also, radiation beams other than the usual photons and electrons are now under investigation. Beams of protons, neutrons, or pions (π-mesons) afford better dose localization on the tumor and radiobiologic efficiency, with sparing of the surrounding normal tissues. Another way of insuring dose localization is through radioimmunotherapy, where a monoclonal antibody coupled to a radionuclide is introduced into the tumor.165 The monoclonal antibody is designed to bind only to receptors expressed by tumor and not by normal cells, thus spearing normal tissue. There are some adjuvant methods, used to enhance the radiosensitivity of tumor cells, particularly the hypoxic cells (nitroimidazoles, hyperbaric oxygen, metabolic or pharmacologic manipulation, and adjuvant hyperthermia), and methods of normal tissue radioprotection with hyperfractionation schedules or the use of chemical compounds (aminothiol compounds). RSR13, an allosteric modifier of hemoglobin, is a novel radiosensitizer that binds covalently to hemoglobin and reduces its oxygen-binding affinity, thus increasing oxygen release in the capillaries. RSR13 is now used in clinical trials for the treatment of gliomas and brain metastases.166 Other trials are investigating the efficacy of a Gd-DTPA analog, gadolinium texaphyrin, as radiosensitizer. The difference in survival compared with conventional RT is not yet significant. Patients younger than 60 seem to benefit most. Chemotherapy The unique cytoarchitecture of the brain, with a very effective blood-brain barrier, as well as the infiltrative pattern of growth of some primary brain tumors and the heterogeneity of tumor cells, are all factors that influence the efficacy (or lack of it) of chemotherapeutic agents. Unfortunately, the rat animal models used to develop chemotherapeutic drugs do not reproduce reliably these elements of human brain tumors, and the results of clinical trials have been rather disappointing. Also, most drugs used for the treatment of brain tumors have been borrowed from the general oncology arsenal, rather than being specifically designed for use against brain tumor cells. New CT approaches are directed at circumventing the blood-brain barrier, overcoming drug resistance mechanisms, and minimizing systemic and neurotoxicity. The blood-brain barrier can be circumvented by increasing the dose of the drug (with subsequent increased toxicity), intraarterial chemotherapy with blood-brain barrier modification, or the use of new delivery systems. Selective opening of the blood-brain barrier with agents such as the bradykinin analog RMP-7 increases the penetration of cytotoxic agents int o brain tumors.167,168 Intratumoral administration has the advantage that it allows delivery of cytotoxic concentrations of drugs to the tumor bed, with no

Brain tumors in the older person

1345

systemic toxicity. Its disadvantages are related to diffusion problems and to local toxicity (necrosis). CT can be administered intratumorally via an Ommaya reservoir or through liposomes or biodegradable polymers. Phase I and II clinical studies are underway using drugs such as carmustine, methotrexate, and bleomycin.169–173 Carmustine wafers are now available commercially, and can be placed into the tumor bed at the time of resection. Bone marrow transplantation has been used for the treatment of pediatric brain tumors and of brain tumors in young adults. Because it involves very intensive chemotherapy, with high toxicity and high risk for infectious complications, it is doubtful that elderly patients could tolerate this modality. New cytotoxic agents are now being developed to target tumor-specific enzyme systems and growth factor receptors. Farnesyl transferase inhibitors, matrix metalloproteinase inhibitors (e.g. marimastat), EGFR-specific tyrosine kinase inhibitors (e.g. Iressa), and protein kinase inhibitors (e.g. imatinib) have shown some activity against malignant gliomas in vitro, and are now being investigated in phase I/II clinical trials. Some of these agents are administered orally, with a very mild side-effect profile, and thus less likely to have a negative impact on patient quality of life. Novel therapies Photodynamic therapy Photodynamic therapy takes advantage of the selective uptake of photosensitizers such as hematoporphyrin derivatives by tumor cells compared with normal brain tissue. When exposed to light of an appropriate wavelength (630nm) to activate the sensitizer, there is release of free radicals in the tumor cells, with subsequent damage to blood vessels and cell membranes. The highest uptake of the hematoporphyrin derivatives was noted in glioblastomas, with good local control. Patients with infiltrating tumors are less likely to benefit from this treatment.174,175 Boron neutron capture therapy (BNCT) Boron neutron capture therapy (BNCT) is a form of radiation therapy presently under investigation for the treatment of malignant gliomas. BNCT is mediated by short-range (<10µm) high-energy particles resulting from neutron-induced disintegration of boron-10 (10B). There is preferential accumulation of 10B in conjunction with a high thermal neutron flux at the tumor site. Bombardment of the boron nucleus with a slow neutron induces nuclear disintegration, which yields ionizing radiation. The best results with BNCT have been reported by Japanese investigators. Their studies do not specify differences (if any) in response based on tumor type, age, or performance status. The initial clinical trials were marred by significant brain necrosis. The improved technologies have rekindled the interest in this treatment modality.176,177

Comprehensive Geriatric Oncology

1346

Gene therapy Gene therapy refers to the introduction of new genetic material into cells, with beneficial effect to the patient. The preferred method for gene transfer is through viral vectors, which have a high efficiency in infecting host cells by inserting their own genetic material into the host cell genome. The viruses infect preferentially dividing cells, and this makes them attractive vectors for gene therapy for malignant brain tumors. The DNA sequence of interest is inserted into the viral genome, from which the genes encoding for replication and capsid formation have been deleted. The virus becomes a harmless gene carrier. Both retroviruses and adenoviruses have been studied for use as vectors for gene therapy.178–186 The most publicized gene therapy clinical trial for brain tumors involves transfer of the herpes simplex virus thymidine kinase (HSV-TK) gene into tumor cells, using retroviral vectors. HSV-TK is an enzyme that phosphorylates the antiviral prodrug ganciclovir, which becomes virocidal and cytotoxic.181 Other gene therapy studies are still in an experimental phase.182–186 There are still very few animal and clinical data regarding the efficacy of gene therapy for brain tumors, their long-term effects, and the safety of viral vectors. Antisense oligonucleotide therapy Antisense therapy involves the introduction into cells of oligonucleotide sequences complementary to mRNA, thus achieving a highly specific inhibition of gene expression. The antisense DNA sequence undergoes complementary base pairing with the target mRNA. The antisense oligonucleotide can be introduced into cells through gene therapy techniques. There are many potential targets in brain tumor cells, including growth factor receptors and oncogene products. Experimental work is directed at investigating the efficacy of antisense gene therapy on inhibition of tumor growth by blocking EGFR and inhibition of angiogenesis.187 Immunotherapy Most clinical trials with IFNs or interleukins attempt to enhance the host’s immunity in a non-specific manner.188 Recent studies have focused on adoptive immunotherapy, utilizing sensitized T lymphocytes, lymphokine-activated killer (LAK) cells or tumorinfiltrating lymphocytes (TIL). The brain is considered to be an immunologically privileged site, with no lymphatic drainage. There are immunocompetent cells in the brain at the site of brain tumors (macrophages and perivascular lymphocytes); however, the immune response is not powerful enough to induce regression of the tumor.188–194 Adoptive immunotherapy is the transfer of tumor-reactive lymphoid cells into the tumorbearing host, resulting in tumor regression. ‘Tumor vaccines’ are under development.191,194,195 The immune status of the patient is evaluated prior to starting therapy. Optimal candidates are patients who are fully immunocompetent and have a complete or near-complete resection of the tumor.

Brain tumors in the older person

1347

Immunoconjugates Immunoconjugates are cytotoxic compounds that combine a ligand and a cytotoxic agent, which can be a radioisotope, a chemotherapeutic drug, or a toxin.196 Clinical trials have been conducted on small numbers of patients with leptomeningeal carcinomatosis using immunoradiotherapy. Current clinical trials are underway for treatment of malignant gliomas. Glioma cells express transferrin receptors, which are targeted with immunoconjugates using as ligands monoclonal antibodies either to transferrin receptors or to transferrin, conjugated with a toxin. The toxins are ribosomal inhibitors, either of plant (ricin) or of bacterial (CRM-107) origin. The dose of toxin necessary for a tumoricidal effect is smaller than predicted by the tumor volume, which indicates a bystander effect. The results of these trials are not yet available.197–199 Other experimental studies are investigating the combined effect of immunoconjugates and chemotherapeutic drugs.200 Other biologic agents A number of studies are evaluating other biologic agents for the treatment of malignant gliomas, targeting factors that play a role in cell replication or angiogenesis. Malignant gliomas utilize mevalonate for synthesis of cholesterol and intermediates involved in cell replication. Lovastatin and phenylacetates inhibit the enzymes HMGCoA reductase and MVA-PP decarboxylase, and thus affect mevalonate synthesis and utilization, as well as inducing cytostasis and apoptosis. Both lovastatin and phenylacetates are presently in clinical trials.201,202 Angiogenesis is an important feature in malignant gliomas. There are multiple angiogenesis factors, which can be targeted specifically. Fumagillin, an antibiotic derived from the fungus Aspergillus fumigatus fresenius, was noted to inhibit angiogenesis in vitro. The fumagillin analog TNP-470 is less toxic and has greater potency in vivo than fumagillin. This compound is presently under investigation in clinical trials, alone or in combination with chemotherapeutic agents, for different malignancies, including gliomas. Another antiangiogenic agent, AGM-1470, is also used in experimental studies.203,204 Thalidomide, a drug with antiangiogenic properties, is now used in combination with cytotoxic agents for the treatment of malignant gliomas and other cancers.205 These novel therapies are still in an experimental phase. Larger studies and longer follow-up periods will be necessary to evaluate their safety and efficacy against brain tumors in all age groups, and the differences, if any, in older patients. An attractive feature of these treatment modalities is the fact that many of them are administered intratumorally, with minimal systemic toxicity. The long-term potential for neurotoxicity will need to be evaluated. New oral chemotherapeutic agents (e.g. Iressa and imatinib), with specific activity targeting enzyme systems and mild side-effects, are now entering phase I/II clinical trials for various malignancies, including brain tumors. Treatment of brain metastases A detailed discussion regarding the management of brain metastases is beyond the scope of this chapter. The treatment modalities are similar for primary and metastatic brain

Comprehensive Geriatric Oncology

1348

tumors. For brain metastases, the choice of treatment is based also on the status of the systemic disease. When feasible, surgical resection will significantly improve the performance status and prolong survival. Brain metastases are optimal lesions for radiosurgery. Chemotherapy can be considered for control of both brain and active systemic metastatic disease.206–209 Quality of life issues Brain tumors are debilitating diseases, affecting both cognitive and physical abilities of patients. Therapy must be aimed at improving both symptoms and patient’s performance status. Even if the long-term prognosis is poor for patients with malignant gliomas, physical and occupational therapy will improve a patient’s ability to perform activities of daily living. It is important to provide the necessary home equipment, and to actively involve the family in the rehabilitation process.210–213 The majority of brain tumor patients develop reactive depression, which seems to be more severe in elderly patients and needs to be treated with medication. The choice of antidepressant depends on the patient’s medical history (drugs with anticholinergic side-effects must be avoided in patients with prostate hypertrophy or hypotension), and the chemotherapy regimen (tricyclics and monoamine oxidase inhibitors should not be prescribed in patients taking procarbazine). The nature of the tumor and the prognosis must be discussed with the patient and the family at the time of diagnosis, in a manner that will not discourage therapy, but also will not raise false hopes. Therapy can prolong survival with reasonably good quality of life, and all the options should be discussed and the patient allowed a choice.212 Visiting nurses and therapists, and (when necessary) acute or subacute rehabilitation units, can also

Brain tumors in the older person

1349

Figure 57.3 MRI scans of the brain of a 66-year-old patient with glioblastoma multiforme of the right parietal lobe, with good performance status and minimal neurologic deficit. He underwent surgery, radiotherapy (RT) and adoptive immunotherapy, and at 8 months since diagnosis had no recurrence of the tumor and had a normal neurologic examination and a Karnofsky performance score of 100. (a) Gadolinium-enhanced coronal T1 MRI at diagnosis, showing a necrotic mass in the right parietal lobe, with ring enhancement, and edema and mass effect. (b) Gadolinium-enhanced

Comprehensive Geriatric Oncology

1350

coronal T1 MRI after surgery and RT, before adoptive immunotherapy. The edema and mass effect have resolved, and there is minimal enhancement at the edges of the surgical cavity, possibly related to surgery. (c) Gadolinium-enhanced coronal T1 MRI 6 months after adoptive immunotherapy. There is no evidence of tumor recurrence, and no enhancement. (d) Axial T2 MRI, showing gliosis around the surgical cavity.

Figure 57.4 CT scan of the brain of a 73-year-old patient with hemiplegia and aphasia, and with a Karnofsky performance score of 60. The tumor involves the left temporal lobe, with extension into the midbrain. Because of her poor performance status, the family agreed with supportive care only. (a) Contrast-enhanced axial image, showing a large necrotic mass in the left temporal lobe, with ring enhancement, suggestive of a malignant glioma (glioblastoma

Brain tumors in the older person

1351

multiforme). (b) Contrast-enhanced axial image, showing extension of the tumor into the left cerebral peduncle and midbrain, which explains the patient’s hemiplegia. improve the quality of survival.213 Treating physicians need to involve patient and family actively in management decisions, thus creating a support system for the patient.214,215 Age-related practical considerations Diagnosis Diagnosis of primary brain tumors in the elderly is more difficult owing to non-specific symptoms that mimic the physical and cognitive changes seen in the normal aging process. If symptoms evolve over a relatively short period of time (<6 months), then a primary brain tumor or primary central nervous system lymphoma should be considered. An imaging study, preferably an MRI scan of the brain, should be included in the diagnostic workup. Treatment There are no therapies designed specifically for the treatment of brain tumors in the elderly, even though molecular biology studies indicate that there are specific age-related genetic alterations that determine both the clinical course and the tumor response to therapy. Furthermore, most clinical studies exclude patients over the age of 70. Although patients aged 65 and older represent 44% of patients with brain tumors (SEER data), only 19% were enrolled in Southwest Oncology Group (SWOG) clinical trials.216 This is due to stringent age and general health criteria, and the misconception that elderly patients would not benefit from clinical trials. The decision to initiate treatment for a brain tumor in an elderly person should not be based only on age, but also on life-expectancy factors such as performance status, neurologic deficits, and coexistent chronic illnesses. These factors will determine the surgical risk in deciding for resection or biopsy, as well as whether to consider radiosurgery or brachytherapy in addition to standard external beam radiotherapy. For elderly patients with malignant gliomas who have a poor long-term prognosis, biopsy followed by conventional fractionation or hypofractionation radiotherapy provide palliation and can improve quality of life over the short term. Age is an important factor in determining the response of brain tumors to chemotherapy. Patients over the age of 60 have a lower response rate and a shorter duration of response than younger patients.144,145 It is not yet known whether the same age-related outcomes will be observed for the new cytotoxic agents currently in clinical trials (e.g. temozolomide, imatinib, and Iressa).

Comprehensive Geriatric Oncology

1352

Many elderly patients have chronic illnesses requiring medication; thus, special attention must be paid to potential drug interactions of chemotherapeutic agents with antihypertensive, anticonvulsant, and antidepressant medications. Also, elderly patients have a decreased creatinine clearance, which must be considered when calculating the dose of chemotehrapeutic drugs. In elderly patients, brain tumors behave more aggressively, and tend to be more resistant to treatment. It is important, however, to consider each case in deciding on therapy. The goal of therapy is to control tumor growth, and improve the patient’s neurologic status.217 Age alone should not be the major determinant for therapeutic decisions. More aggressive therapy can benefit patients with good performance status and relatively small tumors that can be resected (Figure 57.3). For patients with poor performance status, significant neurologic deficit that is not likely to improve with treatment, multifocal tumors, and debilitating medical problems, it is reasonable to limit the management to steroids and supportive care or (if desired by the patient) to palliative radiation therapy (Figure 57.4). Conclusions Brain tumors continue to carry a poor prognosis in spite of aggressive multimodality therapy. Age does influence prognosis in a negative manner. Treatment at present is not curative, except for low-grade tumors such as meningiomas. New treatment modalities are being developed based on molecular biology data. At present, the longterm efficacy of these new therapies is not known. Elderly patients can benefit from therapy for brain tumors, and the treatment must be individualized. Recent advances in the treatment of brain tumors, with limited surgery, radiosurgery, and controlled toxicities, have improved the access to and acceptance of brain tumor therapy by elderly patients. References 1. Mahaley MS Jr, Mettlin C, Natarajan N et al. National survey of patterns of care for brain tumor patients. J Neurosurg 1989; 71: 826–35. 2. Laws ER, Thapar K. Brain tumors. CA Cancer J Clin 1993; 43: 263–271. 3. Boring CC, Squires TS, Tong T. Cancer statistics. CA Cancer J Clin 1991; 141:19–36. 4. Boring CC, Squires TS, Tong T. Cancer statistics. CA Cancer J Clin 1993; 43:7–26. 5. Crawford J, Cohen HJ. Relationship of cancer and aging. Clin Geriatr Med 1987; 3:419–23. 6. Larsen NS. Experts divided over rising incidence of brain tumors. Primary Care Cancer 1993; 13:26–9. 7. Legler JM, Ries LA, Smith MA et al. Cancer surveillance series (corrected): brain and other central nervous system cancers. Recent trends in incidence and mortality. J Natl Cancer Inst 1999; 91: 1382–90. 8. Greig NH, Ries LG, Yancik R, Rappaport SI. Increasing annual incidence of primary brain tumors in the elderly. J Natl Cancer Inst. 1990; 82:1621–4. 9. Davis DL, Hoel D, Percy C et al. Is brain cancer mortality increasing in industrial countries? Ann NY Acad Sci 1990; 609:191–204.

Brain tumors in the older person

1353

10. Radhakrishnan K, Mokri B, Parisi JE et al. The trends in incidence in primary brain tumors in the population of Rochester, Minnesota. Ann Neurol 1995; 37:67–73. 11. Lowry JK, Snyder JJ, Lowry PW. Brain tumors in the elderly: recent trends in a Minnesota cohort study. Arch Neurol 1998; 55:922–8. 12. Polednak AP. Time trends in incidence of brain and central nervous system cancer in Connecticut. J Natl Cancer Inst 1991; 83:1679–81. 13. Werner MH, Phuphanich S, Lyman GH. Increasing incidence of primary brain tumors in the elderly in Florida. Cancer Control 1995; 2:309–14. 14. Sant M, Crosignani P, Bordo M et al. Incidence and survival of brain tumors: a populationbased study. Tumori 1988; 74:243–52. 15. Fleury A, Mengoz F, Grosclaude P et al. Descriptive epidemiology of cerebral gliomas in France. Cancer 1997; 79:1195–202. 16. van der Sanden GA, Schouten LJ, Coebergh JW. Incidence of primary cancer of the central nervous system in southeastern Netherlands during the period 1980–94: specialists in neurooncology in southeastern Netherlands. Cancer Causes Control 1998; 9: 225–8. 17. Desmeules M, Mikkelsen T, Mao Y. Increasing incidence of primary malignant brain tumors: influence of diagnostic methods. J Natl Cancer Inst 1992; 84:442–5. 18. Modan B, Wagner DK, Feldman JJ et al. Increased mortality from brain tumors: a combined outcome of diagnostic technology and change of attitude towards the elderly. Am J Epidemiol 1992; 135: 1349–57. 19. Velema JP, Walker AM. The age curve of nervous system tumour incidence in adults: common shape but changing levels by sex, race and geographical location. Int J Epidemiology 1987; 16:177–83. 20. Boyle P, Maisonneuve P, Sacci R et al. Is the increased incidence of primary brain tumors in the elderly real? J Natl Cancer Inst 1990; 82:1594–6. 21. Riggs JE. Rising primary malignant brain tumor mortality in the elderly: a manifestation of differential survival. Arch Neurol 1995; 52:571–5 22. Salcman M. Brain tumors and the geriatric patient. J Am Geriatr Soc 1982; 30:501–8. 23. Giles GG, Gonzales MF. Epidemiology of brain tumors and factors in prognosis. In: Brain Tumors. An Encydopedic Approach (Kaye AH, Laws ER, eds). Edinburgh: Churchill Livingstone, 1995:47–68. 24. Bondy ML, Wrensch M. Update on brain cancer epidemiology. Cancer Bull 1993; 45:365–9. 25. Mack W, Preston-Martin S, Peters JM. Astrocytoma risk related to job exposure to electric and magnetic fields. Bioelectromagnetics. 1991; 12:57–66. 26. Tsung RW, Laperierre NJ, Simpson WJ et al. Glioma arising after radiation therapy for pituitary adenoma. A report of four patients and estimation of risk. Cancer 1993; 72:2227–33. 27. Schoenberg BS, Christine BW, Whisnant JP. Nervous system neoplasms and primary malignancy of other sites. The unique association between meningiomas and breast cancer. Neurology 1975; 28:817–23. 28. Ahsan H, Neugut AJ, Bruce JN. Association of malignant brain tumors and cancers of other sites. J Clin Oncol. 1995; 13:2931–5. 29. Burger PC, Green SB. Patient age, histologic features, and length of survival in patients with glioblastoma multiforme. Cancer 1987; 59:1617–25. 30. Hildebrand J, Thomas DGT. Report of a workshop sponsored by the European Organization for Research and Treatment of Cancer (EORTC) on the treatment of primary malignant brain tumors. J Neurol Neurosurg Psych 1991; 54:182–3. 31. Davis FG, Freels S, Grutsch J et al. Survival rates in patients with primary malignant brain tumors stratified by patient age and tumor histological type: an analysis based on Surveillance, Epidemiology, and End Results (SEER) data. 1973–1991. J Neurosurg 1998; 88:1–10. 32. Davis FG, McCartney BJ, Freels S et al. The conditional probability of survival of patients with primary malignant brain tumors: Surveillance, Epidemiology, and End Results (SEER) data. Cancer 1999; 85:489–91.

Comprehensive Geriatric Oncology

1354

33. McDermott MW. How to diagnose and manage adult astrocytomas. Contemp Oncol 1993; 12:11–21. 34. Black PM. Brain tumors. (Part I) N Engl J Med 1991; 324:1471–5. 35. Pfund Z, Szapary L, Jaszberenyi O et al. Headache in intracranial tumors. Cephalalgia 1999; 19:789–90. 36. Eisenschenk S, Gilmore R. Adult-onset seizures: clinical solutions to a challenging patient work-up. Geriatrics 1999; 54:22–4. 37. Morgenstern LB, Frankowski RF. Brain tumor masquerading as stroke. J Neuro Oncol 1999; 44:47–52. 38. Pramstaller PP, Salerno A, Bhatia KP et al. Primary central nervous lymphoma presenting with a parkinsonan syndrome of pure akinesia. J Neurol 1999; 246:934–8. 39. Patronas NJ, Moore WD, Schellinger DR. Brain imaging in the diagnosis of intracranial neoplasms. In: Advances in Neuro-Oncology (Kornblith PL, Walker MD, eds). Mount Kisco, NY: Futura, 1988:197–247. 40. Mineura K, Sasajima T, Kowada M et al. Perfusion and metabolism in predicting the survival of patients with central gliomas. Cancer 1994; 73:2386–94. 41. Vertosick FT, Selker RG, Grossman SJ, Joyce JM. Correlation of thallium-201 single photon emission computed tomography and survival after treatment failure in patients with glioblastoma multiforme. Neurosurgery 1994; 34:396–401. 42. Burtscher IM, Skagerberg G, Geijer B et al. Proton MR spectroscopy and preoperative diagnostic accuracy: an evaluation of intracranial mass lesions characterized by stereotactic biopsy findings. AJNR 2000; 21:84–93. 43. Smirniotopoulos JG. The new WHO classification of brain tumors. Neuroimag Clin North Am 1999; 9:595–613. 44. Kernohan JN, Mabon RF, Suien HS et al. A simplified classification of gliomas. Proc Staff Mtg Mayo Clin 1949; 24:71–74. 45. Daumas-Duport C, Scheitauer B, O’Fallon J et al. Grading of astrocytomas: a simple reproducible method. Cancer 1988; 62:2152–65. 46. Kim TS, Halliday AL, Hedley-Whyte ET et al. Correlates of survival and the Daumas-Duport grading system for astrocytomas. J Neurosurg 1991; 74:27–37. 47. Nelson DF, Nelson JS, Davis DR et al. Survival and prognosis of patients with astrocytoma with typical anaplastic features. J Neuro Oncol 1985; 3:99–103. 48. Shaw EG, Scheitauer BW, O’Fallon JR, Davis DH. Mked oligoastrocytomas: a survival and prognostic factor analysis. Neurosurgery 1994; 34:577–82. 49. Saarinen UM, Pinko H, Makipernaa A. Prognostic factors for high-grade malignant glioma: development of a prognostic index. A report of the Medical Research Council Brain Tumor Working Party. J Neuro Oncol 1990; 9:47–56. 50. Salmon I, Dewhite O, Pasteels JL et al. Prognostic scoring in adult astrocytic tumors using patient age, histopathologic grade and DNA histogram type. J Neurosurg 1994; 80:877–83. 51. Bruner JM, Langford LA, Fuller GN. Neuropathology, cell biology, and newer diagnostic methods. Curr Opin Oncol 1993; 5:441–9. 52. McKeever PE, Strawderman MS, Yamini B et al. MIB-1 proliferation index predicts survival among patients with grade II astrocytoma. J Neuropathol Exp Neurol 1998; 57:931–7. 53. McKeever PE, Junck L, Strawderman MS et al. Proliferation index is related to patient age in glioblastoma. Neurology 2001; 56: 1216–18. 54. Steck PA, Bruner JM, Pershouse MA. Molecular, genetic and biologic aspects of primary brain tumors. Cancer Bull 1993; 45: 365–9. 55. Chozik BS, Pezullo JC, Epstein MH et al. Prognostic implications of p53 overexpression in supratentorial astrocytic tumors. Neurosurgery 1994; 35:831–7. 56. Kokolopoulou P, Christodoulou P, Konzelis K et al. MDM2 and p53 expression in glomas: a multivariate survival analysis including proliferation markers and epidermal growth factor receptor. Br J Cancer 1997; 75:1268–78.

Brain tumors in the older person

1355

57. Simmons ML, Lamborn KR, Takahashi M et al. Analysis of complex relationship between age, p53, epidermal growth factor receptor, and survival in glioblastoma patients. Cancer Res 2001; 61:1122–28. 58. Rasheed BK, Stenzel TT, McLendon RE et al. PTEN gene mutations are seen in high-grade but not in low-grade gliomas. Cancer Res 1997; 57:4187–90. 59. Salcman M, Scholtz H, Kaplan RS, Kulik S. Long-term survival in patients with malignant astrocytoma. Neurosurgery 1994; 34: 213–19. 60. Fernandez PM, Brem S. Malignant brain tumors in the elderly. Clin Geriatr Med 1997; 13:327– 38. 61. Phillipon JH, Clemenceau SH, Fauchon FH et al. Supratentorial low-grade astrocytomas in adults. Neurosurgery 1993; 32:554–9. 62. Lote K, Egeland T, Hager B et al. Survival, prognostic factors, and therapeutic efficacy in lowgrade glioma: a retrospective study in 379 patients. J Clin Oncol 1997; 15:3129–40. 63. Vecht CJ. Effect of age on treatment decisions in low-grade glioma. J Neurol Neurosurg Psych 1993; 56:1259–64. 64. Kallio M. Therapy and survival of adult patients with intracranial glioma in a defined population. Acta Neurol Scand 1990; 81:541–9. 65. Flowers A. Brain tumors in the older person. Cancer Control 2000; 7:523–38. 66. Halperin EC. Malignant gliomas in older adults with poor prognostic signs. Going nowhere and taking a long time to do it. Oncology 1995; 9:229–34. 67. Silverstein MD, Cascino TL, Harmsen WS. High-grade astrocytomas: resource use, clinical outcomes, and cost of care. Mayo Clin Proc 1996; 71:936–44. 68. Layon AJ, George SE, Hamby B et al. Do elderly patients overutilize healthcare resources and benefit less from them than younger patients? A study of patients who underwent craniotomy for treatment of neoplasm. Crit Care Med 1995; 23:829–34. 69. Jelsma R, Bucy PG. Glioblastoma multiforme, its treatment and some factors affecting survival. Arch Neurol 1969; 20:161–71. 70. Brandes A, Fiorentino MV. Treatment of high-grade gliomas in the elderly. Oncology 1998; 55:1–6. 71. Pierga JY, Hoang-Xuan K, Feuvret L et al. Treatment of malignant gliomas in the elderly. J Neuro Oncol 1999; 43:187–93. 72. Kandil A, Khafaga Y, El Husseini G et al. Low-grade astrocytoma - a retrospective analysis of 102 patients. Acta Oncol 1999; 38: 1051–6. 73. Bauman G, Lote K, Larson D et al. Pretreatment factors predict overall survival for patients with low-grade glioma: a recursive partitioning analysis. Int J Radiat Oncol Biol Phys 1999; 54:923–9. 74. Janus TJ, Kyritsis AP, Forman AD, Levin VA. Biology and treatment of gliomas. Ann Oncol 1992; 3:423–33. 75. Weingart J, Brem H. Current management of high grade gliomas. Contemp Oncol 1993; 2:19– 31. 76. Whittle IR, Gregor A. The treatment of primary malignant brain tumors. J Neurol Neurosurg Psych 1991; 54:101–103. 77. Shapiro WR. Therapy of malignant brain tumors: What have the clinical trials taught us? Semin Oncol 1986; 1:38–45. 78. McVic JC. The therapeutic challenge of gliomas. Eur J Cancer 1993; 29A: 936–9. 79. Ushio Y. Treatment of gliomas in adults. Curr Opin Oncol 1991; 3: 467–75. 80. Whittle IR, Denholm SW, Gregor A. Management of patients aged over 60 years with supratentorial glioma: lessons from an audit. Surg Neurol 1991; 36:106–11. 81. Duncan GG, Goodman GB, Ludgate CM, Rheaume DE. The treatment of adult supratentorial high grade astrocytoma. J Neuro Oncol 1992; 13:63–72. 82. Salcman M. Surgery for malignant glioma. In: Brain Tumors: A Comprehensive Text (Morantz RA, Walsh JW, eds). New York: Marcel Decker, 1984:417–27.

Comprehensive Geriatric Oncology

1356

83. Devaux BC, O’Fallon JR, Kelly PJ. Resection, biopsy and survival in malignant glial neoplasms: a retrospective study of clinical parameters, therapy and outcome. J Neurosurg 1993; 78:762–75. 84. Ammirati M, Vick N, Liao Y et al. Effect of the extent of surgical resection on survival and quality of life in patients with supratentorial glioblastomas and anaplastic astrocytomas. Neurosurgery 1987; 21:201–6. 85. Kelly PJ, Hunt C. The limited value of cytoreductive surgery in elderly patients with malignant gliomas. Neurosurgery 1994; 34: 62–6. 86. Berger MS, Deliganis AV, Dobbins J, Keles GE. The effect of extent of resection on recurrence in patients with low grade cerebral hemispheric gliomas. Cancer 1994; 74:1784–91. 87. Andreou J, George AE, Wise A et al. CT prognostic criteria of survival after malignant glioma surgery. AJNR 1983; 4:488–90. 88. Albert FK, Forsting M, Sartor K et al. Early postoperative magnetic resonance imaging after resection of malignant glioma: objective evaluation of residual tumor and its influence on regrowth and prognosis. Neurosurgery 1994; 34:45–60. 89. Pietila TA, Stendel R, Hassler WE et al. Brain tumor surgery in geriatric patients. A critical analysis in 44 patients over 80 years. Surg Neurol 1999; 52:259–64 90. Winger MJ, MacDonald DR, Cairncross JG. Supratentorial anaplastic gliomas in adults: the prognostic importance of extent of resection and low grade glioma. J Neurosurg 1989; 71:487– 93. 91. Mohan DS, Suh JH, Phan JL et al. Outcome in elderly patients undergoing definitive surgery and radiation therapy for supratentorial glioblastoma multiforme at a tertiary care institution. Int J Radiat Oncol Biol Phys 1998; 42:981–7. 92. Barnett GH, Kormos DW, Steiner CP, Weisenberger J. Use of a frameless, armless stereotactic wand for brain tumor localization with two-dimensional and three-dimensional neuroimaging. Neurosurgery 1993; 33:4. 93. Salcman M, Karvan RS, Ducker TB et al. Effect of age and reoperation on survival in the combined modality treatment of malignant astrocytomas. Neurosurgery 1982; 10:454–63. 94. Bramdes AA, Vastola F, Monfardini S. Reoperation in recurrent high-grade gliomas: literature review of prognostic factors and outcome. Am J Clin Oncol 1999; 22:387–90. 95. Guyotat J, Signorelli F, Frappaz D et al. Is reoperation for recurrence of glioblastoma justified? Oncol Rep 2000; 7:899–904. 96. Sheline GE. Radiation therapy of brain tumors. Cancer 1977; 39: 873–81. 97. Meckling S, Dold O, Forsyth PA et al. Malignant supratentorial glioma in the elderly: Is radiotherapy useful? Neurology 1996; 47: 501–5. 98. Villa S, Vinolas N, Verger E et al. Efficacy of radiotherapy formalignant gliomas in elderly patients. Int J Radiat Oncol Biol Phys 1998; 42:977–80. 99. Grau JJ, Verger E. Radiotherapy of the brain in elderly patients. Pro. Eur J Cancer 2000; 36:443–7. 100. Brandes AA, Rigon A, Monfardini S. Radiotherapy of the brain in elderly patients. Contra. Eur J Cancer 2000; 36:447–51. 101. Shaw EG. Low-grade gliomas: to treat or not to treat. A radiation oncologist’s viewpoint. Arch Neurol 1990; 47:1138–9. 102. Leibel SA, Sheline GE, Wara NBM et al. The role of radiation therapy in the treatment of astrocytomas. Cancer 1975; 35:1551–7. 103. Kreth FW, Warnke PC, Scremet R, Ostertag CB. Surgical resection and radiation therapy versus biopsy and radiation therapy in the treatment of glioblastoma multiforme. J Neurosurg 1993; 78:762–6. 104. Hercberg AA, Tadmor A, Findler S et al. Hypofractionated radiation therapy and concurrent cisplatin in malignant cerebral gliomas—rapid palliation in low performance status patients. Cancer 1989; 64:816–20.

Brain tumors in the older person

1357

105. Hernandez JC, Manuyama Y, Yates R, Chin HW. Accelerated fractionation radiotherapy for hospitalized glioblastoma multiforme patients with poor prognostic factors. J Neuro Oncol 1990; 9:41–6. 106. Hoegler DB, Davey P. A prospective study of short course radiotherapy in the elderly patients with malignant glioma. J Neuro Oncol 1997; 33:201–4. 107. Brada M, Laing R. Radiotherapy/stereotactic external beam radiotherapy for malignant brain tumors. The Royal Marsden Hospital experience. Rec Res Cancer Res 1994; 135:91–104. 108. Regine WF, Patchell RA, Strottmann JM et al. Preliminary report of a phase I study of combined fractionated stereotactic radiosurgery and conventional external beam radiation therapy for unfavorable gliomas. Int J Radiat Oncol Biol Phys 2000; 48:421–6. 109. Southam L, Olivier A, Podgorsak EB et al. Fractionated stereotactic radiation therapy for intracranial tumors. Cancer. 1991; 68: 2101–8. 110. Wen PY, Alexander E, Brack PM et al. Long term results of stereotactic brachytherapy used in the initial treatment of patients with glioblastomas. Cancer 1994; 73:3029–36. 111. Kitchen ND, Hughes SW, Taub NA et al. Survival following brachytherapy for recurrent malignant glioma. J Neuro Oncol 1993; 18:33–9. 112. Gaspar LE, Zamorano LJ, Shamsa F et al. Permanent 125iodine implants for recurrent malignant gliomas. Int J Radiat Oncol Biol Phys 1999; 43:977–82. 113. Patel S, Breneman JC, Warnick RE et al. Permanent iodine-125 interstitial implants for the treatment of recurrent glioblastoma multiforme. Neurosurgery 2000; 46:1123–8. 114. Sheline GE, Wara WM, Smith V. Therapeutic irradiation and brain injury. Int J Radiat Oncol Biol Phys 1980; 6:1215–28. 115. Forsyth PA, Kelly PJ, Cascino TL et al. Radiation necrosis or glioma recurrence: Is computerassisted stereotactic biopsy useful? J Neurosurg 1995; 82:436–44. 116. Armstrong C, Ruffer J, Corn B et al. Biphasic patterns of memory deficits following moderate-dose partial-brain irradiation: neuropsychologic outcome and proposed mechanisms. J Clin Oncol 1995; 13:2263–71. 117. Trouette R, Caudry M, Maire JP, Demeaux H. Adult mental deterioration, the main limiting factor in cerebral radiotherapy? Bull Cancer Radiother 1993; 80:209–21. 118. Crossen JR, Garwood D, Glatstein E, Neuwelt EA. Neurobehavioral sequelae of cranial irradiation in adults: a review of radiation-induced encephalopathy. J Clin Oncol 1994; 12:627– 42. 119. Nieder C, Leicht A, Motaref B et al. Late radiation toxicity after whole brain radiotherapy: the influence of antiepileptic drugs. Am J Clin Oncol 1999; 22:573–9. 120. Schlegel U, Pels H, Oehring R, Blumcke I. Neurologic sequelae of treatment of primary CNS lymphomas. J Neuro Oncol 1999; 43: 277–86. 121. Yung WKA. Chemotherapy for malignant brain tumors. Curr Opin Oncol 1990; 2:673–8. 122. Kyritsis A. Chemotherapy for malignant gliomas. Oncology 1993; 7: 93–100. 123. Flowers A, Levin VA. Chemotherapy of brain tumors. In: Brain Tumors: An Encyclopedic Approach, 2nd edn (Kaye AH, Laws Jr ER, eds). Edinburgh: Churchill Livingstone, 2001:375– 92. 124. Donelli MG, Zuchetti M, Dincalci M. Do anticancer drugs reach the tumor target in the human brain? Cancer Chemother Pharmacol. 1992; 30:251–60. 125. Boaziz C, Breau JL, Morere JF, Israel L. The blood-brain barrier: implications for chemotherapy in brain tumors. Pathol Biol 1991; 39:789–94. 126. Vendrick CP, Berger JJ, Dejong WH, Steernberger PA. Resistance to cytostatic drugs at the cellular level. Cancer Chemother Pharmacol 1992; 29:413–29. 127. Belanich M, Pastor M, Randall T et al. Retrospective study of the correlation between the DNA repair protein alkyltransferase and survival of brain tumor patients treated with carmustine. Cancer Res 1996; 56:783–8.

Comprehensive Geriatric Oncology

1358

128. Friedman HS, McLendon RE, Kerby T et al. DNA mismatch repair and O6-alkylguanine— DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma. J Clin Oncol 1998; 16:3851–7. 129. Yung WKA, Janus TJ, Maor M, Feung LG. Adjuvant chemotherapy with carmustine and cisplatin in patients with malignant glioma. J Neuro Oncol 1992; 12:131–5. 130. Rogers LR, Purvis JB, Lederman RJ et al. Alternating sequential intracarotid BCNU and cisplatin in recurrent malignant glioma. Cancer. 1991; 68:15–21. 131. Gelman M, Chakeres DW, Newton HB. Brain tumors: complications of cerebral angiography accompanied by intraarterial chemotherapy. Radiology 1999; 213:135–40. 132. Newton HB, Bromberg J, Junck L et al. Comparison between BCNU and procarbazine chemotherapy for treatment of gliomas. J Neuro Oncol 1993; 15:257–63. 133. Yung WK, Albright RE, Olson J et al. Aphase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 2000; 83:588–93. 134. Chang CH, Horton J, Schoenfeld D et al. Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas. Cancer 1983; 52:997–1007. 135. Fine HA, Dear KB, Loeffler JS et al. Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer. 1993; 71:2585–97. 136. Walker MD, Green SB, Byar DP et al. Randomized comparison of radiotherapy and nitrosoureas for the treatment of malignant gliomas after surgery. N Engl J Med 1980; 303:1323–9. 137. Levin VA, Silver P, Hannigan J et al. Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine and vincristine (PCV) over BCNU for anaplastic glioma: NCOG 6C61 final report. Int J Radiat Oncol Biol Phys 1990; 18:321–4. 138. Sandberg WM, Malmstrom P, Stromblod LG et al. A randomized study of chemotherapy with procarbazine, vincristine and lomustine with and without radiation therapy for astrocytoma grades 3 and/or 4. Cancer 1991; 68:22–9. 139. Prados MD, Scott C, Curran W et al. Procarbazine, lomustine and vincristine (PCV) chemotherapy for anaplastic astrocytoma: a retrospective review of radiation therapy oncology group protocols comparing survival with carmustine or PCV adjuvant chemotherapy. J Clin Oncol 1999; 17:3389–95. 140. Krishnasamy S, Vokes EE, Dohrman G et al. Concomitant chemoradiotherapy, neutron boost, and adjuvant chemotherapy for anaplastic astrocytoma and glioblastoma multiforme. Cancer Invest 1995; 13:453–9. 141. Mason WP, Krol GS, DeAngelis LA. Low-grade oligodendroglioma responds to chemotherapy. Neurology 1996; 46:203–7. 142. Watne K, Nome O, Hager B, Hirschberg H. Pre irradiation chemotherapy in glioma patients with poor prognostic factors. J Neuro Oncol 1992; 13:261–4. 143. Eagon RT, Scott M. Evaluation of prognostic factors in chemotherapy of recurrent brain tumors. J Clin Oncol 1983; 1:38–44. 144. Grant R, Liang BC, Page MA et al. Age influences chemotherapy response in astrocytomas. Neurology 1995; 5:929–33. 145. Rosenblum ML, Gerosa M, Dougherty DV et al. Age, related chemosensitivity of stem cells from human malignant brain tumors. Lancet 1982; i: 885–7. 146. Vertosick FT, Selker RG, Pollack IF, Arena V. The treatment of intracranial malignant gliomas using orally administered tamoxifen therapy: preliminary results in a series of ‘failed’ patients. Neurosurgery 1992; 30:897–903. 147. Couldwell WT, Weiss MH, DeGiorgio CM et al. Clinical and radiographic response in a minority of patients with recurrent malignant gliomas treated with high-dose tamoxifen. Neurosurgery 1993; 32:485–90. 148. Olson JJ, Beck DW, Schlechte J et al. Hormonal manipulation of meningiomas in vitro. J Neurosurg 1986; 65:99–107.

Brain tumors in the older person

1359

149. Grunberg SM, Weiss MH, Spitz IM et al. Treatment of unresectable meningiomas with the antiprogestational agent mifepristone. J Neurosurg 1991; 74:861–6. 150. Chatel M, Lebrun C, Frenay M. Chemotherapy and immunotherapy in adult malignant gliomas. Curr Opin Oncol 1993; 5:464–73. 151. Lippman SM, Kessler JF, Meyskens FL. Retinoids as preventive and therapeutic anticancer agents (Part II). Cancer Treat Rep 1987; 17: 493–515. 152. Yung WKA, Lotan D, Lee P et al. Modulation of growth and EGF receptor activity by retinoic acid in human glioma cells. Cancer Res 1989; 49:1014–19. 153. Yung WKA, Simaga M, Levin VA. 13-cis-retinoic acid. A new and potentially effective agent for recurrent malignant astrocytomas. Proc Am Soc Clin Oncol 1993; 12:175. 154. Schneider J, Hoffman FM, Appuzo MLJ, Hinton DR. Cytokines and immunoregulatory molecules in malignant glial neoplasms. J Neurosurg 1992; 77:265–73. 155. Acevedo-Duncan N, Zhang R, Byvoet P et al. Interferon modulates human glioma protein kinase C II. Proc Am Assoc Cancer Res 1993; 34:176. 156. Nagai M, Arai T. Clinical effect of interferon in malignant brain tumors. Neurosurg Rev 1984; 7:55–64. 157. Duff TA, Borden E, Bay J et al. Phase II trial of interferon-α for treatment of recurrent glioblastoma multiforme. J Neurosurg 1986; 64:408–13. 158. Yung WKA, Castellanos AM, van Tassel P et al. A pilot study of recombinant interferon (3 (IFN (3) in patients with recurrent glioma J Neuro Oncol 1990; 9:29–34. 159. Yung WKA, Prados M, Levin VA et al. Intravenous recombinant interferon β in patients with recurrent malignant gliomas: a phase I/II study. J Clin Oncol 1991; 9:1945–9. 160. Fine HA, Wen P, Alexander E et al. α-Interferon, BCNU and 5-fluorouracil in the treatment of recurrent high-grade astrocytomas. Proc Am Soc Clin Oncol 1993; 12:175. 161. Buckner JC, Brown LD, Kugler JW et al. Phase II evaluation of recombinant interferon a and BCNU in recurrent glioma. J Neurosurg 1995; 82:430–5. 162. Young HF. Treatment of recurrent malignant glioma by repeated intracerebral injections of human recombinant interleukin-2, alone or in combination with systemic interferon-α: results of a phase-I clinical trial. J Neuro Oncol 1992; 12:75–83. 163. Moser RP, Bruner JM, Grimm EA. Biologic therapy for brain tumors. Cancer Bull 1991; 48:117–26. 164. Hosli P, Sappino AP, de Tribolet N, Dietrich PY. Malignant glioma: Should chemotherapy be overthrown by experimental treatments? Ann Oncol 1998; 9:589–600. 165. Riva P, Arista A, Sturiale C et al. Intralesional radio-immunotherapy of malignant gliomas. An effective treatment in recurrent tumors. Cancer 1994; 73:1076–82. 166. Kleinberg L, Grossman S, Piantados S et al. Preliminary result of a phase II trial of RSR13 in newly diagnosed GMB. Neurooncology 1999; 3: A318. 167. Neuwelt EA, Frenkel EP, Diehl J et al. Reversible osmotic blood-brain barrier disruption in humans: implications for the chemotherapy of malignant brain tumors. Neurosurgery 1980; 7: 44–52. 168. Neuwelt EA, Specht HD, Barnett PA et al. Increased delivery of tumor-specific monoclonal antibodies to brain after osmotic blood-brain barrier modification in patients with melanoma metastatic to the central nervous system. Neurosurgery 1987; 20: 885–95. 169. Garfield J, Dayan AD. Postoperative intracavitary chemotherapy of malignant supratentorial astrocytomas using BCNU. J Neurosurg 1973; 39:315–22. 170. Avellanosa A, West C, Barua N, Patel A. Intracavitary combination chemotherapy of recurrent malignant glioma via Ommaya shunt—a pilot study. Proc Am Soc Clin Oncol 1983; 2:234. 171. Bouvier G, Penn RD, Krohn JS et al. Direct delivery of medication into a brain tumor through multiple chronically implanted catheters. Neurosurgery 1987; 20:286–91. 172. Firth G, Oliver AS, McKeran TO. Studies on the intracerebral injection of bleomycin free and entrapped with liposomes in the rat. J Neurol Neurosurg Psych 1984; 47:585–9.

Comprehensive Geriatric Oncology

1360

173. Brem H, Mahaley MS, Vick NA et al. Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas. J Neurosurg 1991; 74:441–6. 174. Kaye AH, Morstyn G, Apuzzo MLJ. Photoradiation therapy and its potential in the management of neurological tumors. J Neurosurg 1988; 69:1–24. 175. Hill IS, Kaye AH, Sawyer WH et al. Selective uptake of hematoporphyrin derivative into human cerebral glioma. Neurosurgery 1990; 26:248–54. 176. Barth RF, Soloway AH, Fairchild RG. Boron neutron capture therapy of cancer. Cancer Res 1990; 50:1061–70. 177. Saris SC, Solares GR, Wazer DE et al. Boron neutron capture therapy for murine malignant gliomas. Cancer Res 1992; 52: 4672–7. 178. Culver KW, Ram Z, Wallbridge S et al. In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Science 1993; 256:988–90. 179. Markert JM, Coen DM, Malick A et al. Expanded spectrum of viral therapy in the treatment of nervous system tumors. J Neurosurg 1992; 77:590–4. 180. Takamya Y, Short MA, Moolten FL et al. An experimental model of retroviral gene therapy for malignant brain tumors. J Neurosurg 1993; 79:104–10. 181. Zerbe LK, Hughes TL, Josephs SA et al. Rapid cytotoxicity with ganciclovir following adenovirus transduction of glioma cells with herpes virus thymidine kinase. Proc Am Assoc Cancer Res 1995; 36: 423. 182. Trojan J, Johnson TR, Rudin SD et al. Treatment and prevention of rat glioblastoma by immunogenic C6 cells expressing antisense insulin-like growth factor I RNA. Science. 1993; 259:94–6. 183. Yu IS, Wei MK, Chiocca A et al. Treatment of glioma by genetically engineered interleukin4-secreting cells. Cancer Res 1993; 53: 3125–8. 184. Sobol RE, Fakhrai H, Shawler D et al. Immuno-gene therapy of glioblastoma. Proc Am Assoc Cancer Res 1995; 36:439. 185. Yung WKA, Shi YX, Zhang WW et al. Growth suppression of human glioma cells by restoration of wild-type p53 gene utilizing an adenovirus vector. Proc Am Assoc Cancer Res 1995; 36:423. 186. Gomez-Manzano C, Fueyo J, Kyritsis AP et al. Adenovirusmediated transfer of the p53 gene produces rapid and generalized death of human glioma cells via apoptosis. Cancer Res 1996; 56: 694–9. 187. Saleh M, Stacker SA, Wilks AF. Inhibition of growth of C6 glioma cells in vivo by expression of antisense vascular endothelial growth factor sequence. Cancer Res 1996; 56:393–401. 188. Hayes RL. The cellular immunotherapy of primary brain tumors. Rev Neurol 1992; 148:454– 66. 189. Yanasaki T, Handa H, Yamashita J et al. Specific adoptive immunotherapy with tumorspecific cytotoxic T lymphocytes clone for murine malignant gliomas. Cancer Res 1984; 44:1776–83. 190. Holladay FP, Lopez GL, Morantz RA, Wood GW. Generation of cytotoxic immune response against a rat glioma by in vivo priming and secondary in vitro stimulation with tumor cells. Neurosurgery 1992; 30:499–505. 191. Merchant RE, Coquia EM, Novitzki MR et al. Adoptive immunotherapy using gliomasensitized cytotoxic T cells. Proc Am Assoc Cancer Res 1995; 36:474. 192. Merchant RE, Merchant LH, Cook SHS et al. Intralesional infusion of lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2) for the treatment of patients with malignant brain tumor. Neurosurgery 1988; 23:725–32. 193. Merchant RE, Ellison MD, Young HF. Immunotherapy for malignant glioma using human recombinant interleukin-2 and activated autologous lymphocytes. J Neuro Oncol 1990; 8:173– 88. 194. Granger G, Ioli G, Hiserodt J et al. Basic and clinical studies of intralesional therapy of gliomas with allogeneic, lymphoid cells. Proc Am Assoc Cancer Res 1995; 36:472.

Brain tumors in the older person

1361

195. Lillehei KO, Mitchell DH, Johnson SD et al. Long term follow-up of patients with recurrent malignant gliomas treated with adjuvant adoptive immunotherapy. Neurosurgery 1991; 28:16– 23. 196. Hall WA, Fodstad O. Immunotoxins and central nervous system neoplasia. J Neurosurg 1992; 76:1–12. 197. Johnson VG, Wrobel C, Wilson D et al. Improved tumor-specific immunotoxins in the treatment of CNS and leptomeningeal neoplasia. J Neurosurg 1989; 70:240–8. 198. Recht LD, Griffm TW, Raso V, Salimi AR. Potent cytotoxicity of an antihuman transferrin receptor-ricin A-chain immunotoxin on human glioma cells in vitro. Cancer Res 1990; 50:6696–700. 199. Hall WA, Godal A, Juell S, Fodstad O. In vitro efficacy of transferrin-toxin conjugates against glioblastoma multiforme. J Neurosurg 1992; 76:838–44. 200. Flowers A, Steck PA, Donato NJ, Yung WKA. Enhanced cytotoxicity of cisplatin and BCNU on glioma cell lines by pretreatment with an EGF receptor targeted immunoconjugate. Proc Am Assoc Cancer Res 1994; 35:504. 201. Shack S, Prasanna P, Hudgins WR et al. Experimental therapies for malignant gliomas: targeting the mevalonate pathway of cholesterol synthesis. Proc Am Assoc Cancer Res 1994; 35:409. 202. Samid D, Shack S, Liu L et al. Phenylacetate and related non-toxic differentiation inducers in treatment of prostate, brain and skin cancer. Proc Am Assoc Cancer Res 1993; 34:377. 203. Ingber D, Fujita T, Kishimoto S et al. Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumor growth. Nature 1990; 348:555–7. 204. Teicher BA, Holden SA, Ara G, Brem H. Potentiation of cytotoxic cancer therapies by AGM1470 (AGM) alone and with other angiogenic antiangiogenic agents. Proc Am Assoc Cancer Res 1994; 35: 324. 205. Fine HA, Figg WD, Jaeckle K et al. Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas. J Clin Oncol 2000; 18:708–15. 206. Sawaya R, Ligon BL, Flowers A, Bindal R. Management of metastatic brain tumors: a review. Neurosurg Q 1994; 4:140–57. 207. Nieder C, Nestle U, Motaref B et al. Prognostic factors in brain metastases: Should patients be selected for aggressive treatment according to recursive partitioning analysis (RPA) classes? Int J Radiat Oncol Biol Phys 2000; 46:297–302. 208. Noordjik EM, Vecht CJ, Haaxma-Reiche H et al. The choice of treatment of single brain metastases should be based on extracranial tumor activity and age. Int J Radiat Oncol Biol Phys 1994; 29: 711–18. 209. Maor MH, Dubey P, Tucker SL et al. Stereotactic radiosurgery for brain metastases: results and prognostic factors. Int J Cancer 2000; 90:157–62. 210. Trojanowski T, Peszynski J, Turowski K et al. Quality of survival in patients with brain gliomas, treated; with postoperative CCNU and radiation therapy. J Neurosurg 1989; 70:18–23. 211. Weitzner MA, Meyers CA, Gelke CK et al. The Functional Assessment of Cancer Therapy (FACT) scale. Development of a brain subscale and revalidation of the general version (FACTG) in patients with primary brain tumors. Cancer 1995; 75:115–16. 212. Mayers CA, Boeke C. Neurobehavioral disorders in brain tumor patients: rehabilitation strategies. Cancer Bull 1993; 45:362–4. 213. Huang ME, Cifu DX, Keyser-Markus L. Functional outcomes in patients with brain tumor after inpatient rehabilitation: comparison with traumatic brain injury. Am J Phys Med Rehab 2000; 79: 324–35. 214. Wegmann JA. CNS tumors. Supportive management of the patient and family. Oncology 1991; 5:109–13. 215. Kaplan CP, Miner ME. Relationships: importance for patients with cerebral tumours. Brain Inj 2000; 14:251–9.

Comprehensive Geriatric Oncology

1362

216. Hutchins LF, Linger JM, Crowley JJ et al. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 1999; 341:2061–7. 217. Balducci L, Ades T, Carbone PP et al. Cancer control and the older person; issues in treatment. Cancer. 1991; 68(Suppl): 2527–9.

58 Gynecologic cancers in the elderly Tate Thigpen While cancers of the female genital tract can originate in virtually every portion of the tract, three lesions account for over 90% of all cases: celomic epithelial carcinomas of the ovary, carcinoma of the cervix, and endometrial carcinoma. These three lesions will form the focus of the following discussion. Celomic epithelial carcinoma of the ovary Cancer of the ovary includes several different types of malignancy: celomic epithelial carcinomas, germ cell neoplasms, and stromal tumors. Celomic epithelial carcinomas (henceforth referred to as ovarian carcinoma) account for almost 90% of these and are the most common cause of death due to gynecologic cancers in the USA. General considerations Proper management of ovarian carcinoma depends on an understanding of specific characteristics of the disease: etiology, the impact of age, and prognostic factors, including especially stage. Etiology Although the etiology of ovarian carcinoma is not known, there is an association between uninterrupted ovulation and the disease.1 Familial factors are also evident from the identification of hereditary breast-ovarian cancer syndrome, hereditary ovarian cancer syndrome, and Lynch II (colon carcinoma in association with ovarian cancer) syndrome.2 Mutations of chromosomes 17 (BRCA1) and 13 (BRCA2) account for the first two.3,4 These syndromes characteristically produce ovarian carcinoma at a younger age (median 45–52 years versus 59 years for other cases), are associated with a positive family history, and account for approximately 5% of ovarian carcinomas. Impact of age Age is a significant factor in ovarian carcinoma. In terms of incidence, ovarian carcinoma becomes increasingly common from age 30 through 80.5 For women under 50, the incidence of ovarian carcinoma is 20 per 100 000; whereas it increases to 40 per 10 000 for women over 50.

Comprehensive Geriatric Oncology

1364

With reference to outcome, cancer registry data show that older patients exhibit a much higher incidence of advanced disease than do younger patients (41% of patients aged between 25 and 34 with advanced disease as compared with 73% of patients older than 85).6 Extensive data from cooperative group trials also show that, independent of stage and comorbid conditions, older patients have poorer survival than younger patients; hence, older patients appear to have more aggressive disease than their younger counterparts.7,8 Whether older patients respond more poorly to treatment than younger patients is obscured by the tendency of physicians to reduce chemotherapy dose intensity or to employ regimens regarded as less toxic but also less effective. The use of such ‘more conservative’ regimens is contrary to scientific evidence, which shows that older patients tolerate aggressive therapy as well as their younger counterparts.7,9,10 Other prognostic factors Other than age, the most significant prognostic factors for ovarian carcinoma are histologic type and grade,11 extent of disease (stage), and volume of residual disease.12–15 Patients with serous or endometrioid tumors have a better prognosis than those with mucinous or clear cell lesions. More poorly differentiated tumors are associated with a poorer prognosis. The most important determinant of prognosis, however, is the extent of disease at the time of diagnosis, as expressed in the International Federation of Gynecology and Obstetrics (FIGO) staging system (Table 58.1).16 The FIGO staging system incorporates two important characteristics of ovarian carcinoma. First, the most common route of spread is peritoneal dissemination.

Table 58.1 IGO staging system for ovarian carcinoma16 Stage Description I

Growth limited to the ovaries

IA

One ovary; no ascites; capsule intact; no tumor on external surface

IB

Two ovaries; no ascites; capsule intact; no tumor on external surface

IC

One or both ovaries, with surface tumor, ruptured capsule, or ascites or peritoneal washings with malignant cells

II

Pelvic extension

IIA

Involvement of uterus and/or tubes

IIB

Involvement of other pelvic tissues

IIC

IIA or IIB with factors as in IC

III

Peritoneal implants outside pelvis and/or positive retroperitoneal or inguinal nodes

IIIA

Grossly limited to true pelvis; negative nodes; microscopic seeding of abdominal peritoneum

IIIB

Implants of abdominal peritoneum ≤2 cm; nodes negative

Gynecologic cancers in the elderly

1365

IIIC

Abdominal implants >2 cm and/or positive retroperitoneal or inguinal nodes

IV

Distant metastases

Stage III, which includes those patients who have disseminated disease confined to the peritoneal cavity, is by far the most common stage at presentation. Secondly, among patients with stage III disease, volume of disease is an important determinant of response to chemotherapy and survival (those with nodules smaller than 2 cm have a higher response rate and a longer survival); hence, stage III is subdivided according to volume of disease at the time the abdomen is opened. Clinical presentation and evaluation Screening Because ovarian carcinoma is an intraabdominal process with few specific early symptoms, a majority of patients present with advanced disease. Since regular pelvic examination has failed to yield a higher frequency of early diagnosis, more recent efforts have focused on serum CA-125 and transvaginal sonography.17 CA-125 is a celomic epithelial marker elevated in more than 80% of patients with ovarian carcinoma, the frequency of elevation varying directly with the extent of disease from 50% in stage I to more than 90% in stage III and IV disease.18 The marker is also elevated in a number of benign gynecologic and other conditions; hence, eleva tions are not specific for ovarian carcinoma. Two trials17,19 assessing the value of CA-125 as a screening test demonstrate that the test can detect ovarian carcinoma with a specificity as high as 0.970; but sensitivity is lacking, particularly in those patients with stage I disease, where CA-125 is elevated in only 15–50% of clinically detectable tumors and even fewer with sonographically detectable tumors. Transvaginal sonography is a second approach advocated for the early detection of ovarian carcinoma. In two trials of 1300 and 776 women, respectively, a total of 5 stage I ovarian cancers were detected.20,21 In the larger of these two trials, 27 laparotomies were performed to detect 2 stage I cancers. Because of the lack of sensitivity for early-stage tumors and the relatively large number of laparotomies required to diagnose a single case of early-stage ovarian carcinoma, CA-125 and transvaginal sonography cannot be recommended for routine screening at present. Randomized trials in a high-risk group are needed to determine whether these two approaches used together in a serial fashion constitute effective screening for ovarian carcinoma. Family history provides the means for selecting the high-risk group to be investigated, since patients with one or more relatives with ovarian carcinoma are at a 2.9- to 4.5-fold increased risk for developing the disease.

Comprehensive Geriatric Oncology

1366

Table 58.2 Active systemic agents in celomic epithelial carcinoma of the ovary21–31 Agents

Response rate (%)

Available agents Alkylating agents

33

Cisplatin

32

Carboplatin

24

Paclitaxel

29

Docetaxel

28

Doxorubicin

33

5-Fluorouracil

29

Methotrexate

18

Mitomycin C

16

Hexamethylmelamine

24

Oral etoposide

30

Topotecan

19

Navelbine

29

Gemcitabine

16

Investigational agents Prednimustine

28

Dihydroxybusulfan

27

Galactitol

15

Hormones and biologicals Progestins

12

Antiestrogens

19

Interferon-α

19

Interferon-γ

29

Gynecologic cancers in the elderly

1367

Table 58.3 Gynecologic Oncology Group (GOG) Protocol 111 and European-Canadian OV-10: comparisons of cisplatin plus either cyclophosphamide or paclitaxel32,33 GOG 111 Parameter

PC

Response rate (%)

OV-10

PT

PCa

PTC

60

73

66

77

Clinical complete response rate (%)

31

51

36

50

Grossly disease-free rate (%)

24

40

Progression-free survival (months)

13

18

12

16

Overall survival (months)

24

38

25

35

a

b

The differences in response rate, progression-free survival and overall survival are statistically significant in both studies a

Cisplatin 75mg/m2 plus cyclophosphamide 750mg/m2 intravenously every 3 weeks. Paclitaxel 135mg/m2 intravenously over 24 hours followed by cisplatin 75mg/m2 intravenously every 3 weeks. c Paclitaxel 175mg/m2 intravenously over 3 hours followed by cisplatin 75mg/m2 intravenously every 3 weeks. b

Clinical presentation and evaluation Patients usually present with non-specific symptoms such as a heavy sensation in the pelvis or increasing abdominal girth because of ascites. Although physical examination and various imaging techniques are employed in evaluation, all patients without demonstrated stage IV disease require an exploratory laparotomy to establish the diagnosis and extent of disease. Management of advanced disease Patients with advanced (stage III or IV) disease, unless stage IV is already established, undergo exploratory laparotomy, which, in addition to establishing the extent of disease, affords the first step in therapy. The laparotomy is performed through an incision sufficient to permit the exploration of the entire peritoneal cavity. In the absence of gross disease outside of the pelvis, multiple biopsies are taken to rule out microscopic disease. Finally, based on considerations noted above, an aggressive attempt at surgical cytoreduction is undertaken.22 The mainstay of the treatment of advanced disease is systemic therapy. A number of drugs are active against ovarian carcinoma: platinum compounds, alkylating agents, taxanes, doxorubicin, hexamethylmelamine, 5-fluorouracil (5-FU), methotrexate, topotecan, oral etoposide, gemcitabine, and tamoxifen (Table 58.2).23–31 The current standard of care for first-line therapy is a combination of paclitaxel 175 mg/m2 over 3

Comprehensive Geriatric Oncology

1368

hours followed by carboplatin AUC 6–7.5, with the combination being repeated every 3 weeks for six cycles (Tables 58.3 and 58.4).32–35 This combination should yield regressions of 50% or greater in 75% of patients with large-volume disease, complete regression of a disease in 40–50% of such patients, a pathologic complete response (disease-

Table 58.4 Gynecologic Oncology Group (GOG) Protocol 158 and AGO (German) trials: comparisons of paclitaxel plus either cisplatin or carboplatin34,35 AGO Patients

GOG 158

798 a

798 b

Regimens

TP vs TC

TPc vs TCd

Overall survival hazard ratio

1.07

0.86

The differences noted here are not statistically significant, with the survival trend favoring paclitaxel-cisplatin in the AGO trial and paclitaxel-carboplatin in the GOG trial a

Paclitaxel 185mg/m2 intravenously over 3 hours followed by cisplatin 75mg/m2 intravenously every 3 weeks. b Paditaxel 185mg/m2 intravenously over 3 hours followed by carboplatin AUC 6 every 3 weeks. c Paclitaxel 135mg/m2 intravenously over 24 hours followed by cisplatin 75mg/m2 intravenously every 3 weeks. d Paclitaxel 175mg/m2 intravenously over 3 hours followed by carboplatin AUC 7.5 every 3 weeks

free at second-look laparotomy at the conclusion of chemotherapy) in 20–25%, a median progression-free survival of 18 months, and a median overall survival of 26–37 months. Results in those with small-volume disease will be better. Other combinations that have been used, with somewhat less success, include cisplatin plus cyclophosphamide, carboplatin plus cyclophosphamide, and cisplatin plus doxorubicin plus cyclophosphamide.36 In patients with small-volume disease, the frequency of pathologic complete response, the duration of response, and the overall survival will be significantly better than in patients with large-volume disease.12–15

Table 58.5 Risk groups of patients with limited ovarian carcinoma11 Risk group

Characteristics

Low risk

Grade 1 or 2 disease Intact capsule No tumor on external surface Negative peritoneal cytology No ascites

Gynecologic cancers in the elderly

1369

Growth confined to ovaries High risk

Grade 3 disease Ruptured capsule Tumor on external surface Positive peritoneal cytology Ascites Growth outside ovaries

If any high-risk factors are present, the patient is considered high risk

Management of limited disease As with advanced disease, exploratory laparotomy determines whether disease is truly confined to the ovaries (stage I) or pelvis (stage II).11,37 Information from the laparotomy characterizes the patient as low risk for recurrence (grade 1 or 2, intracystic disease, no extraovarian disease, no ascites, and negative peritoneal cytology) or high risk (grade 3, extracystic disease, extraovarian disease, ascites, or positive peritoneal cytology) (Table 58.5).11 Patients at low risk have a cure rate exceeding 90% with total abdominal hysterectomy, bilateral salpingooophorectomy, and omentectomy alone, and require no additional therapy. Those at high risk have a recurrence rate that may reach as high as 40%, and should receive additional therapy after surgical resection.38

Table 58.6 Recommendations for management of previously untreated patients Disease status

Recommendation

Limited disease: Low risk

Total abdominal hysterectomy, bilateral salpingo-oophorectomy, and observation

High risk

Same surgery as low risk, followed by adjuvant platinum-based chemotherapy (paclitaxel-carboplatin)

Advanced disease Small volume

Maximum surgical cytoreduction, followed by paclitaxel-carboplatin

Large volume

Paclitaxel-carboplatin

The selection of additional therapy is based on randomized trials. An Italian trial demonstrated that the use of adjuvant platinum-based chemotherapy in patients at high risk for recurrence produced a superior progression-free survival.38 A subsequent

Comprehensive Geriatric Oncology

1370

combined analysis of two trials39 showed that adjuvant platinum-based chemotherapy produced not only a superior progression-free survival (absolute 11% difference) but also a superior overall survival (absolute 8% difference). This trial did not specify the precise composition of the platinum-based regimen; hence, the relative merits of one regimen over another cannot be assessed. Most clinicians prefer to use the current regimen of choice in advanced disease: a combination of paclitaxel plus carboplatin. Table 58.6 summarizes the front-line management of both advanced and limited disease based on current evidence. Salvage therapy For patients who recur after initial therapy, appropriate management is determined by the response to initial treatment (Table 58.7).40 Patients who initially respond to platinumbased chemotherapy and then recur more than 6 months after completion of initial treatment should be considered ‘platinum-sensitive’. Such patients respond well to repeat treatment with platinum-based therapy. A recent randomized trial suggests an advantage for a taxane-platinum combination in this setting.41 On the other hand, those who have progressive disease on platinum-based treatment, who exhibit persistent disease at the end of initial platinum-based therapy, or who recur within 6 months respond infrequently to repeat platinum-based treatment and should be considered ‘platinum-resistant’. Such patients, if they have not received a taxane as a part of initial therapy, should be treated with a taxane. Other agents that have been reported to yield at least some responses include a different taxane, liposomal doxorubicin, oral etoposide, topotecan, gemcitabine, ifosfamide, vinorelbine, tamoxifen, and 5-FU-leucovorin.

Table 58.7 Gynecologic Oncology Group definitions of platinum-sensitive and platinumresistant ovarian carcinoma40 Platinum-sensitive •

Initial response to platinum

•

Platinum-free interval >6 months

Platinum-resistant •

Progression on platinum

•

Stable disease on prior platinum

•

Relapse <6 months after prior platinum

At present, data do not support the use outside of clinical trials of either intraperitoneal therapy or high-dose chemotherapy with autologous hematopoietic stem cell support as part of either first-line or salvage treatment. Intraperitoneal cisplatin can induce responses in patients who have had prior platinum-based chemotherapy and remain platinumsensitive; and two major randomized phase III trials suggest that intraperitoneal cisplatin yields a modest, statistically significant improvement in survival compared with intravenous cisplatin.42,43 Because of problems with the design of the phase III trial and

Gynecologic cancers in the elderly

1371

the toxicity of the intraperitoneal regimens, routine clinical application of intraperitoneal therapy should await further refinement of these regimens. The use of high-dose chemotherapy supported by stem cells has been tested only in phase II trials in patients who have had prior chemotherapy. This approach remains an investigational concept, with insufficient evidence to support its use outside of clinical trials. Management of the individual at high risk for ovarian carcinoma Much attention has recently been directed to individuals at high risk for the development of ovarian carcinoma. The overall lifetime risk for the development of ovarian carcinoma for women in the USA is approximately 1.4% (1 chance in 70). Reasonable evidence supports an enhanced risk for women with one first-order relative (mother or sibling) that approximates 5%.2 For women with two or more first-order relatives with ovarian carcinoma, the risk is considerably higher (estimates range from 10% to more than 50%, with the actual level of risk not yet clear).44 As noted above, no screening test of proven efficacy is available. In the absence of an effective screening test, some have suggested that women at high risk should undergo prophylactic oophorectomy.44,45 While such an approach certainly has appeal, recent reports of celomic epithelial carcinomas of the peritoneal surface in women who have undergone prophylactic oophorectomy raise questions about whether such an approach is truly effective. Six such cases have been reported among 324 high-risk women who had undergone prophylactic oophorectomy, for an overall incidence of 1.8%.45 Although such a rate is lower than would be anticipated in a high-risk group, further follow-up is needed before any conclusions can be drawn. For the present, no dogmatic recommendations can be made. Issues regarding the use of CA-125 and transvaginal sonography for screening and prophylactic oophorectomy in women at high risk for developing ovarian cancer should be discussed with patients, but such approaches cannot be recommended for widespread application based on currently available data. Squamous cell carcinoma of the uterine cervix Cancer of the uterine cervix includes a variety of histologies: squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, clear cell carcinoma, and mixed histologies. The most common of these is squamous cell carcinoma, which accounts for more than 80% of all cases. The following discussion does not address differences in management among the various histologies, because the frequency of nonsquamous histology is too low to permit separate studies. General considerations Etiology Although the etiology of squamous cell carcinoma of the uterine cervix is not fully understood, certain facts are clear. The process exhibits the epidemiology of a venereal

Comprehensive Geriatric Oncology

1372

disease46 with associated factors including lower socioeconomic status, onset of coitus at an early age, frequentc oitus, multiple sexual partners, and coitus with an uncircumcised partner or one who practices poor genital hygiene. There is also an intimate connection between the disease and human papillomavirus (HPV), which, as would be expected from epidemiologic evidence, is believed to be transmitted by sexual intercourse.47 Preinvasive disease Squamous cell carcinoma of the uterine cervix is associated with a well-described premalignant state that is variously described as cervical intraepithelial neoplasia (CIN 1– 3) or a squamous intraepithelial lesion (SIL: low-grade (LGSIL) and high-grade (HGSIL)).48 These lesions can be detected by cervical cytology, which constitutes the most effective screening test for cancer. The process by which cells go from mild through severe dysplasia and carcinoma in situ to frankly invasive cancer usually takes years; hence, there is a significant window of opportunity for early diagnosis and cure of the vast majority of women with the disease. Staging The most important prognostic feature of invasive disease is the extent of disease at the time of diagnosis, as expressed in the FIGO staging system (Table 58.8).49 This clinical staging system will form the basis for treatment selection. An appropriate staging evaluation should include careful history and physical examination (including a thorough pelvic and rectal examination), complete blood count, tests to evaluate hepatic and renal status,

Table 58.8 FIGO staging system for cervical cancer49 Stage Description 0

Carcinoma in situ

I

Cervical carcinoma confined to uterus (disregard extension to corpus)

IA

Invasive carcinoma diagnosed by microscopy only

IA1

Minimal microscopic stromal invasion

IA2

Invasive component <5mm depth from base of epithelium and ≤7mm horizontal spread

IB

Larger than IA2

II

Invasion beyond uterus but not to pelvic wall or lower third of vagina

IIA

No parametrial invasion

IIB

Parametrial invasion

III

Extension to pelvic wall and/or involvement of lower third of vagina or hydronephrosis or non-functioning kidney

IIIA

Lower third of vagina only

Gynecologic cancers in the elderly

1373

IIIB

Pelvic wall involvement or hydronephrosis or non-functioning kidney

IV

Spread or adjacent organs or extension beyond true pelvis

IVA

Involvement of mucosa of bladder or rectum

IVB

Extension beyond true pelvis

urinalysis, flexible sigmoidoscopy, barium enema, intravenous pyelogram, computed tomographic (CT) scan of the abdomen and pelvis, and histologic confirmation of malignancy and cell type. Histologic confirmation may require cytologic smears, colposcopy, conization, punch biopsies of the four quadrants of the cervix, or dilatation and curettage as well as cystoscopy. While the extent of the workup will be determined by the findings of each procedure, it must yield sufficient information to stage the patient accurately. Impact of age Because of its relationship to sexual activity, carcinoma of the cervix tends to occur at a younger average age (50 years) than either ovarian or endometrial carcinoma. This has prompted physicians to perform fewer Pap smears in older women (11.8 per 1000 visits in women aged 65 and older) than in younger women (121.3–143.4 per 1000 visits in women aged 25–44). As a result, the incidence of localized disease drops from 98% in younger women to 59% in older women, with a corresponding rise in the death rate.50 Adding to this problem are technical difficulties in older women, such as problems in identifying the squamocolumnar junction and the presence of a stenotic atrophic cervix. The choice of therapy for older women also represents an age-related problem in carcinoma of the cervix. Current practice tends to avoid radical surgery in women over the age of 65 and to employ radiotherapy instead. Studies, however, do not support such practice. Two trials of radical hysterectomy and pelvic lymphadenectomy show similar survival rates in elderly and younger patients, with no significant differences in morbidity and mortality from the surgery.51,52 In contrast, three studies showed an increase in complications in elderly patients with radiotherapy for carcinoma of the cervix.53,56 These data suggest that decisions regarding treatment in elderly patients should be based on factors other than age and, for those without major medical problems, should not differ from decisions in younger patients. Management of limited disease Patients who have disease confined to the cervix, detectable by microscopy only, and limited in invasion to 5 mm or less in depth taken from the base of the epithelium and 7 mm or less in horizontal spread have either stage 0 (carcinoma in situ), stage IA1 (minimal microscopic stromal invasion), or stage IA2 (more invasive up to the limits described). The definitive treatment for these lesions is total abdominal hysterectomy, although non-surgical candidates can be treated with radiotherapy.55 Selected patients, in particular those with carcinoma in situ and those with minimally invasive lesions (<1mm

Comprehensive Geriatric Oncology

1374

in depth), can be managed with more conservative measures such as conization, provided that all margins are clear (Table 58.9).56 Management of locoregionally advanced disease Patients with stage IB-IVA disease have more advanced disease still confined to the pelvis. In addition to the

Table 58.9 Management of cervical cancer by stage of disease Disease status

Recommendations

Preinvasive or IA

Total abdominal hysterectomy; lesser procedures in selected cases of preinvasive disease

Selected stage IB

Radical hysterectomy

Stage IB-IVA

Concurrent cisplatin-based chemoradiation

Stage IVB or recurrent

Systemic therapy with a combination to include a platinum compound plus either paclitaxel or ifosfamide

extent of pelvic disease, the status of the para-aortic lymph nodes is an important prognostic factor.57 Management of patients with uninvolved para-aortic nodes will be discussed here stage-by-stage, followed by consideration of the management of those with involved para-aortic nodes. For selected patients with non-bulky stage IB disease, either pelvic radiotherapy or radical hysterectomy constitutes reasonable treatment. The 5-year survival rate should exceed 80% in carefully staged patients with either approach. For all other patients with stage IB-IVA disease, solid evidence from randomized trials supports the enhanced effectiveness of concurrent chemoradiation.57–63 Five randomized trials show superiority for concurrent cisplatin-based chemoradiation over radiation alone or radiation plus hydroxyurea. Among the cisplatin-based regimens, weekly cisplatin 40 mg/m2 given concurrently with radiation produces results similar to any other regimen, with much simpler logistics. The standard of care is thus concurrent chemoradiation with weekly cisplatin plus radiation.57–63 This approach offers a

Table 58.10 Active drugs in cervical carcinoma23,65 Drug

Response rate

Alkylating agents Cyclophosphamide

38/251 (15%)

Chlorambucil

11/44 (25%)

Melphalan

4/20 (20%)

Ifosfamide

25/157 (15%)

Gynecologic cancers in the elderly

1375

Dibromodulcitol

23/102 (29%)

Galactitol

7/36 (19%)

Platinum complexes Cisplatin

190/815 (23%)

Carboplatin

27/175 (15%)

Antibiotics Doxorubicin

45/266 (20%)

Porfiromycin

17/78 (22%)

Antimetabolites 5-Fluorouracil

29/142 (20%)

Methotrexate

17/96 (18%)

Baker’s antifol

5/32 (16%)

Viaca alkaloids Vincristine

10/55 (18%)

Vindesine

5/21 (24%)

Other agents ICRF-159

5/28 (18%)

Hexamethylmelamine

12/64 (19%)

Paclitaxel

9/52 (18%)

reduction in mortality ranging from 24% to 51% in the various studies. In patients with positive para-aortic nodes, survival is much worse.64 The standard approach to these patients is extension of the radiation port to include the para-aortic node area. The 5-year survival rate is 10–15%. There have been no well-designed randomized studies of systemic therapy in combination with radiation, although the rationale for such an approach is excellent. Management of advanced or recurrent disease Patients who present with stage IVB disease or who recur after initial therapy for more limited disease are candidates for systemic therapy. There are a number of chemotherapeutic agents with moderate activity (Table 58.10),23,65 but three drugs have been of particular interest: the platinum compounds, ifosfamide, and paclitaxel. A number of studies of combination chemotherapy have been reported; virtually all of these are uncontrolled trials in selected patients and are very difficult to interpret. The Gynecologic Oncology Group recently completed two randomized trials in which a combination produced superior response rates and progression-free survival as compared with cisplatin alone, with no difference in overall survival (Tables 58.11 and 58.12).66–67

Comprehensive Geriatric Oncology

1376

In summary, the treatment of choice for patients with advanced or recurrent disease at present is combination chemotherapy with cisplatin plus either paclitaxel or ifosfamide. These combinations should yield response rates of 31–36%, progression-free survivals of 4.6–4.8 months, and overall survivals of 8.3–9.0 months.

Table 58.11 Results of Gynecologic Oncology Group Protocol 110, a randomized trial of patients with advanced or recurrent squamous cell carcinoma of the cervix66 Regimena

Response rate (%)

Cisplatin 50mg/m2 i.v.

18

2

2

Cisplatin 50mg/m i.v. + ifosfamide 5g/m i.v. 24 hours 2

31

2

Cisplatin 50mg/m i.v. + mitolactol 180mg/m p.o. days 2–6

21

Progression-free survival (4–5 months) and overall survival (8 months) were not significantly different among the regimens a

Cisplatin is given as an infusion at a rate of 1mg/min, and ifosfamide as a 24-hour infusion with mesna. All regimens are repeated every 3 weeks.

Table 58.12 Results of Gynecologic Oncology Group Protocol 169, a randomized trial of patients with advanced or recurrent squamous cell carcinoma of the cervix67 Regimen

Response rate Time to progression (%) (months)

Survival (months)

Cisplatin 50 mg/m2 i.v.

19

2.8

9

Cisplatin 50 mg/m2 i.v. paclitaxel 135 mg/m2 i.v. 24 hours

+36

4.8

9

The differences in both response rate and progression-free survival are statistically significant

Endometrial carcinoma The more than 30 000 new cases of endometrial carcinoma in the USA each year make this tumor the most common invasive malignancy of the female genital tract. Although the cure rate is high at 66%, a significant proportion of patients will suffer recurrence and die of their disease; hence, efforts at treatment must focus on systemic therapy as well as the management of localized disease.

Gynecologic cancers in the elderly

1377

General considerations Endometrial carcinoma is a disease primarily of menopausal and postmenopausal women, with a median patient age of 61 years. Personal risk factors include obesity, nulliparity, late menopause, diabetes, hypertension, immunodeficiency, and exogenous estrogens.68 The most common presenting manifestation is dysfunctional uterine bleeding. Such bleeding in postmenopausal women results from malignancies is approximately 20% of cases; a majority of these will be endometrial carcinomas. In contrast, over 90% of endometrial carcinomas present with dysfunctional bleeding. Impact of age Endometrial carcinoma is a disease of older women. There is no evidence, however, that age alone should be a consideration in management decisions. Differences in stage at presentation for older versus younger patients appear to relate entirely to a less aggressive approach to the evaluation of postmenopausal bleeding in older patients. Although adverse effects associated with treatment are more common in older patients, there is no evidence that survival is compromised. Factors other than age should drive management decisions. Pathology Endometrial carcinoma most commonly is adenocarcinoma, which accounts for 70% of cases.69 Most of the remainder will have adenocarcinoma mixed with either squamous metaplasia (adenoacanthoma) or squamous carcinoma (adenosquamous carcinoma). After stage and grade are considered, the three most common cell types have little bearing on prognosis or approach to therapy. Clinical course Endometrial carcinoma arises from the glandular component of the endometrium. Development of malignant changes may be preceded by endometrial hyperplasia with dysplastic changes (adenomatous hyperplasia).70 Early growth within the uterine cavity yields an exophytic, friable mass with spontaneous bleeding. Both vertical and horizontal spread occur, with involvement of the myometrium and the cervix. Spreading beyond the uterus occurs as a result of lymphatic spread to parametrial, pelvic, inguinal, and paraaortic nodes, hematogenous dissemination to distant sites such as the lungs, liver, and bones, and peritoneal implantation from either transtubal spread or vertical penetration of the entire thickness of the uterine wall. Recurrence after initial treatment is most commonly extrapelvic, in such locations as the lungs, liver, bone, abdominal cavity, and lymph nodes. A majority of failures will occur within 2 years of initial treatment.

Comprehensive Geriatric Oncology

1378

Prognostic factors The most important determinant of prognosis is the extent of the disease at presentation as reflected in the FIGO staging system (Table 58.13).71 Stage I disease is by far the most common stage at presentation (75%), with an excellent 5-year survival rate of 76%. Survival decreases dramatically as the initial extent of disease increases, but the overall 5-year survival rate is 66%, as a result of the frequency of stage I disease. Stage I-IVA disease is disease limited to the pelvis clinically, whereas stage IVB and recurrent disease is disseminated disease. Factors in stage I-IVA disease Patients with stage I-IVA disease are at a level of risk for recurrence based on features of the primary lesion and its regional spread (Table 58.14).69,72 Six pathologic features determine the prognostic categories that form the basis for a rational approach to management: histologic grade, depth of myometrial invasion, involvement of pelvic and/or para-aortic lymph nodes, peritoneal cytology, adnexal spread, and involvement of the cervix. Using these features, patients at low risk for recurrence are those with disease limited to the corpus without

Table 58.13 FIGO staging system for endometrial carcinoma71 Stage

Description

0

Carcinoma in situ. Histologic findings suspicious for malignancy

I

Carcinoma confined to corpus

IAG123

Tumor limited to endometrium

IBG123

Invasion of less than half of myometrium

ICG123

Invasion of over half of myometrium

II

Carcinoma involving corpus and cervix but not extending outside uterus

IIAG123

Endocervical glandular involvement only

IIBG123

Cervical stromal invasion

III

Carcinoma extending outside uterus but not outside true pelvis

IIIAG123 Tumor invades serosa or adnexae or positive peritoneal cytology IIIBG123 Vaginal metastases IIICG123 Metastases to pelvic or para-aortic lymph nodes IV

Carcinoma extending outside true pelvis or involving bladder or rectal mucosa

IVAG123 Tumor invasion of bladder and/or bowel mucosa

Gynecologic cancers in the elderly

IVB

1379

Distant metastases, including intraabdominal and/or inguinal lymph nodes

Table 58.14 Classification of patients with endometrial carcinoma based on clinical and pathologic variables provides a clinically practical approach to the disease • Limited disease: stage I-IVA: Low-risk disease: stage IA grades 1–2 Intermediate-risk disease: all other stage I, stage II High-risk disease: stage III-IVA • Disseminated disease: stage IVB or recurrent

myometrial invasion and with a histologic grade of 1 or 2. Those at intermediate risk for recurrence are all others with stage I disease and all with stage II disease. Those at high risk for recurrence include all stage III and IVA patients. Factors in advanced disease Patients who present with advanced (stage IVB) or recurrent disease are at the greatest risk for death as a result of their disease. Diagnosis and evaluation Patients with dysfunctional uterine bleeding should have a thorough evaluation, the key to which is obtaining an adequate endometrial tissue sample. The Pap smear, the simplest technique, suffers from a low diagnostic accuracy of 40%. Aspiration techniques in the ambulatory setting yield a better accuracy of 70%, but a negative result does not rule out endometrial carcinoma. A more accurate and complete evaluation is provided by dilatation and fractional curettage, which allows for assessment for endocervical involvement. Pretreatment evaluation should delineate those disease features essential to assignment of stage and prognostic category. This information will then be used to make appropriate management decisions. Management of limited disease Patients with limited (stage I-IVA) endometrial carcinoma constitute the vast majority of patients and have an excellent chance of cure. The management of an individual patient will depend upon the patient’s risk status (Table 58.15). Virtually all patients with limited disease should have surgical resection of the primary disease unless the operative risk is unacceptably high. The surgical procedure should include a total abdominal hysterectomy and bilateral salpingo-oophorectomy, as well as assessment of peritoneal cytology and pelvic and para-aortic lymph nodes.

Comprehensive Geriatric Oncology

1380

Low-risk patients Patients at low risk for recurrence have greater than 95% chance of remaining diseasefree beyond 5 years when treated with surgery alone.72 Appropriate management is therefore total abdominal hysterectomy and bilateral salpingo-oophorectomy, with assessment for high-risk features. Intermediate-risk patients Patients at intermediate risk for recurrence have been treated with a variety of approaches combining surgery

Table 58.15 Management recommendations for endometrial carcinoma Disease status

Recommendations

Limited disease: Low risk

Total abdominal hysterectomy, bilateral salpingo-oophorectomy

Intermediate risk

Same surgery as for low risk, followed by pelvic radiation

High risk

Aggressive surgical resection, followed by chemotherapy

Disseminated disease

Systemic therapy: chemotherapy or progestins

and radiotherapy, including surgery preceded by radium and/or external-beam radiotherapy, surgery followed by radium and/or external-beam radiotherapy, and surgery both preceded and followed by radiotherapy. Proof of the value of radiation awaited the completion of a Gynecologic Oncology Group trial of surgery followed by either observation or pelvic radiation.73 The study showed a statistically significant reduction in relapse rate and an improvement in relapse-free survival through 3 years of follow-up. Standard treatment for the intermediate-risk patient is therefore a combination of surgery followed by pelvic radiation. There are no studies evaluating the potential role of systemic adjuvant therapy. High-risk patients Patients with limited disease at high risk for recurrence are less common and hence have been difficult to study. Generally accepted treatment has included surgical resection followed by radiation to the areas of greatest disease involvement. More light has recently been shed on the proper approach to these patients. The Gynecologic Oncology Group recently completed and reported a study of surgery followed by either abdominopelvic radiation or chemotherapy consisting of doxorubicin 60 mg/m2 plus cisplatin 50 mg/m2 every 3 weeks.74 This study shows a statistically superior survival for patients treated with chemotherapy, and represents a potential paradigm change in the approach to endometrial carcinoma. The standard of care for these patients is therefore surgical resection to the greatest extent possible, followed by chemotherapy.

Gynecologic cancers in the elderly

1381

Management of advanced or recurrent disease The management of patients with stage IVB or recurrent endometrial carcinoma consists of the use of systemic therapy consisting of either hormones or chemotherapy (Table 58.16).

Table 58.16 Active single drugs in endometrial carcinoma23,78–86 Drug

No. of patients

Response rate (%)

Medroxyprogesterone acetate

609

20

Doxorubicin

161

26

Cisplatin

124

24

Carboplatin

52

31

Ifosfamide

33

24

Paclitaxel

28

36

Hormonal therapy With regard to hormonal therapy, the only clearly active agents are the progestins. Studies by the Gynecologic Oncology Group demonstrate response rates of 20–24% with oral preparations.75–77 The median duration of response is 3–4 months, and the median survival 9–10 months. A randomized trial looking at standard versus high-dose progestin therapy showed no advantage to the higher doses.76 Based on these data, standard hormonal therapy is therefore either medroxyprogesterone acetate 200mg/day orally or megestrol acetate 160mg/day orally. A number of factors potentially predictive of response to hormonal therapy have been evaluated.78 The two factors that predict best are histologic grade (the better the differentiation, the greater the frequency of response) and hormone receptor status (positive estrogen and progesterone receptor assays are associated with higher response rates).23,77 Among other hormonal therapies tested, none have significant activity. Chemotherapy Chemotherapy has been studied intensively only in the last two decades. Active drugs identified to date include doxorubicin,78,79 the platinum compounds,80–83 ifosfamide,83 and paclitaxel,84 each with response rates in excess of 20%, median durations of response ranging from 4 to 7 months, and median survivals of 9–12 months (Table 58.16). Trials of combination chemotherapy in endometrial carcinoma have, for the most part, been single-arm studies of relatively small numbers of patients—trials that permit

Comprehensive Geriatric Oncology

1382

Table 58.17 Gynecologic Oncology Group Protocol 177: a randomized trial of doxorubicin plus cisplatin versus doxorubicin plus cisplatin plus paclitaxel86 Parameter

Dox/Cis/Paca

Number of patients Number of responses Number of complete responses c

5-month progression-free survival rate (%) d

12-month survival rate (%) a

Dox/Cisb 134

131

77 (57%)

44 (33%)

29 (22%)

9 (7%)

67

50

58

o

o

50 2

Doxorubicin 50mg/m2 n day 1 pldus cisplatin 60mg/m2 n day 1 plus paclitaxel 160mg/m every 3 hours on day 2 with prophylactic granulocyte colony-stimulating factor support, repeated every 3 weeks. b Doxorubicin 60 mg/m2 plus cisplatin 50 mg/m2 repeated every 3 weeks. c Hazard ratio 0.57. d Hazard ratio 0.79.

no definitive conclusions about the relative merits of the combination versus single-agent therapy. A Gynecologic Oncology Group study compared doxorubicin alone versus doxorubicin plus cisplatin, and showed a statistically superior response rate and progression-free survival for patients receiving the combination regimen.85 More recent data show still further improvement in both response rate and progression-free survival with a three-drug combination of paclitaxel plus doxorubicin plus cisplatin as compared with doxorubicin plus cisplatin (Table 58.17).86 The chemotherapy of choice for patients with advanced or recurrent disease is therefore a combination of paclitaxel plus doxorubicin plus cisplatin intravenously every 3 weeks in the doses and schedule shown in Table 58.17. Summary The proper clinical approach to endometrial carcinoma rests on attention to early diagnosis. Any patient with dysfunctional uterine bleeding must be evaluated with uterine tissue sampling and, in most instances, dilatation and fractional curettage. Once a diagnosis of endometrial carcinoma has been made, careful staging is essential. This will form the basis for the clinical approach to the disease. Patients with limited (stage I-IVA) disease should be categorized according to risk for recurrence. Patients at low risk for recurrence require total abdominal hysterectomy and bilateral salpingo-oophorectomy only, and should have a 5-year survival rate exceeding 95%. Patients at intermediate risk for recurrence have a 15% risk of recurrence with surgery alone. Surgery followed by pelvic radiation further reduces this risk of recurrence and constitutes the standard of care. High-risk patients have a risk of recurrence exceeding 50%. The basis for current management, a recent randomized trial,

Gynecologic cancers in the elderly

1383

recommends aggressive surgical resection to the greatest extent possible followed by chemotherapy. This approach results in an improved survival. Patients with disseminated (stage IVB) or recurrent disease require systemic therapy. Active systemic agents include progestins, doxorubicin, the platinum compounds, ifosfamide, and paclitaxel. Current recommendations are to use hormonal agents in patients with receptor-positive or well-differentiated disease and to employ cytotoxic drugs in patients with receptor-negative or poorly differentiated disease or those patients no longer responsive to hormonal therapy. The chemotherapy of choice is a three-drug combination of doxorubicin plus cisplatin plus paclitaxel. References 1. Cassagrande JT, Pike MC, Russ RK et al. Incessant ovulation and ovarian cancer. Lancet 1979; ii: 170. 2. Lynch HT, Watson P, Lynch JF et al. Hereditary ovarian cancer: heterogeneity in age at onset. Cancer 1993; 71:573–81. 3. Miki Y, Swensen J, Shattuck-Eidens D et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994; 266:66–71. 4. Takahashi H, Chiu H, Bandera CA et al. Mutations of the BRCA2 gene in ovarian carcinoma. Cancer Res 1996; 56:2738–41. 5. Yancik R. Ovarian cancer: age contrasts in incidence, histology, disease stage at diagnosis, and mortality. Cancer 1993; 71:517–23. 6. Grover SA, Cook EF, Adam J et al. Delayed diagnosis of gynecologic tumors in elderly women: relation to national medical practice patterns. Am J Med 1989; 86:151–7. 7. Thigpen T, Brady M, Omura G et al. Age as a prognostic factor in ovarian carcinoma: the Gynecologic Oncology Group experience. Cancer 1993; 71:606–14. 8. Alberts DS, Dahlberg S, Green SJ et al. Analysis of patient age as an independent prognostic factor for survival in a phase III study of cisplatin-cyclophosphamide versus carboplatincyclophosphamide in stages III (suboptimal) and IV ovarian cancer: a Southwest Oncology Group study. Cancer 1993; 71:618–27. 9. Edmondson J, Su J, Krook JE. Treatment of ovarian cancer in elderly women: Mayo ClinicNorth Central Cancer Treatment Group studies. Cancer 1993; 71:615–7. 10. Bicher A, Sarosy G, Kohn E et al. Age does not influence Taxol dose intensity in recurrent carcinoma of the ovary. Cancer 1993; 71:594–600. 11. Young RC, Walton L, Ellenberg SS et al. Adjuvant therapy in stage I and stage II epithelial ovarian cancer. Results of two prospective randomized trials. N Engl J Med 1990; 322:1021–7. 12. Omura G, Blessing J, Ehrlich C et al. A randomized trial of cyclophosphamide and doxorubicin with or without cisplatin in advanced ovarian carcinoma. Cancer 1986; 57:1725–30. 13. Ehrlich C, Einhorn L, Williams S et al. Chemotherapy for stage III-IV epithelial ovarian cancer with ds-dichlorodiammineplatinum(n), Adriamycin, and cyclophosphamide: a preliminary report. Cancer Treat Rep 1979; 63:281–8. 14. Greco F, Julian C, Richardson R et al. Advanced ovarian cancer: brief intensive combination chemotherapy and second-look operation. Obstet Gynecol 1981; 58:199–205. 15. Young R, Howser D, Myers C et al. Combination chemotherapy (CHex-UP) with intraperitoneal maintenance in advanced ovarian adenocarcinoma. Proc Am Soc Clin Oncol 1981; 2:465. 16. The new FIGO stage grouping for primary carcinoma of the ovary (1985). Gynecol Oncol 1986; 25:383.

Comprehensive Geriatric Oncology

1384

17. Van Nagell JR, DePriest PD, Gallion HH, Pavlik EJ. Ovarian cancer screening. Cancer 1993; 71:1523–8. 18. Jacobs J, Bast R. The CA-125 tumor-associated antigen: a review of the literature. Hum Reprod 1989; 4:1–12. 19. Jacobs I, Bridges J, Reynolds C et al. Multimodal approach to screening for ovarian cancer. Lancet 1988; ii: 268–71. 20. Van Nagell JR, DePriest PD, Puls LE et al. Ovarian cancer screening in asymptomatic postmenopausal women by transvaginal sonography. Cancer 1991; 68:458–62. 21. Bourne TH, Whitehead M, Campbell S et al. Ultrasound screening for familial ovarian cancer. Gynecol Oncol 1991; 43:92–7. 22. Hoskins WJ. Surgical staging and cytoreductive surgery of epithelial ovarian cancer. Cancer 1993; 71:1534–40. 23. Bloss J, Thigpen T. Chemotherapy of gynecologic cancers. In: The Chemotherapy Source Book, 3rd edn (Perry M, ed). Philadelphia: Lippincott Williams and Wilkins, 2001:732–59. 24. Kaye SB, Piccart M, Aapro M et al. Phase II trials of docetaxel in advanced ovarian cancer: an updated overview. Eur J Cancer 1997; 33:2167–70. 25. Rose P, Blessing J, Mayer A, Homesley H. Prolonged oral etoposide as second line therapy for platinum resistant and platinum sensitive ovarian carcinoma: a Gynecologic Oncology Group study. Proc Am Soc Clin Oncol 1996; 15:282. 26. Gordon A, Bookman M, Malmstrom H et al. Efficacy of topotecan in advanced epithelial ovarian cancer after failure of platinum and paclitaxel: International Topotecan Study Group trial. Proc Am Soc Clin Oncol 1996; 15:282. 27. Carmichael J, Gordon A, Malfetano J et al. Topotecan, a new active drug vs paclitaxel in advanced epithelial ovarian carcinoma: International Topotecan Study Group trial. Proc Am Soc Clin Oncol 1996; 15:283. 28. Ten Bokkel Huinink W, Gore M, Bolis G et al. A phase II trial of topotecan for the treatment of relapsed advanced ovarian carcinoma. Proc Am Soc Clin Oncol 1996; 15:284. 29. Hochster H, Speyer J, Wadler S et al. Phase II study of topotecan 21-day infusion in platinumtreated ovarian cancer: a highly active regimen. Proc Am Soc Clin Oncol 1996; 15:285. 30. Burger R, Burman S, White R, DiSaia P. Phase II trial of Navelbine in advanced epithelial ovarian cancer. Proc Am Soc Clin Oncol 1996; 15:286. 31. Underhill C, Parnis F, Highley M et al. A phase II study of gemcitabine in previously untreated patients with advanced epithelial ovarian cancer. Proc Am Soc Clin Oncol 1996; 15:290. 32. McGuire WP, Hoskins WJ, Brady MF et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996; 334:1–6. 33. Piccart M, Bertelsen K, James K et al. Randomized intergroup trial of cisplatin-paclitaxel versus cyclophosphamide-cisplatin in women with advanced epithelial ovarian cancer: threeyear results. J Natl Cancer Inst 2000; 92:699–708. 34. Ozols RF, Bundy BN, Fowler J et al. Randomized phase III study of cisplatin/paclitaxel versus carboplatin/paclitaxel in optimal stage III epithelial ovarian cancer: a Gynecologic Oncology Group Trial (GOG 158). Proc Am Soc Clin Oncol 1999; 18:356a. 35. du Bois A, Lueck HJ, Meier W et al. Cisplatin/paclitaxel vs carboplatin/paclitaxel in ovarian cancer: update of the Arbeitgemeinschaft Gynaecologie (AGO) Study Group trial. Proc Am Soc Clin Oncol 1999; 18:356a. 36. McGuire WP. Primary treatment of epithelial ovarian malignancies. Cancer 1993; 71:1541–50. 37. Day TG, Smith JP. Diagnosis and staging of ovarian carcinoma. Semin Oncol 1975; 2:217. 38. Bolis G, Colombo N, Pecorelli S et al. Adjuvant treatment for early epithelial ovarian cancer: results of two randomized clinical trials comparing cisplatin to no further treatment or chromic phosphate. Ann Oncol 1995; 6:887–93.

Gynecologic cancers in the elderly

1385

39. Vergote I, Trimbos B, Guthrie D et al. Results of a randomized trial in 923 patients with highrisk early ovarian cancer, comparing adjuvant chemotherapy with no further treatment following surgery. Proc Am Soc Clin Oncol 2001; 20:201a. 40. Thigpen JT, Vance RB, Khansur T. Second-line chemotherapy for recurrent carcinoma of the ovary. Cancer 1993; 71:1559–64. 41. Ledermann J. Randomized trial of paclitaxel in combination with platinum chemotherapy versus platinum-based chemotherapy in the treatment of relapsed ovarian cancer (ICON4/OVAR 2.2). Proc Am Soc Clin Oncol 2003; 22. 42. Alberts DS, Liu PY, Hannigan EV et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 1996; 335:1950. 43. Markman M, Bundy BN, Alberts DS, et al. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, South-western Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol 2001; 19:1001. 44. Piver MS, Baker TR, Jishi MF et al. Familial ovarian cancer: a report of 658 families from the Gilda Radner Familial Ovarian Cancer Registry (1981–1991). Cancer 1993; 71:582–8. 45. Piver MS, Jishi MF, Tsukada Y et al. Primary peritoneal carcinoma after oophorectomy in women with a family history of ovarian cancer. Cancer 1993; 71:2751–5. 46. Keighley E. Carcinoma of the cervix among prostitutes in a women’s prison. Br J Vener Dis 1968; 44:254–5. 47. Boon ME, Susanti I, Tasche MJA, Kok KP. Human papillomavirus-associated male and female genital carcinomas in a Hindu population: the male as a vector and victim. Cancer 1989; 64:559–65. 48. Richart RM, Wright TC. Controversies in the management of low-grade cervical intraepithelial neoplasia. Cancer 1993; 71:1413–21. 49. Beahrs OH, Henson DE, Hutter RVP, Myers MH. Manual for Staging of Cancer, 3rd edn. Philadelphia: JB Lippincott, 1988:151–3. 50. Grover SA, Cook EF, Adams J et al. Delayed diagnosis of gynecologic tumors in elderly women: relation to national medical practice patterns. Am J Med 1989; 86:151–7. 51. Fuchtner C, Manetta A, Walker JL et al. Radical hysterectomy in the elderly patient: analysis of morbidity. Am J Obstet Gynecol 1992; 166: 593–7. 52. Kinney WK, Egorshin EV, Podratz KC. Wertheim hysterectomy in the geriatric population. Gynecol Oncol 1984; 31:227. 53. Grant PT, Jeffrey JF, Fraser RC et al. Pelvic radiation therapy for gynecologic malignancy in geriatric patients. Gynecol Oncol 1989; 33: 185–8. 54. McGonigle KF, Lavey RS, Juillard GJF et al. Complications of pelvic radiation therapy for gynecologic malignancies in elderly women. Int J Gynecol Cancer 1996; 6:149–55. 55. Grigsby PW, Perez CA. Radiotherapy alone for medically inoperable carcinoma of the cervix: stage IA and carcinoma-in-situ. Int J Radiat Oncol Biol Phys 1991; 21:375–8. 56. Kolstad P. Follow-up study of 232 patients with stage IA1 and 411 patients with stage IA2 squamous cell carcinoma of the cervix (microinvasive carcinoma). Gynecol Oncol 1989; 33:265–72. 57. Stehman F, Bundy B, Keys H et al. A randomized trial of hydroxyurea versus misonidazole adjunct to radiation therapy in carcinoma of the cervix. Am J Obstet Gynecol 1988; 159:87–94. 58. Hreshchyshyn M, Aron B, Boronow R et al. Hydroxyurea or placebo combined with radiation to treat stages IIIB and IV cervical cancer confined to the pelvis. Int J Radiat Oncol Biol Phys 1979; 5:317–22. 59. Keys HM, Bundy BN, Stehman FB et al. Cisplatin, radiation, and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 1999; 340:1154.

Comprehensive Geriatric Oncology

1386

60. Morris M, Eifel PJ, Lu J et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and paraaortic radiation for high-risk cervical cancer. N Engl J Med 1999; 340:1137. 61. Peters WAI, Liu PY, Barrett R et al. Cisplatin, 5-fluorouracil plus radiation therapy are superior to radiation therapy as adjunctive therapy in high-risk, early-stage carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy. Report of a phase III intergroup study. Gynecol Oncol 1999; 72:443. 62. Rose PG, Bundy BN, Watkins J et al. Concurrent cisplatin-based chemotherapy and radiotherapy for locally advanced cervical cancer. N Engl J Med 1999; 340:1144. 63. Whitney CW, Sause W, Bundy BN et al. A randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stages IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 1999; 17:1339. 64. DiSaia P, Bundy B, Curry S et al. Phase III study on the treatment of women with cervical cancer, stage IIB, IIIB, and IVA (confined to the pelvis and/or periaortic nodes), with radiotherapy alone versus radio therapy plus immunotherapy with intravenous Corynebacterium parvum: a Gynecologic Oncology Group study. Gynecol Oncol 1987; 26:386–97. 65. McGuire WP, Blessing JA, Moore D et al. Paclitaxel has moderate activity in squamous cervix cancer: a Gynecologic Oncology Group study. J Clin Oncol 1996; 14:792–5. 66. Omura G, Blessing J, Vaccarello L et al. A randomized trial of cisplatin versus cisplatin + mitolactol versus cisplatin+ifosfamide in advanced squamous carcinoma of the cervix by the Gynecologic Oncology Group. Gynecol Oncol 1996; 60:120. 67. Moore D, McQuellon R, Blessing J et al. A randomized phase III study of cisplatin versus cisplatin plus paclitaxel in stage IVB, recurrent or persistent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Proc Am Soc Clin Oncol 2001; 20:201a. 68. MacMahon B. Risk factors for endometrial cancer. Gynecol Oncol 1974; 2:122. 69. Creasman WT, Morrow CP, Bundy BN et al. Surgical pathological spread patterns of endometrial cancer (a Gynecologic Oncology Group study). Cancer 1987; 60:2035–41. 70. Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia: a long-term study of ‘untreated’ hyperplasia in 170 patients. CA Cancer J Clin 1985; 56:403. 71. FIGO. Corpus cancer staging. Int J Gynecol Obstet 1989; 28:190. 72. Boronow RC, Morrow CP, Creasman WT et al. Surgical staging in endometrial cancer: 1. Clinical-pathologic findings of a prospective study. Obstet Gynecol 1984; 63:825–32. 73. Roberts J, Brunetto V, Keys H et al. A phase III randomized study of surgery vs surgery plus adjunctive radiation therapy in intermediate-risk endometrial adenocarcinoma (GOG No. 99). Gynecol Oncol 1998; 68:135. 74. Randall M et al. Whole abdominal radiotherapy versus combination doxorubicin-cisplatin chemotherapy in advanced endometrial carcinoma. Proc Am Soc Clin Oncol 2003; 22. 75. Thigpen T, Blessing J, DiSaia P et al. A randomized comparison of Adriamycin with or without cyclophosphamide in the treatment of advanced or recurrent endometrial carcinoma. J Clin Oncol 1994; 12: 1408–14. 76. Thigpen T, Blessing J, Hatch K et al. Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose-response study by the Gynecologic Oncology Group. J Clin Oncol 1999; 17:1736–44. 77. Thigpen JT, Blessing J, DiSaia P. Oral medroxyprogesterone acetate in advanced or recurrent endometrial carcinoma: results of therapy and correlation with estrogen and progesterone receptor levels. The Gynecologic Oncology Group experience. In: Endocrinology of Malignancy (Baulieu EE, Slacobelli S, McGuire WL, eds). Park Ridge, NJ: Parthenon, 1986:446. 78. Thigpen T, Vance R, Lambuth B et al. Chemotherapy for advanced or recurrent gynecologic cancer. Cancer 1987; 60:2104–6. 79. Thigpen T, Buchsbaum H, Mangan C, Blessing J. Phase II trial of Adriamycin in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. Cancer Treat Rep 1979; 63:21–27.

Gynecologic cancers in the elderly

1387

80. Thigpen T, Blessing J, Homesley H et al. Phase II trial of cisplatin as first-line chemotherapy in patients with advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 1989; 33:68–70. 81. Thigpen JT, Blessing JA, Lagasse LD et al. Phase II trial of cisplatin as second-line chemotherapy in patients with advanced or recurrent endometrial carcinoma (a Gynecologic Oncology Group study). Am J Clin Oncol 1984; 7:253–6. 82. Thigpen T. Systemic therapy with single agents for advanced or recurrent endometrial carcinoma. In: Endometrial Carcinoma (Alberts D, Surwit E, eds). Boston: Martinus Nijhoff, 1989. 83. Sutton G, Blessing J, DeMars L et al. A phase II Gynecologic Oncology Group trial of ifosfamide and mesna in advanced or recurrent adenocarcinoma of the endometrium. Gynecol Oncol 1996; 63:25–7. 84. Ball H, Blessing J, Lentz S, Mutch D. A phase II trial of paclitaxel in patients with advanced or recurrent adenocarcinoma of the endometrium: a Gynecologic Oncology Group study. Gynecol Oncol 1996; 62:278–81. 85. Thigpen T, Blessing J, Homesley H et al. Phase III trial of doxorubicin + cisplatin in advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol (to be published). 86. Fleming G, Brunetto V, Mundt A et al. Randomized trial of doxorubicin plus cisplatin versus doxorubicin plus cisplatin plus paclitaxel in patients with advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. Proc Am Soc Clin Oncol 2002; 21:202a.

59 Skin cancer in the aging patient Matthew J Reschly, Karen Laszlo Keller, Dan Smith, Neil A Fenske, L Frank Glass Introduction Cancers of the skin are very common in the aging population. Incidence rates continue to increase as our elderly are living longer and more active lives. Improved health and social trends lead to more time spent outdoors in leisurely activity, exposing patients to ultraviolet (UV) radiation. Appropriate care of the geriatric population therefore requires diligence in the education and monitoring of patients, as well as prevention and treatment of cutaneous premalignancies and malignancies. Skin cancers that commonly occur in the older patient include basal cell carcinoma, squamous cell carcinoma, Bowen’s disease, and keratoacanthoma. Less common, but potentially fatal, are malignant melanoma, Merkel cell carcinoma, and angiosarcoma. Premalignant lesions include actinic keratoses and possibly dysplastic nevi. The clinical features, diagnosis, and management of these tumors will be discussed in this chapter. Ultraviolet radiation and tumorigenesis The increased incidence of skin cancer in the aging population is related to a combination of cumulative photodamage and intrinsic aging.1 A greatly expanded understanding of the relationship between ultraviolet radiation and tumorigenesis has occurred in the last 5–10 years. It is now known that mutations in the tumor suppressor gene p53 are the most common gene defects in actinic keratoses, squamous cell carcinomas, and up to 56% of basal cell carcinomas.2,3 It has been shown that UV radiation causes unique mutations in p53 as well as other DNA damage through the formation of pyrimidine dimers.2,4 Mutations in p53 interfere with the ability to destroy abnormally behaving cells through apoptosis. Clonal expansion of UV-altered cells can then occur unchecked, leading eventually to cutaneous malignancies.2 Evidence suggests that this process is initiated early in life, since epidemiologic studies show a correlation between cutaneous malignancies and sun exposure in childhood or adolescence, especially if this has been intermittent and severe.5 Cutaneous immune function may also play a role in skin cancer in the elderly. Langerhans cells are known to decrease in number with aging and UV radiation exposure, and because these cells play a role in cell-mediated immunity, their reduction likely results in enhanced tumor permissiveness.1 Other abnormalities that can contribute to carcinogenesis include defective repair mechanisms, immune suppression, and damaged cell cycle controls.3,4

Skin cancer in the aging patient

1389

Actinic keratosis (Figure 59.1) Actinic keratoses, or solar keratoses, are extremely common neoplasms of the skin. They are premalignant lesions displaying chromosomal abnormalities and the ability to progress into invasive squamous cell carcinoma if left untreated.6 Actinic keratoses typically develop on habitually sun-exposed skin of middle-aged or older individuals.7 Cumulative UV-light exposure is the greatest

Figure 59.1 Actinic keratosis: erythematous, hyperkeratotic plaques on the dorsal surface of the hand in a patient with severely sun-damaged skin. risk factor. Accordingly, skin phenotype is the other major risk factor, given that fair complexion, blond to reddish hair, blue eyes, and failure to tan all indicate an inability to protect oneself from ultraviolet damage. Associated risk factors include a history of childhood sun exposure, outdoor occupation or recreation, sunbelt latitudes, male sex, and age. Young adults may develop actinic keratoses if they have a fair complexion and sufficient sun exposure. Prevalence rates have been recorded from 10% in the third decade of life to 80% in the seventh decade.6 Clinically, actinic keratoses are slightly raised, scaly, erythematous 1–15 mm papules or plaques found on habitually exposed skin such as the face, neck, bald scalp, back, dorsal hands, forearms, and legs. The surrounding skin usually shows signs of sun damage, including wrinkling, dryness, telangiectasias, yellowish discoloration, and blotchy pigmentation.8 Early lesions may have only subtle erythema, and their

Comprehensive Geriatric Oncology

1390

characteristic roughness may be easier to feel than see. Most patients have more than one lesion, and severely damaged skin may have nearly confluent actinic keratoses. Lesions are often asymptomatic, although patients may report tenderness, burning, or pruritus.8 Clinical variants include hypertrophic, pigmented, lichen planus-like keratosis, and actinic cheilitis.8,9 Each variant is capable of progression to squamous cell carcinoma. Hypertrophic actinic keratoses develop most commonly on the dorsal hands and forearms, and may be a result of rubbing and scratching. A form of hypertrophic actinic keratosis is the cutaneous horn, although small proportions of these are actually squamous cell carcinomas on histologic examination. A pigmented actinic keratosis sometimes resembles a solar lentigo, an early seborrheic keratosis, melanocytic nevus, or early in situ melanoma. Lichen planus-like keratoses may mimic a lichenoid dermatosis or a lichenoid drug eruption. Actinic cheilitis is actinic keratosis occurring on the lips or vermilion border. The lower lip is typically rough, red, and scaly. Patients often complain of persistently irritated lips. Care must be taken in the management of these lesions, since squamous cell carcinoma of the lip has a metastatic rate of approximately 11%— significantly higher than that of UV-induced squamous cell carcinomas at other sites.8 In most cases, the diagnosis of actinic keratosis can be made clinically. Since there is a clinical and histologic continuum between actinic keratosis and squamous cell carcinoma, however, the distinction can sometimes be difficult. A change in thickness or size, erythema, pain, ulceration, or a recurrence of a previously treated lesion may indicate progression to squamous cell carcinoma. A biopsy should be performed in such cases. On histologic examination, actinic keratoses are proliferations of atypical keratinocytes with loss of polarity in the lower portions of the epidermis. There may be an irregular dermoepidermal junction, acanthosis, hyperkeratosis, and parakeratosis. Follicular units and the acrosyringia are characteristically spared. There is almost always associated solar elastosis in the dermis. Cytologic changes are indistinguishable between actinic keratoses and squamous cell carcinoma.10 Actinic keratoses, as mentioned above, are part of a continuum of neoplasias initiated by DNA damage and mutation, and culminating in invasive to metastatic squamous cell carcinoma. Actinic keratoses demonstrate the same p53 gene mutations and tumor markers as invasive squamous cell carcinoma. Given time, actinic keratoses may progress along this continuum. It has been demonstrated that nearly all sun-induced squamous cell carcinomas have a directly contiguous or adjacent actinic keratosis.10 The probability of an individual actinic keratosis evolving into a fully developed squamous cell carcinoma has been estimated at 0.075–0.096% per lesion per year, or nearly 1 in 1000.10,11 In a patient with numerous lesions, the risk is compounded. The incidence of squamous cell carcinoma in such a typical patient has been estimated at 10–20% over a 10-year period.10 What factors govern the biologic activity of an actinic keratosis are unclear; however, the host immune status certainly plays a role. The treatment of actinic keratoses should be conservative destruction in order to address both their relatively banal nature and premalignant potential. There are currently many treatment methods that are both effective and convenient. The choice of treatment method should be individualized to each patient and their clinical presentation. Cryosurgery is the preferred treatment for most patients, with cure rates reported at 98.8%.9,12 It is well tolerated by patients, and complications such as blistering, scarring, infection, and pigmentary changes are rare. Patients may experience some discomfort

Skin cancer in the aging patient

1391

during the procedure; however, there is no need for local anesthesia. Cryosurgery is performed most commonly with liquid nitrogen, using either a cotton-tipped applicator or a spray device. Visible freezing of the lesion is performed for several seconds, depending on the size and amount of hyperkeratosis. The thawing process results in destruction of the treated, cells. A blister may occur owing to separation of the damaged epidermis from the dermis. The skin is repopulated from normal epidermal cells in the follicular units. Cryosurgery is particularly suited to the patient with a small number of lesions (<15) or with thick hyperkeratotic lesions.12 Other destructive measures include curettage with or without electrosurgery, and CO2 lasers. Topical 5-fluorouracil (5-FU) is a chemotherapeutic agent effective in destroying actinic keratoses.13 It is a thymine analog that blocks the methylation reaction of deoxyuridylic acid to thymidylic acid, thereby selectively destroying abnormal cells.12 This action offers a unique benefit in that it destroys not only clinically obvious lesions, but also incipient or subclinical actinic keratoses. The most commonly prescribed regimen consists of twice-daily application by the patient to the entire involved area for 2–4 weeks, or until erosion, necrosis, and ulceration occur.11 The usual treatment interval for the face is 2 weeks, whereas the upper extremities usually require 4–6 weeks. The drawbacks of this method are significant, and include the necessary erythema, inflammation, and erosion to affect clinical benefit, as well as the associated pain, pruritus, and social embarrassment. Topical 5-FU can also worsen conditions such as melasma or acne rosacea.12 In addition to the above side-effects, patients must be warned to avoid sunlight, since increased pain and discomfort can occur. For this reason, topical 5-FU is more easily tolerated in the winter months. Several different regimens have been suggested; however, the regimen described above is the only one that is approved by the US Food and Drug Administration (FDA). A topical corticosteroid may be prescribed to help relieve post-treatment inflammation. Different formulations of topical 5-FU include 0.5%, 1%, 2%, and 5% creams, as well as 2% and 5% solutions. Needless to say, treatment success is highly dependent on patient compliance, with cure rates of 93% being reported with proper use—and failure rates of 60% in those who are less compliant. An emerging treatment for actinic keratoses is photodynamic therapy utilizing δaminolevulinic acid and light from a filtered slide projector.14 This method seems to be most effective on widespread but thin lesions on the face and scalp. In this setting, cure rates equal those of cryosurgery or chemical peels. Other advantages include noninvasiveness, selective treatment of tumorous cells, the ability to treat multiple lesions at one sitting, good cosmetic results, and patient acceptance. Drawbacks include prohibitive price, scheduling difficulties, and poor efficacy in thicker lesions. Topical retinoids may be helpful in the treatment of actinic keratoses, either alone or in combination with other modalities. Isotretinoin cream prescribed for a few weeks prior to initiating 5-FU therapy enhances its penetration, and therefore its efficacy. Some investigators have advocated the use of isotretinoin as a prophylactic measure, especially for those patients with early actinic keratoses. Dermabrasion or chemical peel with trichloroacetic acid (TCA) or phenol may be used to treat extensive, widespread actinic keratoses. Lastly, multiple injections of interferon-α2 have also been shown to induce complete regression of actinic keratoses.15 The presence of actinic keratoses indicates sufficient solar damage to place the patient at high risk for developing skin cancers in the future. These patients should be strongly

Comprehensive Geriatric Oncology

1392

advised to avoid or limit sun exposure, especially between the hours of 11 a.m. and 4 p.m., and to wear a broad-spectrum sunscreen and wide-brimmed hat if sun exposure occurs. Follow-up to monitor the progression of treated actinic keratoses and the development of premalignant or malignant lesions elsewhere is recommended at 4- to 12month intervals.

Figure 59.2 Nodular basal cell carcinoma: pearly papule with rolled borders near the right nasal ala. Basal cell carcinoma (Figure 59.2) Basal cell carcinoma is by far the most common type of skin cancer, accounting for nearly 75% of non-melanoma skin cancers.16 The incidence has been increasing over the past decade, with approximately 800 000 new basal cell carcinomas diagnosed in 1999.17 Risk factors include age, previous basal cell carcinoma, fair skin, red hair, light-colored eyes, high nevus counts on upper limbs, presence of solar lentigos and actinic keratoses, intermittent childhood sun exposure with severe burns, and a family history of skin cancer.5,18 A recent study has demonstrated that the 3-year risk of a basal cell carcinoma after the index lesion is 44%, which is approximately 10 times the risk in the general population.17 Ninety-nine percent of patients who develop basal cell carcinomas are Caucasian. Men have a higher incidence of basal cell carcinoma occurring on habitually exposed skin than do women, whereas women have a three times higher incidence of these lesions developing on the lower legs. Eighty-five percent of basal cell carcinomas occur on the head and neck region, while 25–30% of those lesions occur on the nose.19

Skin cancer in the aging patient

1393

Basal cell carcinomas are fibroepithelial malignancies most likely derived from the outer root sheath of the hair follicle below the isthmus.5,20 The etiology of these neoplasms is related primarily to chronic, cumulative sun exposure; however, the causal relationship is less clear than that of squamous cell carcinoma.5 Mutations in the p53 gene have been shown to be present in a significant number of basal cell carcinomas. Their general location does not always coincide with those areas that receive maximal sunlight. In fact, 20% occur in non-sun-exposed areas.5 In general, these lesions tend to occur in areas where the pilosebaceous units are denser, such as the face. Most lesions are relatively slowly growing and rarely metastasize. They can, however, cause extensive destruction by invasive growth, and can occasionally be fatal if vital structures are involved. Additional etiologic factors include genetic defects (e.g. the PATCHED gene in the basal cell nevus syndrome and xeroderma pigmentosum), ionizing and thermal radiation, immunosuppression, inorganic arsenicals and other chemical carcinogens, including lubricating oils, paraffin, anthralin, creosote, mineral oils, and tars.21 Basal cell carcinomas occasionally occur in scars of old thermal burns and vaccination sites, as well as in epidermal nevi.22 Clinically, there are five variants of basal cell carcinoma: nodulo-ulcerative, cystic, pigmented, superficial, and morpheaform. Nodulo-ulcerative basal cell carcinoma, also called ‘rodent ulcer’, is the most common variety, and usually occurs on the face, with a high incidence on the cheeks, nasolabial folds, forehead, and eyelid margins. This is a slowly growing variant, which starts as a small papule that slowly enlarges and eventually becomes ulcerated in the center of the tumor. The tumor tends to have a characteristic opalescent or translucent, pearly appearance, with overlying telangiectasias and a rolled border. A central crust or scale may be observed, and the tumor bleeds readily. Partial healing of the ulceration may occur, resulting in a central depression, but with time the tumor eventually exceeds its blood supply and again becomes necrotic and ulcerated. Patients do not usually complain of pain, but will at times relate a pruritic sensation at the site. Nodulo-ulcerative basal cell carcinoma may be confused clinically with sebaceous hyperplasia, melanocytic nevi, molluscum contagiosum, squamous cell carcinoma, verruca vulgaris, fibrous papule of the nose, keratoacanthoma, amelanotic melanoma, atypical fibroxanthoma, and certain adnexal tumors, such as trichoepitheliomas. Cystic basal cell carcinoma is a variant of the nodulo-ulcerative subtype. It appears as an erythematous, smooth nodule with a pearly color. These tumors can attain a large size and may ulcerate. They should be differentiated from other cysticappearing lesions such as the epidermal inclusion cyst and hidrocystoma. A pigmented basal cell carcinoma is similar to the nodulo-ulcerative variety, but has excess pigment derived from overproduction of epidermal melanocytes. The color ranges from brownblue to black, and the pigment may be speckled or homogeneous. These lesions have been related to prior arsenic ingestion. It is crucial to differentiate these lesions from malignant melanoma. Superficial basal cell carcinomas are confined to the papillary dermis, and were once said to be multifocal. Morpheaform basal cell carcinoma is an uncommon but extremely recalcitrant and notoriously destructive variety. These lesions, and other aggressive growth basal cell carcinomas, are characterized by an extensive fibrous stroma and infiltration by slender, jagged islands of tumor.23 This results in a subtle indurated plaque with indistinct margins reminiscent of a patch of morphea. The surface is smooth, and the tumor appears sclerotic

Comprehensive Geriatric Oncology

1394

or waxy with an ivory or yellow-red tint. Telangiectasias may be present. Palpation of the lesion will reveal firmness due to the fibrous nature of the tumor. Morpheaform lesions are commonly found on the head and neck and are frequently misdiagnosed as morphea, scars, ‘sun damage,’ or connective tissue nevi. A biopsy should be performed on clinically suspicious lesions before therapy is initiated. The goal of treatment should be complete eradication of the tumor, with optimal cosmetic results. To meet this goal, several types of treatment are routinely used, including curettage and electrodesiccation, excisional surgery, Mohs’ micro-graphic surgery, cryosurgery, and radiation. The choice of treatment should take into account the characteristics of the lesion, patient preference, and available resources.5 Pertinent characteristics of the individual lesion include location, size, histologic pattern and whether the lesion is primary or recurrent. Based on these characteristics, highrisk lesions can be identified. Recurrent basal cell carcinomas tend to be more aggressive, with higher recurrence rates with all forms of therapy. Primary lesions in certain locations such as the midface and ears also have higher recurrence rates—perhaps because of embryonic fusion planes allowing tumor dissection into deeper tissues. Lesions larger than 2 cm have a significantly higher recurrence rate when treated with electrodesiccation and curettage. Aggressive histologic patterns such as morpheaform, micronodular, mked, and infiltrative often have subclinical extensions, making estimation, of adequate margins difficult. Basal cell carcinomas with any of the above characteristics must be treated more aggressively with either Mohs’ micrographic surgery, excision with adequate margins, or radiotherapy.24 Vital areas and areas with emphasis on esthetic integrity, such as the eyelid, lip, nose, and ear, also require specialized care. Clinical factors include the patient’s age and health status, since some procedures may be inconvenient or too stressful for the patient. Mohs’ micrographic surgery offers superior cure rates for all types of basal cell carcinomas, with the distinct advantage of tissue sparing. Mohs’ micrographic surgery consists of excision and immediate microscopic examination of the specimen. If the tumor extends to the edges of the specimen, re-excision and histologic examination are performed repeatedly until the pathologic tissue is completely excised. Since less tissue is removed, a simpler surgical repair is likely to produce a superior cosmetic result.22,25 Overall 5-year cure rates are greater than 99% for primary tumors, and 96% for recurrent tumors.25 Mohs’ micrographic surgery is suitable even for patients aged 90 and older.26 Excisional surgery may be used on all types of basal cell carcinomas, with a cure rate of approximately 90–95%.22,25 By excising the tumor, surgical margins can be reasonably assessed by vertical frozen and/or permanent sections. Radiotherapy can also be used to treat basal cell carcinomas, depending on the location and type of tumor. Radiotherapy is often considered for lesions difficult to remove surgically, such as large lesions involving the head and neck, or for patients who may be unable to undergo surgery. Radiotherapy can have a cure rate of approximately 90%.27 Tumors are treated in 5–20 fractions for a total of approximately 3500–5000 rad. The technique is a ‘field’ treatment, requiring estimation of the tumor margin. Areas treated by radiation have a good cosmetic result; however, they do not equal the cosmesis of surgery.28 A major disadvantage is the requirement for multiple treatment visits.22 Low-risk basal cell carcinomas do not possess any of the characteristics listed above, and include primary nodular or superficial histologic types, located on non-crucial areas,

Skin cancer in the aging patient

1395

and less than 2 cm in size.24 Curettage and electrodesiccation is commonly used for lowrisk basal cell carcinomas, especially on the trunk and extremities. In skilled hands, it has a cure rate of greater than 95%.16 This method, however, is not recommended for deep tumors that may extend into the fat, since healthy, firm dermis is necessary to ‘scrape’ against during curettage. When the physician determines that this treatment modality will biopsy is performed to maintain the underlying dermal likely be used, a shave biopsy rather than a deeper punch integrity. Healing after this treatment varies widely, and cosmetically the scarring may be less desirable in some locations. Cryosurgery with liquid nitrogen can be used for tumors of varying sizes and locations, but is best used on tumors with discrete or easily palpable margins. As with curettage and electrodesiccation, the physician must estimate the tumor border size. The liquid nitrogen (−196°C) is applied to the lesion until a margin of freeze, indicating tissue necrosis, is observed 3–5 mm beyond the clinically apparent tumor border. For deeper tumors, a thermocouple may be necessary to assure that a temperature of -60°C at the base of the tumor has been achieved. The process should be repeated through one freezethaw cycle. Cryosurgery is relatively simple to perform, and has a 5-year cure rate of up to 90%, depending on the tumor type and site treated.29,30 This technique is especially useful in surgically high-risk patients who are on anticoagulants, have pacemakers, are allergic to local anesthetics, or are severely debilitated.20 Cryosurgery is not recommended for morpheaform carcinomas, nor for cancers at locations with a high recurrence rate (nasolabial folds, inner canthi, and posterior ear sulci). This method should be avoided in patients with cryoglobulinemia, cryofibrinogenemia, and cold urticaria. The chief disadvantages include uncertain tumor margin assessment, depigmentation of the skin, possible nerve damage, and irregular scarring. The only proven topical agent for treatment of basal cell carcinoma is 5-FU. It may be used in 5% concentration for about 6 weeks.13 Patient compliance may be a problem because of the severe degree of inflammation resulting from treatment. This treatment modality should only be used for the superficial type, since only the superficial portion of the tumor is effectively treated, while the base may become buried, leading to a recurrence. Recently, treatment of basal cell carcinomas has expanded to include retinoids, CO2 laser therapy, topical 5% imiquimod cream, and intralesional injections of chemotherapeutic agents, although complete clinical regimens have not been fully elucidated.13,20 The 5-year recurrence rates for treatment of primary basal cell carcinomas range from 1% for Mohs’ micro-graphic surgery to an average of 8.7% for curettage and electrodesiccation, surgical excision, radiotherapy, or cryotherapy.23 As part of the continuing treatment for basal cell carcinoma, patients should have an annual skin examination to check for recurrence and search for new lesions. Methods of photoprotection should be discussed with the patient, as described earlier. Patients who have had one basal cell carcinoma have a 44% chance of devel oping another within 3 years.17

Comprehensive Geriatric Oncology

1396

Squamous cell carcinoma (Figure 59.3) Squamous cell carcinomas are invasive malignancies arising from keratinizing cells of the epidermis. They account for 20% of the approximately 1 million new non-melanoma skin cancers per year in the USA.6,31,32 Most are relatively slowly growing and easily cured; however, a significant proportion can become locally invasive, metastatic, and fatal.6

Figure 59.3 Squamous cell carcinoma: indurated, erythematous ulcerated nodule on the dorsal hand. The majority of squamous cell carcinomas are related to cumulative UV radiation exposure, with the same epidemiologic and etiologic factors as actinic keratoses.6,32 In fact, most of these squamous cell carcinomas probably arise from precursor actinic keratoses. The same UV radiation-induced mutations in the p53 gene and cytopathologic changes are found in invasive squamous cell carcinomas and actinic keratoses.2,10 The risk factors include fair-skinned phenotype, excessive cumulative UV radiation exposure, age, recreation, sunbelt latitude, presence of actinic keratoses, and previous nonmelanoma skin cancer.6,31,32 Squamous cell tumors are more common in men than in women, except when on the lower legs, and are less common than basal cell carcinoma, occurring in a ratio of 1:4. The incidence is higher in individuals over age 55, with 60 being the average age of onset. A smaller proportion of squamous cell carcinomas arise in association with other etiologic factors, such as scars, chronic inflammatory processes, ionizing radiation,

Skin cancer in the aging patient

1397

PUVA therapy, chemical carcinogens (topical hydrocarbons and arsenic), viral oncogenesis (human papillomavirus (HPV) types 16, 18, and 31), and chronic immunosuppression.9 Scar carcinomas include squamous cell carcinomas arising in burn scars, leg ulcers, osteomyelitis, sinus tracts, radiation dermatitis, chronic bursitis, chronic bed sores, discoid lupus scars, and scars from the follicular occlusion triad.33 The increase in squamous cell carcinoma with immunosuppression is significantly greater than the increase in basal cell carcinoma. The clinical presentation of squamous cell carcinomas, especially of early lesions may be difficult to distinguish from actinic keratoses. Characteristics suggesting an invasive squamous cell carcinoma include an increase in thickness or induration, erythema, pain, ulceration, and size.8 The surface may be smooth, scaling, or verrucous.32 Lesions are characteristically firm, and may range in size from several millimeters to several centimeters. Occasionally, a cutaneous horn is present. Pain and paresthesia may suggest perineural invasion, as in neurotropic squamous cell carcinoma. The biologic behavior of squamous cell carcinomas can be variable. Most small, welldifferentiated squamous cell carcinomas arising from actinic precursors on chronically sun-damaged skin tend to be quite indolent, exhibiting slower growth and less metastatic potential.7,31 The metastatic rates of these tumors in most studies range from 2.3% to 5.9% Clinical factors that correlate with a higher risk of local recurrence and metastasis include size greater than 2 cm, depth greater than 4 mm, poor histologic differentiation (Broders grades 3 and 4), site (ear or lip), scar carcinoma, neurotropic carcinoma, recurrent lesions, and immunosuppression. The risk of local recurrence and metastasis can be significantly higher when any of these characteristics are present.33 The metastatic rate has been reported as 13.7% in lip squamous cell carcinomas, and 26.2–37.9% in scar carcinomas.7,33 The differential diagnosis of squamous cell carcinoma includes actinic keratosis, keratoacanthoma, amelanotic melanoma, granulomatous disease, and adnexal tumor. Any suspected squamous cell lesion should be biopsied for histopathologic evaluation. Microscopically, squamous cell carcinomas appear as masses, strands, or buds of atypical squamous cells with foci of keratinization that proliferate downward. In the welldifferentiated variety, horn pearls are often present. Adenoid or acantholytic, mucinproducing, and verrucous squamous cell carcinomas are well recognized. The choice of treatment for cutaneous squamous cell carcinoma must take into account the characteristics of the lesion, patient preference, and available resources. The most vital step is to identify which lesions are at a higher risk for local recurrence and metastasis as mentioned above. The standard of care for such high-risk lesions is Mohs’ micrographic surgery, which has a significantly lower recurrence rate and higher cure rate than non-Mohs’ modalities.25,33 Mohs’ micrographic surgery also has the advantage of detecting local or perineural spread, in addition to its tissue-sparing effects in vital areas. The presence of local, regional, or distant metastases should always be evaluated, especially in high-risk cases. Metastasis to local or regional lymph nodes usually occurs first; however, hematogenous spread may occur.31 A recent study has suggested the use of sentinel lymphadenectomy and Mohs’ micrographic surgery for high-risk cases; however, the utility of this combination has yet to be proven.34 Radiotherapy may be used prophylactically to regional lymph nodes in certain high-risk situations, or for palliation

Comprehensive Geriatric Oncology

1398

of metastases. Regional chemotherapy may also be useful for palliation of metastases.32 The 5-year survival rate for metastatic disease is only 25%.31 Non-Mohs’ treatment modalities may be used in low-risk squamous cell carcinomas with excellent, and roughly equivalent, cure rates.33 Treatments include excision, radiation, curettage and electrodesiccation, and cryotherapy. Excisional surgery is the most common method used to remove squamous cell carcinomas, especially in younger patients. Tumors removed in this manner can be evaluated histopathologically to ensure complete removal. A skin flap or graft may be necessary, while a sufficient margin of normal tissue surrounding the lesion should be excised. Curettage and electrodesiccation, as well as cryosurgery, can be used for smaller, well-differentiated tumors. The 5-year cure rate in the hands of experienced clinicians is approximately 90%. Radiotherapy may be useful for those squamous cell tumors that are poorly differentiated and that have neither metastasized nor spread to cartilage or bone. This is an excellent method for patients who cannot undergo surgical procedures. The tumors are treated with 5000 rad in multiple fractions administered over 2 weeks. A 90% cure rate can be achieved by this technique.35 The disadvantages of cryosurgery, curettage and electrodesiccation, radiation, and excisional surgery are similar to those for basal cell tumors discussed above, and the same principles apply. Topical 5-FU is best avoided for invasive lesions. Interferon-oc has been shown to be effective against actinic keratoses, squamous cell carcinomas, and keratoacanthomas, although a practical dosage regimen has yet to be established. Almost 70% of recurrences, metastases, and new primary tumors are diagnosed in the first 2 years of follow-up; therefore, patients should be examined at least every 3 months during this initial period and every 6 months thereafter. Squamous cell carcinoma in situ Squamous cell carcinoma confined entirely to the epidermis is called squamous cell carcinoma in situ. Morphologic forms include Bowen’s disease of the skin and erythroplasia of Queyrat. Squamous cell carcinoma in situ shares the same epidemiologic and etiologic characteristics as actinic keratoses and squamous cell carcinoma. Similar to the invasive tumors, squamous cell carcinoma in situ may be associated with chronic sun exposure, PUVA, or the inhalation of mustard gas. Additionally, Bowen’s disease may result from prior arsenic ingestion or chronic arsenic exposure. In these cases, the lesions are multiple and develop on non-sun-exposed sites. The presence of palmoplantar arsenical keratosis is a diagnostic aid. Sources of arsenic include contaminated mineral spring or well water, pesticides, herbicides, and Fowler’s solution used years ago in the medical field. Bowen’s disease often affects the population over age 60.36,37 Bowen’s disease presents clinically as a well-circumscribed erythematous, scaly, roughened plaque, usually on the trunk. Because the lesion is often mistaken for dermatitis or psoriasis, biopsy may be delayed. While progression to squamous cell carcinoma is generally slow, at least 5% may invade the dermis, resulting in a squamous cell carcinoma. Erythroplasia of Queyrat is a morphologic form of squamous cell carcinoma in situ found on the glans penis of uncircumcised males. It appears as an

Skin cancer in the aging patient

1399

asymptomatic, sharply circumscribed shiny red plaque. Progression to invasive squamous cell carcinoma may occur in up to 10% of cases.38 Histopathologically, the lesion demonstrates full thickness, intraepidermal atypia of keratinocytes with loss of polarity, producing a windblown appearance. These atypical cells may extend to the infundibulum of the hair follicle, and the outer root sheath in some cases, but do not invade the dermis. The upper dermis often shows a mononuclear host inflammatory infiltrate.

Figure 59.4 Keratoacanthoma: erythematous nodule with central keratotic plug. Treatment of squamous cell carcinoma in situ typically includes cryosurgery, electrodesiccation and curettage, topical 5-FU, surgical excision, and Mohs’ microsurgery, similar to the invasive lesions discussed previously. Photo-dynamic therapy can be useful in widespread forms, large patches, and lesions in anatomically difficult areas.14 Patients should be followed annually for the detection of recurrence or the development of new skin cancers Keratoacanthoma (Figure 59.4) Keratoacanthomas are common cutaneous tumors derived from keratinizing cells of the hair follicle. Many authors consider them a benign entity because of their tendency to confined growth and spontaneous involution.39 Considerable confusion exists, however, on how to reliably differentiate keratoacanthomas from invasive squamous cell carcinomas. Their clinical appearance and behavior are often characteristic, although in

Comprehensive Geriatric Oncology

1400

some instances it is impossible to distinguish them from invasive squamous cell carcinoma. Histologically, several criteria can be suggestive for one versus the other, but even a combination of the five most useful criteria does not significantly increase the specificity or sensitivity of the histologic diagnosis in difficult cases.40 In addition, there have been reports of small foci of squamous cell carcinoma within keratoacanthomas, as well as malignant transformation to squamous cell carcinoma from keratoacanthoma.41 Metastases have even been reported from true keratoacanthomas.42 Given this frequent diagnostic uncertainty, and malignant potential, it is prudent to regard keratoacanthoma as a morphologic variant of invasive squamous cell carcinoma. Keratoacanthomas most commonly occur on exposed, hair-bearing skin of the face, neck, and dorsal aspects of the upper extremities. Males are affected twice as often as females, usually in the sixth and seventh decades. Mature, solitary keratoacanthomas are bud- or dome-shaped, slightly erythematous papules or nodules with a central keratinous crater. There is often a shiny, translucent appearance, with telangiectasias around the edge of the lesion. Keratoacanthomas typically appear suddenly and grow rapidly over a 6-week period, followed by spontaneous involution over 2–6 months, leaving a depression in the skin. Occasionally, keratoacanthomas persist and progress. Sunlight, chemical carcinogens, trauma, and even genetic factors have been implicated in the etiology of keratoacanthomas.39,43 In addition to the common solitary form described above, several other clinical types have been described. Giant keratoacanthomas occur as rapidly progressive lesions demonstrating significant local destruction due to their size. Keratoacanthoma centrifugum marginatum is a rapidly enlarging plaque with central clearing, demonstrating an annular configuration. Keratoacanthomas occurring as numerous small eruptive lesions in a generalized distribution are of the Grysbowski type, whereas lesions of the familial Ferguson-Smith type are also numerous, but frequently ulcerated.39 The familial Witten and Zak type includes lesions of both Grysbowski and Ferguson-Smith type.44 The histologic diagnosis of keratoacanthoma versus squamous cell carcinoma, as mentioned above, can be difficult. A constellation of features, several of them architectural, needs to be assessed; this depends on a biopsy of the entire lesion.39,40 Typically, a keratoacanthoma is a cratershaped mass of keratinizing, well-differentiated squamous epithelium. There is characteristic lipping or buttressing of the edges of the lesion, with clear tumor-stromal demarcation. There is usually less cytologic atypia and fewer mitoses than in a squamous cell carcinoma. A review of 296 cases has demonstrated that epithelial lipping and a sharp outline between tumor and stroma favor the diagnosis of keratoacanthoma, whereas ulceration, numerous mitoses, and marked pleomorphism favor squamous cell carcinoma. Even a combination of these criteria, however, could not definitively make the diagnosis in difficult cases.7 Although spontaneous regression may occur, many clinicians treat keratoacanthoma in the same way as a well-differentiated squamous cell carcinoma. Various therapeutic methods have been suggested, including surgical excision, curettage and electrodesiccation, and intralesional injection of 5-FU or methotrexate.45 For cosmetic purposes and definitive treatment with histologic examination, surgical excision is the preferred method. Some clinicians advocate observation of the lesion for changes in appearance or sudden growth. It is recommended to monitor the lesion every 6 months if

Skin cancer in the aging patient

1401

conservative therapy is the treatment of choice. The patient should be followed annually for the development of new lesions.

Figure 59.5 Melanoma: plaque with irregular pigmentation and asymmetric borders. Malignant melanoma (Figure 59.5) Malignant melanoma is a cutaneous malignancy arising from melanocytes. It occurs in all age groups, but the elderly have the highest age-specific incidence. The current risk for developing melanoma among Americans is 1 in 71. This is up from 1 in 100 in 1993, and 1 in 250 in 1985. In fact, melanoma continues to be the only cancer rising in incidence in the USA.46,47 The incidence of melanoma is the same for both men and women, although women tend to have a better overall survival. Of interest, the majority of melanomas currently seen have become thinner, less invasive, less frequently ulcerated, and subsequently more curable.48 The prognosis is poor for advanced stages of the disease, and therefore early diagnosis and treatment are essential to survival.49,50 Risk factors for melanoma include a family history of melanoma, fair skin, blond or red hair, blue eyes, sensitivity to sun, inability to tan, and an antecedent blistering sunburn.51 When melanoma is subdivided into subtypes, the superficial spreading and nodular varieties are more closely related to periodic, intense type of UV light exposure, while lentigo maligna melanoma is related to chronic, cumulative exposure. Lentigo maligna melanoma usually occurs on the face and extensor forearms in those who habitually expose themselves to sunlight, such as outdoor workers. Lentigo maligna melanoma occurs disproportionately in the geriatric group. Melanoma prevalence in the

Comprehensive Geriatric Oncology

1402

elderly may be explained by the inability to repair sun-damaged DNA in this population, and a decline in the immune response with advancing age.51 The clinical features of suspicious lesions for melanoma are based on the characteristic ‘ABCD’ paradigm recommended by the American Academy of Dermatology: ‘A’ stands for asymmetry, ‘B’ for border irregularity, ‘C’ for color variegation, and ‘D’ for diameter greater than 6 mm.52–54 Among the signs and symptoms that suggest melanoma are variegation; and the most common colors for melanoma are shades of red, white, or blue, with blue being the most ominous. White, gray, and pink shades have been related to the ability of melanoma to undergo spontaneous partial regression. Pinks and reds reflect inflammation. Blues are due to the Tyndall effect, whereby light scattering from melanin pigment deep within the dermis imparts a blue rather than brown color. Although there may be a variety of clinical appearances, the most common denominator is their changing nature. Thus, any pigmented lesion that undergoes a change should be considered suspicious, and should be biopsied. The most common presenting symptom is pruritus of the lesion, followed by tenderness, bleeding, and ulceration.54 Melanoma is classically, but perhaps arbitrarily, subdivided into four clinicopathologic variants: superficial spreading melanoma, lentigo maligna melanoma, nodular melanoma, and acral lentiginous melanoma.55 This is a convenient way to think about different varieties of melanoma, but may not necessarily reflect biologic behavior.56 The superficial spreading subtype is the most common, comprising 70% of all cases. It usually presents in the fourth to fifth decade of life, occurring primarily on the legs and backs of women and the backs of men—sites of intermittent sun exposure. It typically begins as a small pigmented lesion that slowly enlarges over several years. Eventually, the lesion develops the typical irregular features of melanoma. Marked variegation in color is often present, in particular, red, white, and blue/black. Superficial spreading melanoma is characterized by a radial growth phase that may continue for months to years before frank invasion occurs. When detected in the radial growth phase as an in situ lesion, these melanomas are curable. Eventually, the radial growth gives way to vertical growth, which signifies dermal invasion of malignant cells.52 The vertical growth phase is sometimes demonstrated clinically by the appearance of a nodule within the plaque. Nodular melanoma accounts for approximately 15% of all cases, and may be more aggressive because of its relatively short radial phase.52 Nodular melanoma occurs in the fifth or sixth decade, most commonly on the legs and trunk—sites of intermittent intense sun exposure. It has a poor prognosis and affects more men than women. Nodular melanomas usually arise as darkly pigmented dome-shaped nodules that may ulcerate and bleed easily. These lesions can appear similar to seborrheic keratoses, pyogenic granulomas, hemangiomas, or pigmented basal cell carcinomas. Some lesions may be amelanotic, because the melanocytes are so anaplastic that they lack pigment. Amelanotic melanomas can present a difficult diagnostic problem. The lesion may completely lack pigmentation and be unrecognizable as a melanoma. However, a small focus of pigmentation is often present, providing a subtle clue to diagnosis. Amelanotic melanoma typically presents as a flesh-colored, pink, or erythematous nodule. Generally, it is a variant of nodular melanoma, with the same vertical growth pattern. Lentigo maligna melanoma represents 5–10% of malignant melanoma cases.57 It arises on severely sun-damaged skin as an in situ lesion, lentigo maligna, which is also known

Skin cancer in the aging patient

1403

by the eponym Hutchinson’s freckle. This lesion occurs in elderly patients on habitually exposed, sun-damaged skin such as the face, neck, extensor forearms, and hands—sites of chronic cumulative sun exposure. This type of melanoma has a prolonged horizontal growth phase, and may persist for several years or decades before developing into invasive melanoma. The horizontal growth phase is demonstrated clinically by an irregularly shaped macule, with varying hues of dark brown, black, and blue. The appearance of an elevated nodule within the lesion indicates vertically invasive growth. Acral lentiginous melanoma comprises 5% of malignant melanomas. It is the predominant subtype affecting Blacks, Orientals, and Hispanics, representing nearly 60% of melanomas in these patients.50,57 This form disproportionately affects the elderly and men more frequently than women. This lesion is characterized by a macular hyperpigmented area with irregular borders and a blue to black color. Eventually, it may develop a nodular component, ulcerate, and bleed when invasion occurs. It is found on the acral or peripheral portions of the limb, the plantar or palmar surfaces of the hands and feet, the mucous membranes, rectum, perineum, vagina, and the subungual areas of the fingers or toes. Subungual melanomas may present as an irregular pigmented streak with black discoloration of the proximal nail fold, referred to as Hutchinson’s sign. This type of melanoma is similar to a superficial spreading melanoma with respect to its horizontal phase, and is considered by most to merely be a variant of this melanoma. Because of their location, and confusion with traumatic hematomas, they are often overlooked and progress into advanced stages. A relatively uncommon variant of melanoma is desmoplastic melanoma, characterized by its propensity for local recurrence and extension along peripheral nerves.47,50,52 Desmoplastic melanomas are often inconspicuous clinically because they lack many of the features usually attributed to melanoma, including the pigmentation. Only one-third of cases are diagnosed clinically, and the average duration prior to diagnosis is 12 months, owing to the lack of recognition. As many as 71% of desmoplastic melanomas may be amelanotic. The majority arise in severely sun-damaged skin of the elderly, and most arise as head and neck lesions. Most cases arise within pre-existing melanomas, such as lentigo maligna melanoma, acral lentiginous melanoma, or recurrent tumors, but also may arise de novo. Neural invasion is a common finding. A significant number recur locally after resection, primarily owing to infiltrative growth, poor organization of the tumor, and neurotropism, but there is some evidence that they are less likely to metastasize compared with other histologic subtypes with comparable thickness. The majority of tumors are Clark level IV or V (see below) at diagnosis, and greater than 4 mm in thickness, yet the mean survival at 34 months has been reported to be 63%.52 The histopathologic patterns in melanoma vary depending on the clinical subtypes mentioned above. However, there are certain features in common to them all.47,50 These include a lack of lesion symmetry and circumscription, the presence of atypical melanocytes in confluence along the dermal-epidermal interface, and the presence of atypical cells in the dermis. Melanocytes may also be found above the interface, which is sometimes referred to a ‘upward migration’ or ‘pagetoid spread’ within the epidermis. The melanocytes in lentigo maligna remain confined to the basal layer of the epidermis, and appear hyperchromatic rather than epithelioid. Acral lentiginous melanomas arise on volar skin, where the epidermis is thick and keratotic. In nodular melanomas, the epidermal involvement may be minimal or even absent when the lesion is sampled—in

Comprehensive Geriatric Oncology

1404

other words, the vertical growth component predominates. Desmoplastic melanoma is composed of a haphazard array of poorly organized fascicles of hyperchromatic, pleomorphic spindle cells separated by dense fibroplasia. It is generally recommended that lesions clinically suspicious for melanoma should undergo an excisional biopsy.47,50 A shave biopsy may be too superficial to permit accurate microstaging of the tumor (e.g. Breslow thickness measurement). For lesions that are too large to be completely excised, or those located in an area where an excisional biopsy is not reasonable, an incisional biopsy may be performed, and there is no evidence that it has an adverse affect on prognosis. Three types of incisional biopsies are acceptable: saucerization, punch biopsy, and elliptical incision biopsy. Saucerization is a variation of the shave biopsy, in which the biopsy extends to the underlying subcutaneous tissue. A narrow 2 mm margin is all that is required for excisional biopsy. The direction is important, however, because an improperly oriented excision may require skin grafting when primary closure is preferable. The wound should be oriented so that it may easily be re-excised with optimal skin margins. Staging in melanoma is based both on the histopathologic appearance of the primary tumor and on the extent of regional or distant metastasis according to the TNM classification.58–63 Microstaging of the primary lesion depends on a variety of factors, including the level of invasion, thickness, mitotic rate, infiltration of lymphocytes, ulceration, and other factors, such as mitotic index and tumor volume. Multiple factors have been associated with a less favorable prognosis, including increased thickness, vertical growth, ulceration, acral location, male gender, advanced age, and tumor regression.63 It is recognized that the most reliable histopathologic parameter is Breslow thickness, but even its usefulness has been questioned recently. The Clark level of invasion indicates the depth of penetration based on a five-stage classification: level I is confined to the epidermis, level II penetrates into the papillary dermis, level III fills the papillary dermis, level IV invades the reticular dermis, and level V penetrates subcutaneous tissue or deeper.64 Since it may be difficult to distinguish between the papillary and reticular dermis, a degree of observer bias may occur based on the Clark classification. The Breslow thickness method of staging measures tumor thickness from the top of the granular layer to the deepest area of penetration.65 According to this method, tumors are subdivided into groups based on thickness: <0.76mm, 0.76–1.5mm, 1.51–4mm, and >4mm. Breslow thickness was reported by Balch et al66 to be the most accurate and reproducible prognostic factor. Other methods have been devised to improve on the thickness measurement, including prognostic index (product of thickness and number of mitoses per square millimeter), cross-sectional area (product of lesion size and thickness), tumor volume, radial growth, ulceration, mitotic rate, regression, and angiolymphatic invasion.67–69 Melanomas in the radial growth phase, according to certain melanoma models, are considered ‘non-tumorigenic’, and are associated with survival rates approaching 100%, compared with 71% with vertical phase tumors. In the radial phase, the melanoma cells appear in small clusters in the dermis, and no mitoses are seen. In the vertical growth phase, the dermal nests tend to be large (>15–25 cells wide), and the morphology of the melanocytes differs from that of the epidermal component. As useful as it may be, the concept of radial and vertical growth phases of melanoma is not universally accepted. A number of authors have argued that accurately categorizing

Skin cancer in the aging patient

1405

lesions into either vertical or radial growth phase is difficult, if not impossible, based on these criteria.67–69 Of interest, much attention has been paid to ulceration as a prognostic factor in patients with melanoma. It is difficult to measure the true depth of the lesion, because of loss of the granular layer when ulceration is present. Despite this, several studies show a significant association between ulceration and poor outcome. This has prompted a proposal to amend the American Joint Committee on Cancer (AJCC) staging system of melanoma to take ulceration into account. The first formal staging criteria for melanoma was introduced and published in 1977, 1978, and revised in 1983.59,60–62,66 The initial staging criteria were based on four groups as follows: stage Ia <0.75mm; stage Ib >0.75–1.5mm; stage Ila >1.5–4.0mm; stage Ilb >4.0mm; stage III nodal metastasis; stage IV advanced regional metastases, regional nodes >5cm or fixed, or five or more in-transit regional nodes During a series of multidisciplinary conferences of the Melanoma Staging Committee of the AJCC, the staging criteria were revised further.59–62 The most recent revision takes thickness and ulceration into account, but not the Clark levels of invasion in the T classification. In addition, the number of metastatic lymph nodes rather than gross dimensions are taken into account in the N classification, and there is no delineation between microscopic and macroscopic nodal metastasis. Information derived from lymphatic mapping and sentinel lymph node (SLN) biopsy procedures is considered. Both the site of distant metastasis and elevation of serum lactate dehydrogenase (LDH) are considered in the M classification. Systematic workup for a patient with a confirmed melanoma should include a total body skin examination and palpation of lymph nodes.47,50 Recommended baseline studies include a complete blood count with differential, liver profile, and chest radiograph, depending on the thickness of the primary. Further studies such as computed tomography (CT) scan of the chest, abdomen, pelvis, and magnetic resonance imaging (MRI) of the brain are recommended for patients with confirmed stage III disease. Once the diagnosis has been made, the mainstay of treatment is local excision.47,50 Narrower surgical margins have been adopted recently based on large, randomized studies with long-term follow-up. The current recommendations for excision margins are 0.5cm margins for in situ melanoma, 1cm for melanomas less than 1mm thick, 2cm for melanomas from 1mm to 4mm, and greater than 2cm for melanomas thicker than 4mm. Subungual or acral lentiginous melanomas often require amputation of the interphalangeal joint proximal to the tumor. Elective lymph node dissection is controversial in patients with melanoma.70,71 Opponents of the procedure contend that no clear survival benefit has been established to justify the substantial morbidity and expense. Advocates argue the advantage of staging patients with thicker melanomas, and the possibility of eliminating tumor burden from the regional lymphatics, but there is general agreement that lymph node dissection is necessary if regional lymph node metastasis is clinically apparent. It is clear that lymph node involvement is an unfavorable prognostic factor for the subsequent development of metastases, and is associated with a decrease in the 5-year survival rate of 40% compared with patients without nodal disease. Techniques of cutaneous lymphatic mapping and SLN biopsy have impacted on the management of patients with melanoma and other solid tumors.72 Lymph node staging

Comprehensive Geriatric Oncology

1406

information is obtainable without a complete lymph node dissection and the degree of risk of lymphedema and infection associated with it. If done properly, SLN identification rates of 97–100% can be expected. The procedure can be learned and applied in a standardized fashion. However, successful results require collaboration between surgery, nuclear medicine, and pathology departments, and a learning curve of 30–50 cases is required. It has been demonstrated that lymphatic mapping using blue dye and radiocolloid together is superior to blue dye alone. It must be emphasized that surgical resection of clinically negative nodes in any capacity remains controversial, and no survival benefit for SLN biopsy has been established. A US National Cancer Institute (NCI)-sponsored national multicenter trial designed to answer this is underway, but the results are pending. In this trial, patients are being randomized into either wide local excision (WLE) and SLN biopsy versus WLE alone, or observation. Preliminary results with SLN surgery indicate, however, that important staging information can be obtained by the procedure. There is a correlation between SLN micrometastasis and survival.72 SLN biopsy is being used as a staging method by investigators at major cancer centers to identify which patients may benefit from further surgery or adjuvant therapy protocols.72 Only patients with tumor-positive SLNs are offered complete nodal dissection, saving the remaining 85% or so the morbidity of the procedure. It appears that SLN biopsy for the sole purpose of selecting patients for interferon therapy can no longer be fully justified. Many require that patients have evidence of nodal disease to qualify for participation. Whether lymphatic mapping and SLN biopsy should be considered standard for care for melanoma patients in the community at large is still a subject of debate. Isolated limb perfusion is a technique that may be used for patients with intralymphatic, in-transit or regionally recurrent disease.50 It allows the delivery of a high concentration of chemotherapy to an extremity, and may provide excellent palliation in patients, especially when combined with hyperthermic limb perfusion. Limb perfusion is considered the treatment of choice, especially when the alternative is amputation. Treatment of patients with high-risk stage III or IV disease includes chemotherapy, biologic therapy, and combinations of the two.73–75 Results with chemotherapy alone have been disappointing. Despite extensive efforts to screen new drugs, only a few produce significant clinical activity, and responses typically range between 15–20%. These include dacarbazine, cisplatin, carmustine (BCNU), and the vinca alkaloids vincristine and vinblastine. Combination chemotherapy regimens have produced a moderate increase in response rates, which range between 25% and 40%. Interferon-α (INF-α) and interleukin-2 (IL-2) have shown a modest level of activity in melanoma, with response ranges of 15–20%. The Eastern Cooperative Oncology Group (ECOG) reported the results of a randomized trial of high dose INF-α in melanoma patients with stage III or regional lymph node disease. The proposed mechanism is that IFN-α upregulates tumor antigens on melanoma cells. High-dose IFN-α increased overall survival 2.8–3.8 years and disease-free survival 1–1.7 years. Toxicity required dose reductions in 65% of patients and led to a significant dropout rate. ECOG 1690 compared high-dose versus low-dose IFN-α, and produced similar improvement in disease-free but not overall survival.

Skin cancer in the aging patient

1407

Combination of INF-α and IL-2 produces higher response rates than either cytokine alone. A biochemotherapy program has been introduced that produced a response rate of 60% in 62 patients with metastatic melanoma.74,75 The program employed concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, IFN-α, and IL-2. Adjuvant therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF) was shown to improve overall and disease-free survival in stage III and IV melanoma. Systemic administration of antisense oligonucleotides targeted against the BCL2 gene has been shown to increase tumor cell apoptosis and tumor response in animal models. Specific immunization of melanoma patients to induce immune-mediated regression has been the purpose of vaccine therapy.74,75 Vaccines generally consist of whole tumor cells or fractions and chemically defined tumor antigens. A commercially available cultured tumor cell vaccine (Melacine) prepared by Ribi ImmunoChem Research is being evaluated in a national trial by SWOG. Preliminary studies have shown antitumor responses in patients with melanoma. A chemically defined tumor cell vaccine that uses antibody responses to the melanoma surface glycolipids GD3, GD2, and GM2 is currently being evaluated. A modest trend towards beneficial response has been reported in a randomized study of GM2 plus BCG followed by cyclophosphamide. A number of immunologic adjuvants have been developed to increase antibody response to GM2, and are currently being studied by ECOG. Patients with a history of melanoma are often susceptible to the development of a second primary, emphasizing the need for close follow-up and early identification. Recurrences most frequently occur within the first 18 months, but may be delayed for decades. Melanoma patients should be educated about the ‘ABCDs’ of melanoma and the importance of monthly self-skin examinations. Follow-up examination should be scheduled every 3 months for 1 year, then every 6 months, at which time a total body skin examination should be performed, with palpation of lymph nodes. A complete blood count, liver profile, and chest radiograph should be obtained yearly on patients with stage III or IV disease. We have recommended that women with stage III or IV melanoma should avoid pregnancy for the first 2 years after diagnosis.

Comprehensive Geriatric Oncology

1408

Figure 59.6 Merkel cell carcinoma: indurated erythematous nodule on sundamaged skin Merkel cell carcinoma (Figure 59.6) Merkel cell carcinoma, or neuroendocrine carcinoma of the skin, is a malignant tumor thought to arise from Merkel cells in the epidermis. The Merkel cell is believed to function as a mechanoreceptor in the skin. Merkel cell carcinoma occurs primarily in people aged 65 and older. Most recent studies have shown an equal incidence in men and women. Most Merkel cell tumors have been reported in Caucasians, although there have been documented reports in Blacks and Polynesians. The most frequently involved sites for primary lesions include the skin of the head and neck (≥50%), followed by the extremities (40%) and trunk (≤10%).76–82 There is an association with congenital ectodermal dyplasia in young adults, Cowden’s disease, and Hodgkin lymphoma. Clinically, Merkel cell carcinoma usually presents as a painless, indurated, red to violet nodules on sun-exposed areas of skin, similar in appearance to basal cell carcinoma. The epidermis may be intact or ulcerated. Tumors range from 0.5 to 5 cm in diameter, but may grow as large as 12–15 cm. Local recurrence develops in 26–44% of patients after excision of the primary tumor.80,83–86 Merkel cell carcinoma frequently metastasizes to regional lymph nodes, with metastases occurring in 55–66% of patients during the course of the disease, 12–31% of patients presenting initially with regional metastasis.87,88 Distant metastasis occurs in approximately one-third of patients. The diagnosis of Merkel cell carcinoma is occasionally missed because of its similar appearance to many other undifferentiated small cell tumors. The tumor is usually composed of small islands or trabeculae of tumor cells within the dermis, but may extend

Skin cancer in the aging patient

1409

into the subcutaneous fat. Three histologic patterns have been described, while some authors have recognized multiple patterns, resulting in confusing descriptions of the histopathology. The diagnosis of Merkel cell carcinoma can be difficult on routine histopathology. A definitive diagnosis can be made by demonstrating positive reactivity with antibodies to low-molecular-weight cytokeratin (often in a perinuclear dot pattern), neuron-specific enolase (NSE), and chromogranin, and negative reactivity for S-100 protein, LCA, and high-molecular-weight cytokeratin.89,90 Localized or stage I disease is best managed by simple surgical excision of the primary tumor.91 Surgical margins of 2.5–3.0 cm are currently recommended when feasible. Local recurrence will develop within 1 year in 26–44% of patients.80,83–86 Because of the high recurrence rate and the aggressive nature of the tumor, many authors have advocated irradiation of the primary site after surgical excision.84,92 Radiotherapy is also an option for patients who are poor surgical candidates, or have unresectable disease or involvement of vital structures such as the eye. While prophylactic lymph node dissection is not routinely recommended for non-palpable lymph nodes, its use remains controversial.91 Some authors propose that SLN biopsy be done at the time of primary excision.93 In patients with regional lymph node metastasis or stage II disease, more aggressive treatment is advocated, because two-thirds of these patients ultimately die of their disease. Most authors recommend excision of the primary tumor, with adjuvant radiotherapy and lymph node dissection. Some authors advocate the use of systemic chemotherapy. Between one-half and three-fourths of patients develop regional nodal metastases during the course of their disease, often occurring 7–8 months after treatment.91 Distant metastases occur in approximately one-third of patients, with the most commonly involved sites being liver, bone, brain, lung, and skin.84,94 Chemotherapy regimens similar to those utilized in small cell lung cancer are used. More recently, radiotherapy has also been used to the primary site after excision, as well as in regional and metastatic disease. While patients may respond well to treatment, their lifespan is generally no longer than 12 months. The average time from initial diagnosis until the discovery of systemic disease is approximately 18 months, with death occurring in another 6 months.91 Overall survival rates are 88% at 1 year, 72% at 2 years, and approximately 55% 3 years.95 Follow-up of patients with Merkel cell carcinoma, similar to melanoma, begins with a thorough history and physical examination and total body skin examination every 3 months for a period of 3 years, and an annual visit to his or her physician thereafter for appropriate follow-up.93 The history and physical examination should place special emphasis on a complete skin examination and palpation of lymph nodes. Additional laboratory and/or radiologic studies should be obtained at this time if symptoms warrant.93

Comprehensive Geriatric Oncology

1410

Figure 59.7 Angiosarcoma: advanced necrotic and destructive tumor. Cutaneous angiosarcoma (Figure 59.7) Cutaneous angiosarcomas are rare, aggressive cancers of mesenchymal origin.96 They occur primarily on the head and neck of elderly patients, and are most likely of vascular or lymphatic origin. Primary cutaneous angiosarcoma is more likely to affect men than women; however, approximately 10% occur in chronically lymphedematous upper extremities of women who have undergone mastectomy.97 Angiosarcoma may also occur in chronic vascular stasis of the lower extremities, in areas of prior trauma, or as a late complication of radiotherapy, occurring up to 20 years after therapy.97,98 Prognosis is generally poor, with a 5-year survival rate of 12–27% when on the face or scalp.98 The clinical presentation of cutaneous angiosarcoma is most often single or multiple bruise-like red-purple macules, papules, or nodules that slowly enlarge. It is generally asymptomatic, although some may be painful, bleed, or become swollen. The lesions are commonly mistaken for bruises, hemangiomas, or infection. Eventually, angiosarcomas become ulcerated and hemorrhagic, and invade subcutaneous tissue and glia. The diagnosis requires clinical suspicion and biopsy. The microscopic appearance is that of irregular anastomosing sinusoids and dilated vascular channels dissecting through collagen bundles in the dermis. Endothelial cells lining the vascular channels are large and hyperchromatic, and protrude into lumina. The histologic grade may vary from low to undifferentiated, and mitotic activity is variable.97 Cutaneous angiosarcomas have a poor prognosis owing to their aggressive nature and frequently delayed diagnosis. Tumors tend to recur locally, spread widely, and have a high rate of lymph node and systemic metastases.96,99 Therapy is centered on excision

Skin cancer in the aging patient

1411

with wide margins and frozen section controls.97 Despite wide surgical excision, the tumor is prone to recur. Radiotherapy has been shown to be useful in locoregional control, whereas chemotherapy has not demonstrated significant benefit. Intralesional or intra-arterial dosing of human recombinant IL-2 may also control tumor activity through enhanced immunity.99 Currently, there is no standard for staging. Prognosis correlates with size less than 5 cm and success of obtaining wide surgical margins. The median survival in patients with cutaneous sarcoma remains at approximately 10–20 months.97 Conclusions Cutaneous malignancies and premalignancies are very common in the older patient. The most common skin cancers include basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, Bowen’s disease, melanoma, Merkel cell carcinoma, and angiosarcoma. Precancerous lesions such as actinic keratoses, and possible dysplastic nevi, may develop into malignancies, and also indicate an increased likelihood for skin cancers elsewhere. Avoiding precipitating factors such as UV radiation is crucial to minimize photoaging and skin cancers. Close monitoring of the skin in the older patient is recommended to detect and treat early precancers and skin cancers to enhance the patient’s appearance and quality of life. References 1. Harvey D, Fenske NA. Intrinsic aging and its role in nonmelanoma skin cancer formation. J Geriatr Dermatol 1993; 1. 2. Leffell DJ. The scientific basis of skin cancer. J Am Acad Dermatol 2000; 42:518–22. 3. Schwartz RA, Stoll HL Jr. Epithelial precancerous lesions. In: Dermatology in General Medicine, 5th edn (Fitzpatrick TB et al, eds). New York, McGraw-Hill, 1999:823–39. 4. Buzzell RA. Carcinogenesis of cutaneous malignancies. Dermatol Surg 1996; 22:209–15. 5. Leffell DJ, Fitzgerald DA. Basal cell carcinoma. In: Dermatology in General Medicine, 5th edn (Fitzpatrick TB et al, eds). New York, McGraw-Hill, 1999:857–64. 6. Salasche SJ. Epidemiology of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol 2000; 42:54–7. 7. Lin AN, Carter DM, Balin AK. Nonmelanoma skin cancers in the elderly. Clin Geriatr Med 1989; 5:161–70. 8. Moy RL. Clinical presentation of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol 2000; 42: s8–10. 9. Kuflik AS, Schwartz RA. Actinic keratosis and squamous cell carcinoma. Am Fam Physician 1994; 49:817–20. 10. Cockerell CJ. Histopathology of incipient intraepithelial squamous cell carcinoma (‘actinic keratosis’). J Am Acad Dermatol 2000; 42: 511–17. 11. Glogau RG. The risk of progression to invasive disease. J Am Acad Dermatol 2000; 42:23–4. 12. Dinehart SM. The treatment of actinic keratoses. J Am Acad Dermatol 2000; 42:25–8. 13. Jansen GT. Topical chemotherapy. Clin Dermatol 1992; 10:305–7. 14. Kalka K, Merk H, Mukhtar H. Photodynamic therapy in dermatology. J Am Acad Dermatol 2000; 42:389–413.

Comprehensive Geriatric Oncology

1412

15. Friedman RJ, Rigel DS, Silverman MK et al. Malignant melanoma in the 1990’s: The continued importance of early detection and self-examination of the skin. CA Cancer J Clin 1991; 41:201–26. 16. Gloster HM, Brodland DG. The epidemiology of skin cancer. Dermatol Surg 1996 22:217–26. 17. Marcil I, Stern RS. Risk of developing a subsequent nonmelanoma skin cancer in patients with a history of nonmelanoma skin cancer. Arch Dermatol 2000; 136:1524–30. 18. Naldi L, Dilandro A, D’Avanzo B, Parazzini F. Host-related and environmental risk factors for cutaneous basal cell carcinoma: evidence from an Italian case-control study. J Am Acad Dermatol 2000; 42:446–52. 19. Miller SJ. Biology of basal cell carcinoma [part 2]. J Am Acad Dermatol 1991; 24:161–71. 20. Jaramillo-Ayerbe F. Cryosurgery in difficult to treat basal cell carci- noma. Int J Dermatol 2000; 39:223–9. 21. Tsao H. Update on familial cancer syndromes and the skin. J Am Acad Dermatol 2000; 42:939– 69. 22. Proper SA, Rose PT, Fenske NA. Nonmelanomatous skin cancer in the elderly: diagnosis and management. Geriatrics 1990; 45:57–63. 23. Miller SJ. Biology of basal cell carcinoma [part 1]. J Am Acad Dermatol 1991; 24:1–10. 24. Randle HW. Basal cell carcinoma: identification and treatment of the high risk patient. Dermatol Surg 1996; 22:255–61. 25. Shriner DL, McCoy DK, Goldberg DJ, Wagner RF. Mohs micrographic surgery. J Am Acad Dermatol 1998; 39:79–95. 26. MacFarlane DF, Pustelny BL, Goldberg LH. An assessment of the suitability of Mohs micrographic surgery in patients aged 90 years and older. Dermatol Surg 1997; 23:389–93. 27. Rowe DE, Carroll RJ, Day CL. Mohs surgery is the treatment of choice for recurrent (previously treated) basal cell carcinoma. J Dermatol Surg Oncol 1989; 15:424–31. 28. Petit JY, Avril MF, Margalis A, Chassagne D et al. Evaluation of cosmetic results of a randomized trial comparing surgery and radiotherapy in the treatment of basal cell carcinoma of the face. Plast Reconstr Surg 2000; 105:2544–51. 29. Rowe DE, Carroll RJ, Day CL. Long-term recurrence rates in previously untreated (primary) basal cell carcinoma: implications for patient follow-up. J Dermatol Surg Oncol 1987; 15:315– 28. 30. Torre D. Cryosurgery of basal cell carcinoma. J Am Acad Dermatol 1986; 15:917–29. 31. Bernstein SC, Lim KK, Brodland DG, Heidelberg KA. The many faces of squamous cell carcinoma. Dermatol Surg 1996; 22:243–54. 32. Schwartz RA, Stoll HL Jr. Squamous cell carcinoma. In: Dermatology in General Medicine 5th edn (Fitzpatrick TB et al, eds). New York, McGraw-Hill, 1999:840–56. 33. Rowe DE, Carroll RJ, Day CL. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip: implications for treatment modality selection. J Am Acad Dermatol 1992; 26:976–90. 34. Weisberg NK, Bertagnolli MM, Becker DS. Combined sentinel lymphadenectomy and Mohs micrographic surgery for high risk cutaneous squamous cell carcinoma. J Am Acad Dermatol 2000; 43: 483–8. 35. Rook A, Wilkinson DS, Ebling FJG et al. Tumors of the skin. In: Textbook of Dermatology, 4th edn. London, Blackwell Science, 1986: 2375–478. 36. Frankel DH. Squamous cell carcinoma of the skin. Hosp Pract 1992; 27:99–102. 37. Hemminki K, Dong C. Subsequent cancers after in-situ and invasive squamous cell carcinoma of the skin. Arch Dermatol 2000; 136:647–51. 38. Sober AJ, Burstein JM. Precursors to skin cancer. Cancer 1995; 75(Suppl 2): 645–50. 39. Ghadially R, Ghadially FN. Keratoacanthoma. In: Dermatology in General Medicine, 5th edn (Fitzpatrick TB et al, eds). New York, McGraw-Hill, 1999:865–72. 40. Cribier B, Asch PH, Grosshans E. Differentiating squamous cell carcinoma from keratoacanthoma using histopathological criteria. Dermatology 1999; 199:208–12.

Skin cancer in the aging patient

1413

41. Weedon D. Tumors of the epidermis. In: Skin Pathology. Edinburgh: Churchill Livingstone, 1998:657–60. 42. Hodak E, Jones RE, Ackerman AB. Solitary keratoacanthoma is a squamous cell carcinoma: three examples with metastases. Am J Dermatopathol 1993; 15:332–42. 43. Tamir G, Morgenstern S, Ben-Amitay D et al. Synchronous appearance of keratoacanthomas in burn scar and skin graft donor site shortly after injury. J Am Acad Dermatol 1999; 40:870–1. 44. Agarwal M, Chander R, Karmaker S, Walia R. Multiple familial keratoacanthoma of Witten and Zak—a report of three siblings. Dermatology 1999; 198:396–9. 45. Spieth K, Gillie J, Kaufmann R. Intralesional methotrexate as effective treatment in solitary giant keratoacanthoma of the lower lip. Dermatology 2000; 200:317–19. 46. Gloster HM, Brodland DG. The epidemiology of skin cancer. Dermatol Surg 1996; 22:217–26. 47. Yohn J, Hoffman S, Norris D et al. Melanoma 2: diagnosis and treatment. Hosp Pract 1994; 29:27–34. 48. Sober AJ, Rhodes AR, Mihm MC. Neoplasms: malignant melanoma. In: Dermatology in General Medicine (Fitzpatrick TB et al, eds). New York: McGraw-Hill, 1987:947–66. 49. Friedman RJ, Rigel DS, Silverman MK et al. Malignant melanoma in the 1990’s: the continued importance of early detection and self-examination of the skin. CA Cancer J Clin 1991; 41:201– 26. 50. Johnson TM, Smith II JW, Nelson BR et al. Current therapy for cutaneous melanoma CME. J Am Acad Dermatol 1995; 32; 689–707. 51. Evans RD, Kopf AW, Lew RA et al. Risk factors for the development of melanoma. I: Review of case controlled studies. J Dermatol Surg Oncol 1988:14:393–408. 52. Hoffman S, Yohn J, Robinson W et al. Melanoma: 1. Clinical characteristics. Hosp Pract 1994; 29; 37–50. 53. Koh HK, Geller AC, Miller DR et al. The current status of melanoma. Early detection and screening. Dermatol Clin 1995; 13:623–34. 54. Perez IR, Fenske NA, Brozena SJ. Malignant melanoma: differential diagnosis of the pigmented lesion. Semin Surg Oncol 1993; 9:168–73. 55. Greenstein DS, Rogers GS. Management of stage I malignant melanoma. Dermatol Surg 1995; 21:927–37. 56. Green MS, Ackerman AB. Thickness is not an accurate gauge of prognosis of primary cutaneous melanoma. Am J Dermatopathol 1993; 15:461–73. 57. Sober AJ. Cutaneous melanoma: opportunity for cure. J Am Cancer Soc 1991; 41:197–9. 58. Reintgen D, Albertini J, Miliotes SB et al. The accurate staging and modern day treatment of malignant melanoma. Cancer Res Ther Control 1994; 8:1–15. 59. American Joint Committee for Cancer Staging and End Result Reporting. Staging of malignant melanoma. In: Manual for Staging of Cancer 1977. Chicago: American Joint Committee, 1977:131–40. 60. American Joint Committee for Cancer Staging and End Results Reporting. Staging of malignant melanoma. In: Manual for Staging of Cancer 1978. Chicago: American Joint Committee, 1978:131–40. 61. American Joint Committee on Cancer Staging. Melanoma of the skin. In: Manual for Staging of Cancer (Beahrs O, Myers M, eds). Philadelphia: JB Lippincott, 1988:140–2. 62. American Joint Committee for Cancer Staging. Melanoma of the skin. Manual for Staging of Cancer. (Beahrs O, Myers M, eds). Philadelphia: JB Lippincott, 1992:143–8. 63. Balch CM, Buzaid AC, Atkins MB et al. A new American Joint Committee on Cancer staging system for cutaneous melanoma. Cancer 2000; 88:1484–91. 64. Clark W, From L, Bernardino E, Mihm M. The histogenesis and biologic behavior of primary human malignant melanomas of the skin. Cancer Res 1969; 29:705–26. 65. Breslow A, Thickness, cross sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg 1970; 172: 902–8.

Comprehensive Geriatric Oncology

1414

66. Balch C, Murad T, Soong S et al. A multitactorial analysis of melanoma: prognostic histologic features comparing Clark’s and Breslow’s staging methods. Ann Surg 1978; 188:732–42. 67. Clark W, Elder DE, Guerry D et al. Model predicting survival in stage I melanoma based on tumor progression. J Natl Cancer Inst 1989; 81:1893. 68. Worth AJ, Gallagher RP, Elwood JM et al. Pathologic prognostic factor for cutaneous malignant melanoma: the Western Canada Melanoma Study. Int J Cancer 1989; 43:370. 69. Balch CM, Soong SJ, Shaw HM et al. An analysis of prognostic factors in 8500 patients with cutaneous melanoma. In: Cutaneous Melanoma (Balch CM, Houghton AN, Milton GW et al, eds). Philadelphia: JB Lippincott, 1992:165–97. 70. Balch CM. The role of elective lymph node dissection in melanoma: rationale, results, and controversies. J Clin Oncol 1988; 6:163–72. 71. Crowley NJ. The case against elective lymphadenectomy. Surg Oncol Clin North Am 1992; 1:223–46. 72. Morton DL, Wen DR, Wong JH et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992; 127:392–99. 73. Kirkwood JM Strawderman MH, Ernstoff MS et al. Interferon α2b adjuvant therapy of high risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group trial EST 1684. J Clin Oncol 1996; 14:7–12. 74. Demierre MF, Koh HK Adjuvant therapy for cutaneous malignant melanoma. J Am Acad Dermatol 1997; 36:747–64. 75. Agarwala SS, Kirkwood JM. Adjuvant therapy of melanoma. Semin Surg Oncol 1998; 14:302– 10. 76. Messina JL, Reintgen DS, Cruse CW et al. Selective lymphadenectomy in patients with Merkel cell (cutaneous neuroendocrine) carcinoma. Ann Surg Oncol 1997; 4:389–95. 77. Ratner D, Nelson BR, Brown MD et al. Merkel cell carcinoma. J Am Acad Dermatol 1993; 29:143–56. 78. Rice RD Jr, Chonkich GD, Thompson KS et al. Merkel cell tumor of the head and neck. Five new cases with literature review. Arch Otolaryngol Head Neck Surg 1993; 119:782–6. 79. Rubsamen PE, Tanenbaum M, Grove AS et al. Merkel cell carcinoma of the eyelid and periocular tissues. Am J Ophthalmol 1992; 113: 674–80. 80. Shaw JH, Rumball E. Merkel cell tumour: clinical behavior and treatment. Br J Surg 1991; 78:138–42. 81. Silva EG, Mackay B, Goepfert H et al. Endocrine carcinoma of the skin (Merkel cell carcinoma). Pathol Annu 1984; 19:1–28. 82. Suntharalingam M, Rudoltz MS, Mendenhall WM et al. Radiotherapy for Merkel cell carcinoma of the skin of the head and neck. Head Neck 1995; 17:96–101. 83. Frigerio B, Capella C, Eusebi V et al. Merkel cell carcinoma of the skin: the structure and origin of normal Merkel cells. Histopathology 1983; 7:229–49. 84. Hitchcock CL, Bland KI, Laney RG III et al. Neuroendocrine (Merkel cell) carcinoma of the skin: its natural history, diagnosis and treatment. Ann Surg 1988; 207:201–7. 85. Pilotti S, Rilke F, Bartoli C et al. Clinicopathologic correlations of cutaneous neuroendocrine Merkel cell carcinoma. J Clin Oncol 1988; 6:1863–73. 86. Pitale M, Sessions RB, Husain S. An analysis of prognostic factors in cutaneous neuroendocrine carcinoma. Laryngoscope 1992; 102: 244–9. 87. Alex JC, Krag DN. Gamma-probe guided localization of lymph nodes. Surg Oncol 1993; 2:137–43. 88. Goepfert H, Remmler D, Silva E et al. Merkel cell carcinoma (endocrine carcinoma of the skin) of the head and neck. Arch Otolaryngol 1984; 110:707–12. 89. Leffell DJ, Fitzgerald DA: Basal cell carcinoma. In: Dermatology in General Medicine, 5th edn (Fitzpatrick TB et al, eds). New York: McGraw-Hill, 1999:857–864. 90. Salasche SJ. Epidemiology of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol 2000; 42:54–57.

Skin cancer in the aging patient

1415

91. Haag ML, Glass LF, Fenske NA. Merkel cell carcinoma: diagnosis and treatment. Dermatol Surg 1995; 21:927–37. 92. Yiengpruksawan A, Coit DG, Thaler HT et al. Merkel cell carcinoma: prognosis and management. Arch Surg 1991; 126:1514–19. 93. Smith DF, Messina JL, Perrott R et al. Clinical approach to neuroendocrine carcinoma of the skin (Merkel cell carcinoma). Cancer Control 2000; 7:72–83. 94. Crown J, Lipzstein R, Cohen S et al. Chemotherapy of metastatic Merkel cell cancer. Cancer Invest 1991; 9:129–32. 95. Fitzpatrick TB, Eisen AZ, Wolff K et al. Cutaneous neuroendocrine carcinoma: Merkel cell. In: Dermatology in General Medicine, 4th edn (Fitzpatrick TB et al, eds). New York: McGrawHill, 1993:898–902. 96. Mentzel T, Kutzner H, Wollina U. Cutaneous angiosarcoma of the face: clinicopathologic and immunohistochemical study of a case resembling rosacea clinically. J Am Acad Dermatol 1998; 38:837–40. 97. Fedok FG, Levin RJ, Maloney ME, Tipirneni K. Angiosarcoma: current review. Am J Otolaryngol 1999; 20:223–31. 98. Lapidus CS, Sutula FC, Stadecker MJ et al. Angiosarcoma of the eyelid: yellow plaques causng ptosis. J Am Acad Dermatol 1996; 34: 308–10. 99. Satoh T, Takahashi Y, Yohozeki H et al. Cutaneous angiosarcoma with thrombocytopenia. J Am Acad Dermatol 1999; 40:872–76.

PART 8 Rehabilitation and supportive care

60 Management of infectious complications in the aged cancer patient John N Greene Introduction Cancer and infection make up the leading causes of death among persons aged 65 and older. Serious infectious complications are the dose-limiting factor for the treatment of the aged cancer patient. Strategies to improve tolerance of intensive therapy are being explored, especially with the use of cytokines and prophylactic antimicrobials. However, delay in diagnosis of infectious complications because of atypical clinical manifestations in the aged is a serious concern. Decremental biologic changes with age, often accelerated by coexisting diseases, can influence the physiologic response to an acute illness and thus alter the clinical manifestations of a geriatric patient with a given disorder.1 Some elderly patients may exhibit minimal or no focal signs pointing to a specifically involved organ system as in acute appendicitis or cholecystitis.1 The high prevalence of multiple chronic and debilitating diseases may further complicate the therapy of infections in the elderly cancer patient. Peak temperatures, maximum white blood cell counts, and intensities of many clinical symptoms and signs are less marked in the elderly.2 The blunting of the febrile response in the elderly was cited by Hippocrates in his Aphorisms.1 The febrile response may be blunted or even absent in a small but significant number of older patients with common infections such as pneumonia.1 Afebrile bacteremia complicating pneumonia, urinary tract infections, and cellulitis occurs predominantly in aged patients.3 In one study, 90% of afebrile patients with culture-proven bacteremia were elderly.3 In addition, medications frequently taken by older patients, such as antipyretics and corticosteroids, may diminish the febrile response.1 Frequently, the elderly may have a low basal temperature. An oral temperature greater than 99°F (37.2°C) should be regarded as elevated represent a significant increase if a low basal temperature in patients older than 65.4 A temperature of 100°F may was present.1 Ninety-five percent of elderly patients who have infection will show some febrile response.5 Elderly patients with fever are more likely to have serious bacterial infections, in contrast to younger patients, in whom fever usually signifies viral or benign bacterial infections.1 Occult bacterial infection should be suspected in the elderly patient with the new onset of fever, and is a frequent cause of fever of unknown origin (FUO) in this population.2 Unlike FUO in the young, a cause for prolonged fever in older patients could be determined in most cases.1 In one series, 36% of cases were treatable infections, 26% connective tissue diseases, and 24% neoplasia (lymphoma and carcinoma).2,5 Lymphoma is the most common neoplasm, most cases being intraabdominal.5

Management of infectious complications in the aged cancer patient

1419

Immunologic and structural changes with age The process of aging leads to immune senescence and thus a moderate immunodeficient state. The susceptibility to and severity of certain viral and bacterial diseases is increased by the waning immunity associated with aging.6 B-cell dysregulation manifesting as clonal expansions and monoclonal gammopathies occurs with higher frequency in older patients.7 Neoplastic transformation of the CD5+ B-cell lineage results in chronic lymphocytic leukemia (CLL), a disease almost exclusively seen in old age.7 No striking changes can be defined in antigen-presenting cells (APC) such as macrophages and dendritic cells with age, and in general their function is preserved.7 Information is inconclusive regarding changes in neutrophil function with increasing age.7 Other elements of the inflammatory response—leukocytosis, phagocytosis, and intracellular killing—have also been reported to be impaired in the elderly.8 The strongest case for a causal relationship between immunosenescence and infectious disease can be made for the reactivation of latent varicella zoster virus (VZV), mycobacterial disease, and some of the dimorphic fungal pathogens.6 Reactivation of these diseases is almost always associated with defects in cell-mediated immunity that occur with immunosuppressive drug therapy, or with the impaired immunity associated with neoplastic disease or aging.6 The change in the distribution and function of T-cell subsets alters cell-mediated immunity with age.7 Helper T-cell activity and cytotoxic T lymphocytes (CTL) decline with age, even though the proportion of CD4+ cells increases and that of CD8+ cells decreases with age.7 The decline in cell-mediated immunity results in an increase in anergy to delayed hypersensitivity skin tests. An increased risk of allcause mortality was noted in anergic individuals aged over 60.9 Beginning at age 45, the incidence of shingles increases markedly. Between the ages of 45 and 85, it increases fivefold despite well-maintained humoral immunity to the virus.6 Therefore, the increased incidence of shingles appears to be related to the loss of cell-mediated immunity to VZV.6 Reactivation of VZV due to waning cellular immunity with age more commonly results in protracted and disabling pain in elderly patients.4 The prevalence of bacteriuria in the elderly is approximately 10% in men and 20% in women.2 Structural changes in the urinary system (e.g. prosthetic hypertrophy and relaxation of the pelvic floor) lead to accumulation of residual urine.6 Urinary stasis from prostate hypertrophy and incomplete emptying in older adults enhances bacterial colonization and persistent bacteuria.7 The gastrointestinal tract maintains host resistance to a variety of pathogens, mainly by gastric acid secretion and by the gut-associated lymphoid tissue.7 Gastric acidity declines with age, and Peyer’s patches are reduced in number, but there are no data suggesting that the function of the gut-associated lymphoid tissue decreases with age.7 With age, the epidermis becomes thinner, the dermis loses its density, vascularity, and elasticity, and the subcutaneous tissues decrease as well.7 The immune senescence of the skin is attributed to the decline in the number and function of Langerhans cells, especially in sun-exposed areas.7 Such skin changes place the older adult at greater risk for skin and soft tissue infections.7 Cellulitis in elderly individuals may resolve more slowly than in younger patients.4 Surgical wound infections may be increased in the elderly because of associated comorbid illnesses such as diabetes, obesity, peripheral vascular disease,

Comprehensive Geriatric Oncology

1420

venous stasis, and peripheral edema. Lymphedema following surgical management of breast cancer is a significant risk factor for recurrent cellulitis. Breast cancer increases in incidence with advancing age. Because of therapeutic equivalency, mastectomy has been replaced by breast conservation therapy, which includes breast lumpectomy, axillary lymph node dissection, and radiotherapy of the remaining breast for stage I and II breast cancer.10 Although breast cellulitis occurs in a minority of patients following breast surgery, certain risk factors for the development of this infection have been identified. Brewer et al10 found that these associated factors included drainage of a hematoma, postoperative ecchymosis, lymphedema, resected breast tissue volume, and previous number of breast seroma aspirations. The median age of the patients in this study was 53, with a range of 33–78. Recurrent cellulitis is most commonly associated with postoperative lymphedema. Sentinel lymph node mapping should be considered when possible to limit the number of lymph nodes resected, thus reducing the complication of lymphedema and recurrent cellulitis. There is a sevenfold increase in the risk of adverse drug reactions in patients aged over 70.11 However, the underlying physiologic condition of the individual patient should dictate selection of therapy, and not age alone.11 Because of decreased renal and hepatic function in older individuals, doses of antimicrobials that are somewhat lower than the maximum dose used for younger patients can be used.4 Certain antimicrobials, such as aminoglycosides, should be used with caution in the elderly. With the reduced muscle mass associated with aging, the serum creatinine level may not accurately reflect the true level of kidney function in the elderly.12 The higher incidence of adverse drug events is related to the physiologic changes of aging, the presence of chronic underlying illnesses, polypharmacy (prescribing multiple drugs), and inappropriate dosing by prescribers.12 Pneumonia Community-acquired pneumonia occurs 50 times more frequently in individuals over the age of 75 than in 15- to 19-year-olds,13 with a mortality rate as high as 30–40%.4 Community-acquired pneumonia in the aged is most commonly due to Streptococcus pneumoniae, followed by gram-negative bacteria (Haemophilus influenzae, Moraxella catarrhalis, and Escherichia coli).4 Other serious causes of pneumonia in the elderly include Staphylococcus aureus, Legionella pneumophila, influenza virus, and Mycobacterium tuberculosis. An altered mental status may be the first sign of pneumonia. The geriatric patient with pneumonia may not exhibit cough, pleuritic chest pain, fever, leukocytosis, or sputum production. There is no evidence of a reduction in mucosal immunity or reduced function of alveolar macrophages with aging.7 The impaired cough reflex and more frequent aspiration increases the risk of pneumonia in the elderly.7 Changes in the lungs (e.g. loss of elastic recoil, decreased mucous production, and impaired ciliary action), as well as depression of the cough reflex, lead to less efficient pulmonary clearance.6 Hospitalized patients above the age of 95 have a threefold higher incidence of nosocomial pneumonia compared with hospitalized younger individuals aged 18–24.14 Gram-negative bacteria colonize the respiratory tract more frequently with advancing age, immobility, debility, chronic disease, and increasing level of care required for a patient.15 In general, in both

Management of infectious complications in the aged cancer patient

1421

community- and hospital-acquired settings, the risk of gram-negative or staphylococcal pulmonary infection appears to be increased in the elderly.13 Prophylaxis of respiratory disease in the elderly by immunization with influenza vaccine and pneumococcal vaccine is recommended. Vaccinations recommended for those over 60 include diphtheria and tetanus toxoids every 10 years, influenza virus vaccine annually, and pneumococcal polysaccharide vaccine once or possibly every 6 years.16 Tuberculosis Reactivation of tuberculosis in the elderly appears to be related to the declining vigor of cell-mediated immunity, poor nutrition, diabetes, or the use of corticosteroid therapy.2,4,6 Viable bacteria in old granulomata escape to disseminate after breakdown of local barriers and cell-medicated immunity with age.6 Individuals over the age of 65 account for perhaps twice the number of cases of tuberculosis that one might predict given their numbers within the population.2 In Arkansas, 53% of cases of tuberculosis occurred in the 14% of the population who were over age 65.17 The occurrence of unexplained weight loss or fever, pulmonary symptoms, unexplained lymphadenopathy, or changes in renal function should all be clues to the possible presence of tuberculosis.2 Unique features of tuberculosis in the elderly include more frequent disseminated disease at presentation and less frequent presentations with tuberculosis-associated symptoms such as night sweats, cough, fever, and hemoptysis.4 Individuals with a recently converted tuberculin test, regardless of age, should be given isoniazid prophylaxis 300 mg in a once-daily dose for 6–12 months.2 However, when patients of various ages with culture-proven tuberculosis have been skin-tested, 10% of tubercular patients under the age of 55 were unresponsive, while 30% of tubercular patients aged over 55 were unresponsive.18 Viral pneumonia Bacterial pneumonia and influenza together comprise the fifth leading cause of death among persons older than 65.19 Influenza among persons aged 65 and older has a fivefold excess death rate compared with influenza among young adults.7 Factors related to this excess death rate are a decline in cell-mediated immunity, failure to provide the influenza vaccine, and failure to form protective antibodies (35% over 65) when vaccinated.7 More than 80% of influenza cases are symptomatic in older individuals, and confusion may preclude an accurate history.19 After or during primary influenza viral pneumonia, secondary bacterial pneumonias may supervene. These secondary bacterial pneumonias occur more often in elderly and chronically ill people. Recrudescence of fever and development of a productive cough and possibly pleuritic chest pain after initial improvement from the classic ‘flu’ symptoms point to secondary bacterial pneumonia. S. pneumoniae, S. aureus, and H. influenzae are the most common pathogens. After influenza, respiratory syncytial virus (RSV) is the next most important cause of viral pneumonia in the elderly.2,16,19,20 Among persons aged 65 or older, admitted to hospital during the winter with acute cardiopulmonary conditions or influenza-like

Comprehensive Geriatric Oncology

1422

illness, 13% of cases were caused by influenza and 10% were caused by RSV.21 During RSV outbreaks in long-term care facilities, rates of pneumonia ranged from 5% to 67% and death rates from 0% to 53%.21 Clinical manifestations of RSV infection in the elderly range from mild cold symptoms to acute respiratory distress and death.21 Distinguishing influenza from RSV infection in the elderly is frequently not possible on clinical grounds alone.21 Of older patients with RSV infection requiring admission, 18% needed intensive care and 10% ventilatory support, and 10% died.20 Besides supportive care, aerosolized ribavirin may be used to treat RSV pneumonia in the immunocompromised and elderly. Other viruses than can cause severe pneumonia in the elderly that rarely can result in death include parainfluenza and coronaviruses.19 Chronic lymphocytic leukemia Of all cases of CLL, 90% occur in persons over the age of 50; nearly 70% of patients are older than 60.22 Infections are the leading cause of death in patients with CLL. The 5-year risk of developing severe infections in 125 patients with CLL (mean age 65.6) was 26%, and 21 out of 71 deaths could be attributed to infectious causes.23 Molica et al23 found that severe infection occurred more frequently in patients with CLL who had an advanced clinical stage, diffuse bone marrow histology, and hypogammaglobulinemia. Cryptococcus neoformins,24 Histoplasma capsulatum,25 Cocddioides immitis,26 and Nocardia asteroides27 can cause a progressive pneumonia or disseminated disease in patients with CLL, especially if they are receiving corticosteroids. Aspergillus spp., M. tuberculosis, M. kansasii, and M. avium-intracellulare can present in a similar fashion, with a progressive pneumonia, in the setting of corticosteroid therapy. In addition to the aforementioned organisms, other unusual infections occurring in patients with CLL are frequently found in HIV-infected individuals. A 78-year-old man with CLL who was HIV-negative developed disseminated angiomatous papules following a cat scratch consistent with bacillary angiomatosis.28 The lesions resolved completely after treatment with erythromycin. Infection and secondary primary malignant tumors were the most common complications and cause of death in 105 patients with B-cell CLL followed for a median period of 5.5 years.29 S. pneumoniae, S. aureus, S. haemolyticus, E. coli, and VZV accounted for most infections. The sites affected were the lungs, skin, and urinary tract. Advancing disease increased the liability to major infection. Immunoglobulin deficiency is the factor that correlates best with the frequency, severity, and pattern of infection. Another study of 59 patients with CLL found that the majority of patients with severe or multiple infections (13 of 18) had low levels of both total IgG and specific antibodies to pneumococcal capsular polysaccharide.30 Although less than half of the patients with hypogamma-globulinemia developed severe or multiple infections, low levels of pneumococcal antibodies were associated with the former and latter. Of 146 patients with CLL in another series, 292 infections were recorded.31 The incidence of moderate to severe infections was 0.47 per patient-year, with 42 patients dying of a severe infection (46% of all causes of death). Patients with hypogammaglobulinemia and advanced disease stage were the most susceptible to death from infection and would be the most likely to benefit from prophylaxis with intravenous

Management of infectious complications in the aged cancer patient

1423

immunoglobulin (IVIG). Patients with CLL and hypogammaglobulinemia, or a history of infection, can be substantially protected from bacterial infection by administration of immunoglobulin every 3 weeks.32 After 1 year of therapy, 14 patients developed a bacterial infection, versus 36 patients receiving placebo.32 IVIG to provide protection for encapsulated bacterial infection such as pneumococcal pneumonia is frequently used for patients with CLL and multiple myeloma. Sklenar et al33 have come up with recommendations on dosage and scheduling of IVIG in these patients. The dosage recommendation in CLL is 0.4 g/kg every 3 weeks until week 12, followed by a maintenance dosage of 0.4 g/kg every 5 weeks. Because of a faster elimination rate of antibodies in multiple myeloma patients, the recommended loading dose is 0.8 g/kg, followed by 0.4 g/kg every week as continuous treatment. Fludarabine, an effective therapy for CLL, is also lymphotoxic, especially for CD4+ lymphocytes.34 Fludarabine can produce neutropenia, with associated pneumonia and bacteremia, and opportunistic protozoal and mycobacterial infections have been described after therapy with this drug.35 Anaissie et al36 found that fludarabine and prednisone resulted in an increased incidence of listeriosis in patients with CLL. A dramatic reduction in CD4+ lymphocytes developed after fludarabine and prednisone treatment and coincided with the development of listeriosis. Of 248 patients with CLL who received fludarabine and prednisone, 7 developed listeriosis, whereas none of the 160 patients treated with fludarabine alone developed listeriosis. Infections occurred regardless of whether patients were in remission, had active CLL, or were neutropenic or hypogammaglobulinemic. Age appeared to play a role in the development of listeriosis: the median age for those infected was 70, whereas that for the non-infected was 62. Listeria infection manifested as bacteremia or meningitis. The major causes of meningitis in the aged are S. pneumoniae, gram-negative bacteria, M. tuberculosis, and Listeria monocytogenes. A brain abscess due to Listeria in a patient with CLL treated with fludarabine has also been reported.37 Cleveland and Gelfand37 proposed that prednisone and fludarabine work synergistically to lower the threshold for listerial infection, because high doses of prednisone alone did not increase the risk of listeriosis. Patients with CLL who receive this combination therapy are advised to avoid foods that may contain large concentrations of Listeria spp., including unpasteurized milk, raw vegetables, and undercooked poultry or meat. The risk period for listeriosis in patients with CLL treated with this combination could be as long as 2 years after completion of therapy, even with a normal CD4+ lymphocyte count.38 Non-infectious causes of fever are not infrequent in patients with CLL, and are probably due to the progression of the disease itself. A sudden development of fever, weight loss, increasing lymphadenopathy, hepatosplenomegaly, lymphopenia, or paraproteinemia should arouse suspicion of Richter syndrome or other acute transformations, which portend a poor prognosis.22 Multiple myeloma Recurrent infections are an important cause of morbidity and the most common cause of death in patients with multiple myeloma. Infection occurs most often during the first 2 months after diagnosis of myeloma and accounts for 20–50% of all deaths.39 Recurrent

Comprehensive Geriatric Oncology

1424

infections are the presenting signs of myeloma in 25% of patients, and more than 75% of patients will develop a serious infection during the course of their illness.39 Gramnegative bacteria have replaced S. pneumoniae as the most common cause of infection in myeloma patients. The frequency of gram-negative infections varies from 70% to 81%, particularly in hospitalized patients, whereas most reported infections caused by S. pneumoniae are community-acquired. This change of spectrum of infection to favor gram-negative bacteria over pneumococci may be due to more nosocomial infections, more aggressive chemotherapeutic regimens, longer periods of neutropenia, and greater use of pneumococcal vaccination.39 Most of these infections involve the urinary and respiratory tracts, with or without the development of sepsis. The occasional infections with fungi, herpesviruses, M. tuberculosis, and Pneumocystis carinii most likely result from steroids and cytotoxic chemotherapy rather than from the myeloma itself.35,39 In patients with myeloma, neutropenia does not appear to be the major factor predisposing to gram-negative infections, even in patients with sepsis. Almost all gramnegative septic episodes occur in non-granulocytopenic patients.40 Over a 13-year period, 141 patients with myeloma were studied.41 Of these patients, 55% developed an infectious complication, most commonly in the first month of diagnosis. During the study period, there was a significant rise in the overall incidence of infections, especially those due to gram-negative bacteria. Risk factors for subsequent infection included renal insufficiency and anemia. Infection was associated with a 275-fold increased risk of death, independent of other risk factors. Azotemia (blood urea nitrogen, BUN >35) is significantly related to infection with gram-negative bacteria, but not with S. pneumoniae or H. influenzae, and is associated with a poor prognosis in myeloma patients.42 Of 75 bacterial infections in 57 patients with myeloma, episodes of infection with S. pneumoniae and H. influenzae occurred at presentation, early in the disease, and in patients responding to chemotherapy.43 Episodes of infection with gram-negative bacteria occurred in patients with active and advancing disease and in those responding to chemotherapy when neutropenic. Gram-negative bacteria and S. aureus caused 80% of infections seen after diagnosis and 92% of deaths from infection. The high mortality due to S. aureus in patients with myeloma was highlighted by a review of bacteremia in Denmark.44 Of 6253 cases of S. aureus bacteremia between 1975 and 1984, 479 occurred in patients with hematologic malignancies and/or agranulocytosis. There was a lower incidence of endocarditis in cancer patients than in non-cancer patients (0.4% versus 4.7%), probably due to a central line accounting for the focus of infection more often in the former. However, mortality was higher in patients with hematologic malignancy or agranulocytosis and S. aureus bacteremia than in noncancer patients (49% and 46% versus 33%). The highest mortality rate was found in patients with myeloma (71%) and the lowest in patients with acute lymphoblastic leukemia (28%), which was possibly related to the greater age of the myeloma patients. The trend favoring gram-negative over pneumococcal infections in patients with myeloma held true in a study of male veterans.45 Thirty-three infectious episodes occurred in 60 patients (mean age 63) with myeloma over a 10-year period. Urinary tract infections caused by gram-negative bacteria (Enterobacteriaceae 31% and Pseudomonas aeruginosa 22%) were the most common, and most were due to bladder catheterization. Pneumo coccal pneumonia occurred infrequently (2 cases), as did HZV infection (2 cases).

Management of infectious complications in the aged cancer patient

1425

Another study found that infectious complications developed in 71 of 126 (56.3%) of patients with myeloma.46 Most infections manifested in the acute stages, the onset, relapse, and the terminal stage of myelomatosis, and during and after induction therapy. Old age, third clinical stage of disease, light-chain myelomas, λ light-chain secretions, leukopenia, azotemia, polyclonal suppression of immunoglobulins, and inadequate therapeutic response were statistically significant risk factors for an infectious complication. However, unlike prior studies, infections did not significantly impact survival in these patients. When evaluating patients with myeloma for infectious complications, the duration and stage of disease, prior and current therapy, and presence or absence of neutropenia should be taken into account when choosing empiric antibiotics, since the causative pathogens may vary with each factor.43 Hargreaves et al47 investigated 102 patients with myeloma to assess whether immunologic risk factors predisposing to serious infection could be identified. Low antipneumococcal and anti-E. coli titers correlated with risk of serious infection. The overall serious infection rate was 0.92 per patient-year, and was four times higher during periods of active disease (1.90) compared with plateau-phase myeloma (0.49). The majority of infections involved the respiratory tract. Several studies have found a subgroup of patients with myeloma with poor IgG responses to exogenous antigens, who are at increased risk of serious infection, can be identified, and may benefit from replacement immunoglobulin therapy to reduce the risk of infection.47,48 Because patients with plateau-phase myeloma have an increased risk of lifethreatening bacterial infections and polyclonal humoral immune suppression, the value of IVIG prophylaxis was evaluated by Chapel et al.48 Monthly infusions of IVIG at 0.4 g/kg or placebo were given to 82 patients with stable myeloma. Sepsis or pneumonia occurred in 10 patients receiving placebo but in none receiving IVIG. Of 57 serious infectious complications, 38 occurred in 470 patient-months on placebo, compared with 19 in 449 patient-months on IVIG. Patients who had a maximum benefit from IVIG were identified by a poor pneumococcal IgG antibody response (<2-fold increase). In addition, IVIG had a statistically significant effect in protecting against recurrent infections in 60 patients who completed a year of therapy when compared with placebo.48 A decreased incidence and severity of infections may be seen with IVIG use.49,50 No episodes of bacteremia or pneumonia occurred and less serious infections and recurrent infections developed in patients treated with monthly IVIG (0.4 g/kg) compared with placebo.50 Prophylactic penicillin may be useful in patients who are non-responders or who cannot tolerate IVIG and who develop recurrent pneumococcal infections, but there are no published data supporting this approach.39 During the past few years, there has been a trend toward intensified treatment of myeloma with allogeneic and autologous hematopoietic stem cell transplantation (HSCT), high-dose melphalan, and high doses of steroids, resulting in improved response rates and survival.40 Early (<30 days after transplant) and later (>30 days after transplant) infectious complications can follow autologous HSCT. Thirty percent of patients develop an early infection, with bacteremia accounting for more than two-thirds (69%).40 Grampositive cocci account for more than 80% of all cases and gram-negative bacteria for 19%.40 Among late infections unrelated to engraftment failure, VZV infection is the most frequent, accounting for 15% of cases, with most infections occurring within the first 12 months after transplant. However, the leading cause of death in patients with myeloma

Comprehensive Geriatric Oncology

1426

receiving high-dose chemotherapy was invasive aspergillosis, according to recent postmortem data.40 Lortholary et al51 reported invasive aspergillosis in 31 patients with Durie-Salmon stage 2 (6%) or 3 (94%) myeloma. The median age of the patients was 58 (range 32–71), with a median time between myeloma and invasive aspergillosis diagnoses of 8 months. Sixteen patients (51%) had a neutrophil count of 500/ml or less for a median duration of 19 days. Fourteen patients (45%) had recently received cortocosteroid therapy and 11 (36%) high doses of melphalan. The lung was involved in 28 cases and the sinus in 3. Forty-five percent of patients died of the Aspergillus infection. The major risk factors for invasive aspergillosis were prolonged neutropenia (>2 weeks) and high doses of steroids. Once thought to be an unusual infection in myeloma patients, invasive aspergillosis is expected to increase in incidence as treatment regimens become more intensive. Myelodysplastic syndromes The myelodysplastic syndromes (MDS) occur predominantly in elderly patients and frequently lead to death from complications of cytopenias or transformation to leukemia. Response to chemotherapy is usually short-lived and the infection-related death rate is very high. Lowenthal et al52 gave idarubicin to 14 patients with a median age of 74, with an overall response rate of 14%. Three patients developed life-threatening infections and two died from cytopenia during therapy. Oguma et al53 assessed risk factors for infection in 430 patients with MDS. The frequency of infectious complications was highest just after diagnosis of MDS (4 per 1000 patient-days) and declined rapidly within 4 years of diagnosis (0.3 per 1000 patientdays). The most frequent infections were of the respiratory tract, followed by sepsis and fever of unknown origin (FUO). Sepsis and FUO comprised the highest proportion of complications resulting in death (40%), followed by respiratory tract infections (39%). Staphylococci were the most frequent pathogens isolated. Subtype, dependence on red blood cell transfusions, sex, and age were risk factors for fatal infection. Pomeroy et al54 analyzed 86 patients with MDS to determine the incidence, characteristics, outcome, and risk factors of infection. One infectious complication occurred per patient-year of observation. Bacterial pneumonia and skin abscesses were the most common infections. Infection accounted for the majority of deaths (64%), and was more common than transformation to acute leukemia as a cause of death. Neutropenia and MDS subgroup were independent risk factors for infection. Acute myeloid leukemia For patients older than 55–70 with acute myeloid leukemia (AML), there is a treatmentrelated mortality rate of 25%.55 Those older than 50 with AML often do poorly compared with younger patients. They frequently die during induction therapy, usually as a result of infection during periods of prolonged neutropenia.56 Because elderly patients do not fare well during prolonged periods of neutropenia, chemotherapy regimens that are less myelosuppressive are often used. Low-dose cytarabine was given to 44 patients (median

Management of infectious complications in the aged cancer patient

1427

age 72) with untreated AML for 42 days or less.57 Complete responses occurred in 10 patients (23%), but infection associated with granulocytopenia was the predominant complication.57 Most elderly patients with AML should be treated with intensive chemotherapy.58 However, with intensive chemotherapy programs, the elderly have a greater risk of early death related to drug toxicity or infection.58 In several studies, more than half of patients older than 60 died from complications within 2 months, before receiving an adequate trial of antileukemic therapy.58 However, high-dose cytarabine, a mainstay of the treatment of AML in young patients, is associated with significant neurotoxicity and infectious complications in the elderly, and should not be routinely used in the latter population except in the context of controlled clinical trials.58 Cytotoxic therapy-related epithelial damage in the gut due to high-dose cytarabine correlated with invasive fungal disease.59 Another potential infectious complication of high-dose cytarabine is viridans streptococcal bacteremia complicated by acute respiratory distress syndrome (ARDS), hypotension, and endocarditis.60,61 Multivariate analysis of predisposing factors showed that high doses of cytarabine, the presence of mucositis, and the absence of previous therapy with parenteral antibiotics were independent risk factors for the development of viridans streptococcal bacteremia.60 In another study, 76 patients with newly diagnosed or relapsed AML developed streptococcal bacteremia.62 Pulmonary symptoms developed in 7 patients and death due to respiratory failure occurred in 5 of these 7 patients. The infections all occurred in the phase of maximum myelosuppression 1–3 weeks after the start of chemotherapy. Streptococcal bacteremia was not limited to patients treated with cytarabine but also occurred with the use of other intensive chemotherapy regimens. Marron et al63 reported 88 cases of viridans streptococci bacteremia in neutropenic patients with cancer. Of these, 10 cases (11%) were associated with ARDS. In addition, septic shock developed in 5 of the 10 cases. Severe oral mucositis and high-dose chemotherapy with cyclophosphamide were found to be significantly associated with the development of these complications. Lazarus et al56 concluded that high-dose cytarabine and daunorubicin was an effective antileukemic therapy but was too toxic to recommend for most patients aged over 60 with AML. Life-threatening infection, the major toxicity or complication, consisted of 13 cases of pneumonia, bacteremia, or fungemia, 5 of which resulted in death. Fever, infection, and low Karnofsky performance status at diagnosis predicted an unfavorable outcome, with 6 of 7 patients with all three characteristics dying within 30 days of the start of antileukemic therapy. Another study found that half of 193 patients older than 50 died during induction; 63% of these deaths were due to infection.64 The degree of myelosuppression of the chemotherapy regimen may have been the major limiting toxicity. The mean time to achieve a neutrophil count in excess of 2000/µl in this study was 27 days (range 23–37 days) after the start of either induction or consolidation therapy. Seven patients had antecedent MDS, with impaired bone marrow reserve leading to greater potential for developing serious infection as the period of neutropenia or failure of bone marrow recovery lengthened. Although the best results for AML have been obtained with intensive consolidation chemotherapy, in the elderly this approach carries a higher risk of morbidity and mortality due to toxicity and infection.58 Most elderly patients cannot tolerate more than one to three courses of consolidation treatment.58 The intensity of these programs must

Comprehensive Geriatric Oncology

1428

often be reduced in elderly patients. Because of the intensity of cytoreductive therapy, patients aged over 50 rarely survive bone marrow transplantation and have a higher incidence of graft-versus-host disease.58 Infectious morbidity, myelosuppression profiles, and outcome of antileukemic therapy using standard cytarabine plus daunorubicin (‘7+3’) remission induction therapy and high-dose cytarabine consolidation was studied in treated adult AML.65 For one, two, and three induction courses, the mean number of days for which the patients experienced severe neutropenia (absolute neutrophil count, ANC <500/µl) were 22.5, 39.3 and 47.4 days, respectively. The infection rates were 1.45, 2.45, and 3 infections per course, respectively. The use of multiple induction courses had consequences of prolonged myelosuppression, increased blood product use, and incremental risks of infectious complications. High-dose cytarabine was the most significant factor related to prolonged disease-free survival, and myelosuppression and infection risk were similar to those for the single ‘7+3’ induction courses. After induction chemotherapy with daunorubicin and cytarabine, 124 patients received granulocyte-macrophage colony-stimulating factor (GM-CSF) or placebo if day-10 bone marrow was aplastic without leukemia.55 Median times to neutrophil recovery were reduced with GM-CSF compared with placebo: 13–14 days versus 17–21 days for an ANC >500/µl or 1000/µl, respectively. Similarly, infectious complications were significantly reduced on the GM-CSF arm. Of 30 patients over the age of 65 with newly diagnosed or relapsed AML, GM-CSF resulted in neutrophil recovery 6–9 days earlier than without this cytokine and in rapid clearance of infections in most patients.66 However, in another study, granulocyte colonystimulating factor (G-CSF) given before, during, and after treatment with fludarabine and cytarabine in elderly patients (median age 63) with newly diagnosed AML or MDS had no effect on complete response rates or infection rates.67 Cytokines and antimicrobial prophylaxis combined with an intensive chemotherapy regimen will allow more elderly patients to benefit from high-dose antileukemic therapy.56 In one study, prophylactic penicillin G and ciprofloxacin given to patients receiving remission induction or intensive consolidation treatment for AML significantly reduced infectious morbidity and mortality due to streptococcal and gramnegative bacterial infections, respectively.68 Febrile neutropenia Management of the febrile neutropenic patient is fairly standard, with infectious complications being similar across all age groups. One-third of patients with absolute granulocyte counts (AGC) <500/µl will develop fever or other clinical evidence of infection.69 In 40% of febrile neutropenic patients, no culture-documented infection can be found, but clinical improvement frequently occurs after instituting broad-spectrum antimicrobials.69 Early empiric therapy for febrile neutropenia with combination antipseudomonal antibiotics followed by an antistaphylococcal and antistreptococcal antibiotic and then an antifungal agent has become standard in cancer centers in the USA. Neutropenic episodes (>2 weeks) frequently require antimicrobial modification to control the development of resistant pathogens. Prolonged neutropenia

Management of infectious complications in the aged cancer patient

Figure 60.1 H Lee Moffitt Cancer Center protocol for empiric antibiotic therapy for febrile neutropenic patients.

1429

Comprehensive Geriatric Oncology

1430

(>4 weeks) from failure to induce remission, consecutive chemotherapy cycles with a short pause, and refractory bone marrow aplasia from chemotherapy or the disease itself invariably result in breakthrough infection, usually with resistant gram-negative bacteria and fungal pathogens. Antimicrobial modification beyond 4 weeks is based on suspected likely pathogens, prior antibiotic and antifungal therapy, and toxicity of current therapy. The protocol for the management of febrile neutropenia at the H Lee Moffitt Cancer Center, Tampa, Florida is presented in Figure 60.1. The duration of granulocytopenia appears to be the most useful index for gauging the risk for infectious complications.70 Whereas less than 30% of patients with short-term neutropenia (<1 week) develop fever or evidence of infection, 100% of patients with long-term neutropenia (>1 week) will do so.70 The longer the period of neutropenia, the more serious are the infectious complications.70 For example, the risk of Aspergillus infection in patients with leukemia increases from 1% per day during the first several weeks of neutropenia to greater than 4% per day after 3 weeks.71 In addition to knowing the predominant pathogens for each week of neutropenia, the infectious diseases acquired during prior periods of neutropenia may be very crucial with certain fungi and viruses. Aspergillus pneumonia and herpes simplex stomatitis have recurrence rates with subsequent neutropenia of 50% and 40–80%, respectively, unless prophylactic or early empiric therapy directed at each organism is initiated. Inpatient management of neutropenia associated with therapy of hematologic malignancies is necessary because of transfusional, nutritional, and antimicrobial requirements during this period. Because patients with cancer, neutropenia, and fever do not make up a homogenous group, Talcott et al69 developed a risk stratification system. Presenting clinical features were used to identify groups that could be managed with less medical supervision, paving the way for outpatient management. Patients with anticipated short-term neutropenia (<1 week), who generally have benign outcomes, can be safely managed as outpatients. Conversely, patients with a high risk of infectious complications are those with prolonged neutropenia (>10 days), and with comorbid medical conditions, including severe mucositis, hemorrhage, dehydration, renal or hepatic insufficiency, cardiac or circulatory failure, or neurologic deficits.72 High-risk patients also include those with severe infections such as bacteremia, pneumonia, catheter tunnel infection, or cellulitis, especially if they are hospitalized at the time of onset of the fever, as well as patients whose hematologic malignancies are not controlled by treatment.72 Outpatient treatment for short-term low-risk febrile neutropenia can be successfully done with G-CSF or GM-CSF and a quinolone plus augmentin or clindamycin until resolution of neutropenia. In two studies, oral outpatient therapy of low-risk febrile neutropenic patients that included ciprofloxacin 750mg twice daily and amoxicillinclavulomate 875mg twice daily was found to be as effective as intravenous antibiotic therapy.73,74 Although advanced age may be a significant risk factor, many elderly patients can be treated as outpatients if they are functional, otherwise healthy, and compliant with the recommended treatment protocol. In general, therapy for older patients with malignancy is becoming more intensive. As oncologists push the limits of chemotherapy to improve disease-free survival in the older cancer patient, the use of cytokines and prophylactic and early empiric antimicrobial therapy with subsequent modification of the latter is crucial to reduce infection-related mortality.

Management of infectious complications in the aged cancer patient

1431

References 1. Norman DC, Toledo SD. Infections in elderly persons. Clin Geriatr Med 1992; 8:713–19. 2. Crossley KB, Peterson PK. Infections in the elderly. In: Principles and Practice of Infectious Diseases, 4th edn (Mandell GL, Bennett JE, Dolin R, eds). New York: Churchill Livingstone, 1995:2737–42. 3. Gleckman RA, Hibert D. Afebrile bacteremia—a phenomenon in geriatric patients. JAMA 1982; 248:1478. 4. Crossley KB, Peterson PK. Infections in the elderly. Clin Infect Dis 1996; 22:209–15. 5. Esposito AL, Gleckman RA. Fever of unknown origin in the elderly. J Am Geriatr Soc 1979; 26:498. 6. Schwab R, Walters CA, Weksler ME. Host defense mechanisms and aging. Semin Oncol 1989; 16:20–7. 7. Ben-Yehuda A, Weksler ME. Host resistance and the immune system. Clin Geriatr Med 1992; 8:701–11. 8. Charpentier B, Fournier C, Fries D et al. Immunological studies in human ageing: I. In vitro function of T-cells and polymorphs. J Clin Lab Immunol 1981; 5:87. 9. Wayne SJ, Rhyme RL, Garry PJ et al. Cell-mediated immunity as a predictor of morbidity and mortality in subjects over 60. J Gerontol 1990; 45:M45. 10. Brewer VH, Hahn KA, Rohrbach BW et al. Risk factor analysis for breast cellulitis complicating breast conservation therapy. Clin Infect Dis 2000; 31:654–9. 11. Ershler WB. Introduction: Geriatric oncology comes of age. Semin Oncol 1989; 16:1–2. 12. Yoshikawa TT. Epidemiology and unique aspects of aging and infectious diseases. Clin Infect Dis 2000; 30:931–3. 13. Marrie TJ. Epidemiology of community-acquired pneumonia in the elderly. Semin Respir Infect 1990; 5:260. 14. Rajul L, Khan F. Pneumonia in the elderly. Geriatrics 1988; 43:51. 15. Valenti WM, Trudell RG, Bentley DW. Factors predisposing to oropharyngeal colonization with gram-negative bacilli in the aged. N Engl J Med 1978; 298:1108. 16. Crossley KB, Thurn JR. Nursing home-acquired pneumonia. Semin Respir Infect 1989; 4:64– 72. 17. Dutt AK, Stead WW. Tuberculosis. Clin Geriatr Med 1992; 8:761–75. 18. Holden M, Dubin MR, Diamond PH. Frequency of negative intermediate-strength tuberculin sensitivity in patients with active tuberculosis. N Engl J Med 1971; 285:1506. 19. Falsey AR, Viral respiratory tract infections in elderly persons. Infect Dis Clin Pract 1996; 5:53–58. 20. Falsey AR, Cunningham CK, Barker WH et al. Respiratory syncytial virus and influenza A in the hospitalized elderly. J Infect Dis 1995; 172:389–94. 21. Mathur U, Bentley DW, Hall CB. Concurrent respiratory syncytial virus and influenza infections in the institutionalized elderly and chronically ill. Ann Intern Med 1980; 93:49–52. 22. Johnson LE. Chronic lymphocytic leukemia. Am Fam Pract 1988; 38: 167–76. 23. Molica S, Levato D, Levato L. Infections in chronic lymphocytic leukemia. Analysis of incidence as a function of length of follow-up. Haematologica 1993; 78:374–7. 24. Whitley TH, Graybill JR, Alford RH. Pulmonary cryptococcosis in chronic lymphocytic leukemia. South Med J 1976; 69:33–6. 25. Kauffman CA, Israel KS, Smith JW et al. Histoplasmosis in immunosuppressed patients. Am J Med 1978; 65:923–32. 26. Deresinski SC, Stevens DA. Coccidioidomycosis in compromised hosts: experience at Stanford University Hospital. Medicine 1975; 54: 377–95. 27. Young LS, Armstrong D, Bleuint A et al. Nocardia asteroides infection complicating neoplastic disease. Am J Med 1971; 50:356–67.

Comprehensive Geriatric Oncology

1432

28. Torok L, Viragh SZ, Borka I et al. Bacillary angiomatosis in a patient with lymphocytic leukaemia. Br J Dermatol 1994; 130:665–8. 29. Robertson TI. Complications and causes of death in B cell chronic lymphocytic leukemia: a long term study of 105 patients. Aust NZ J Med 1990; 20:44–50. 30. Griffiths H, Lea J, Bunch C et al. Predictors of infection in chronic lymphocytic leukaemia. Clin Exp Immunol 1992; 89:374–7. 31. Itala M, Helenius H, Nikoskelainen J et al. Infections and serum IGG levels I in patients with chronic lymphocytic leukemia. Eur J Haematol 1992; 48:266–70. 32. Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia. Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia. N Engl J Med 1988; 319:902–7. 33. Sklenar I, Schiffman G, Jnsson V et al. Effect of various doses of intravenous polyclonal IgG on in vivo levels of 12 pneumococcal antibodies in patients with chronic lymphocytic leukaemia and multiple myeloma. Oncology 1993; 50:466–77. 34. Boldt DH, Von Hoff DD, Kuhn JG et al. Effects of human peripheral lymphocytes of in vivo administration of 9-β-D-arabmofuranosyl-2-fluoroadenine-5-monophosphate (NSC 312887), a new purine antimetabolite. Cancer Res 1984; 44:461–6. 35. Scully RE, Mark EJ, McNeely WF et al. Case records of the Massachusetts General Hospital. N Engl J Med 1994; 330:557–64. 36. Anaissie E, Kontoyiannis DP, Kantarjian H et al. Listeriosis in patients with chronic lymphocytic leukemia who were treated with fludarabine and prednisone. Ann Intern Med 1992; 117:466–9. 37. Cleveland KO, Gelfand MS. Listerial brain abscess in a patient with chronic lymphocytic leukemia treated with fludarabine. Clin Infect Dis 1993; 17:816–17. 38. Girmenia C, Mauro FR, Rahimi S. Late listeriosis after fludarabine plus prednisone treatment. Br J Haematol 1994; 87:407–8. 39. Furman AC, Sepkowitz KA. Infections in patients with multiple myeloma. Infect Med 1995; 12:353, 356, 351–62. 40. Paradisi F, Corti G, Cinelli R. Infections in multiple myeloma. Infect Dis Clin North Am 2001; 15:373–84. 41. Rayner HC, Haynes AP, Thompson JR et al. Perspectives in multiple myeloma: survival, prognostic factors and disease complications in a single centre between 1975 and 1988. Q J Med 1991; 79:517–25. 42. Jacobson DR, Zolla-Pazner S. Immunosuppression and infection in multiple myeloma. Semin Oncol 1986; 13:282–90. 43. Savage DG, Lindenbaum J, Garrett TL. Biphasic pattern of bacterial infection in multiple myeloma. Ann Intern Med 1982; 96:47–50. 44. Espersen F, Frimodt-Milner N, Rosdahl VT et al. Staphylococcus aureus bacteremia in patients with hematological malignancies and/or agranulocytosis. Acta Med Scand 1987; 222:465–70. 45. Doughney KB, Williams DM, Penn RL. Multiple myeloma infectious complications. South Med J 1988; 81:855–8. 46. Goranov S. Clinical problems of infectious complications in patients with multiple myeloma. Fol Med 1994; 36:41–6. 47. Hargreaves RM, Lea JR, Griffiths H et al. Immunological factors and risk of infection in plateau phase myeloma. J Clin Pathol 1995; 48: 260–6. 48. Chapel HM, Lee M, Hargreaves R et al. Randomized trail of intravenous immunoglobulin as prophylaxis against infection in plateauphase multiple myeloma. The UK Group for Immunoglobulin Replacement Therapy in Multiple Myeloma. Lancet 1994; 343: 1059–63. 49. Chapel HM, Lee M. The use of intravenous immune globulin in multiple myeloma. Clin Exp Immunol 1994; 97: S2–24.

Management of infectious complications in the aged cancer patient

1433

50. Chapel HM. Consensus on diagnosis and management of primary antibodies deficiencies. Consensus panel for the diagnosis and management of primary antibody deficiencies. BMJ 1994; 308:913–18. 51. Lortholary O, Ascioglu S, Moreau P et al. Invasive aspergillosis as an opportunistic infection in non-allografted patients with multiple myeloma: European Organization for Research and Treatment of Cancer. Clin Infect Dis 2000; 30:41–6. 52. Lowenthal RM, Lambertenghi-Deliliers G. Oral idarubicin as treatment for advanced myelodysplastic syndrome. Haematologica 1991; 76:398–401. 53. Oguma S, Yoshida Y, Uchino H et al. Infection in myelodysplastic syndromes before evolution into acute non-lymphoblastic leukemia. Int J Hematol 1994; 60:129–36. 54. Pomeroy C, Oken MM, Rydell RE et al. Infection in the myelodysplastic syndromes. Am J Med 1991; 90:338–44. 55. Rowe JM, Anderson JW, Mazza JJ et al. A randomized placebocontrolled phase III study of granulocyte—macrophage colony-stimulating factor in adult patients (>55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood 1995; 86:457–62. 56. Lazarus HM, Vogler WR, Burns P et al. High-dose cytosine arabinoside and duanorubicin as primary therapy in elderly patients with acute myelogenous leukemia. Cancer 1989; 63:1055–9. 57. Powell BL, Copizzi RL, Muss MB et al. Low-dose ARA-C therapy for acute myelogenous leukemia in elderly patients. Leukemia 1989; 3: 23–8. 58. Champlin RE, Gajewski JL, Golde DW. Treatment of acute myelogenous leukemia in the elderly. Semin Oncol 1989; 16:51–6. 59. Bow EJ, Loewen R, Cheang MS et al. Invasive fungal disease in adults undergoing remissioninduction therapy for acute myeloid leukemia: the pathogenic role of the antileukemic regimen. Clin Infect Dis 1995; 21:361. 60. Boshud P-Y, Eggiman PH, Calandra TH et al. Bacteremia due to viridans streptococcus in neutropenic patients with cancer: clinical spectrum and risk factors. Clin Infect Dis 1994; 18:25–31. 61. Tasaka T, Nagai M, Sasaki K et al. Streptococcus mitis septicemia in leukemia patients; clinical features and outcome. Intern Med 1993; 32:221–3. 62. vander Lelie H, Vanketel RJ, von dem Borne AE et al. Incidence and clinical epidemiology of streptococcal septicemia during treatment of acute myeloid leukemia. Scan J Infect Dis 1991; 23:163–8. 63. Marron A, Carratala J, Gonzalez-Barca E et al. Serious complications of bacteremia caused by viridans streptococci in neutropenic patients with cancer. Clin Infect Dis 2000; 31:1126–30. 64. Estey EH, Keating MJ, McCredie KB et al. Causes of remission induction failure in acute myelogenous leukemia. Blood 1982; 60:309–15. 65. Bow EJ, Kilpatrick MG, Scott BA et al. Acute myeloid leukemia in Manitoba. The consequences of standard ‘7+3’ remission-induction therapy followed by high dose cytarabine post remission consolidation for myelosuppression, infectious morbidity, and outcome. Cancer 1994; 74:52–60. 66. Buchner T, Hiddemann W, Koenigsmann M et al. Recombinant human granulocytemacrophage colony-stimulating factor after chemotherapy in patients with acute myeloid leukemia at higher age or after relapse. Blood 1991; 78:1190–7. 67. Estey E, Thall P, Andreeff M et al. Use of granulocyte colony-stimulating factor before, during, and after fludarabine plus cytarabine induction therapy of newly diagnosed acute myelogenous leukemia or myelodysplastic syndromes: comparison with fludarabine plus cytarabine without granulocyte colony-stimulating factor. J Clin Oncol 1994; 12:671–8. 68. de Jong P, de Jong M, Kuijper E et al. Evaluation of penicillin G in the prevention of streptococcal septicaemia in patients with acute myeloid leukaemia undergoing cytotoxic chemotherapy. Eur J Clin Microbiol Infect Dis 1993; 12:750–5.

Comprehensive Geriatric Oncology

1434

69. Talcott JA, Finberg R, Mayer RJ et al. The medical course of cancer patients with fever and neutropenia. Arch Intern Med 1988; 148: 2561–8. 70. Lee JW, Pizzo PA. Management of the cancer patient with fever and prolonged neutropenia. Hematol Oncol Clin North Am 1993; 7: 937–60. 71. Gerson SL, Talbott GH, Hurwitz S et al. Prolonged granulocytopenia: the major risk factor for invasive pulmonary aspergillosis in patients with acute leukemia. Ann Intern Med 1984; 100:345–51. 72. Glauser MP, Pizzo PA, Calandra T. Infections in patients with hematologic malignancies. In: Management of Infections in Immunocompromised Patients (Glauser MP, Pizzo PA, Calandra T, eds). London: Harcourt, 2000:141–88. 73. Freifeld A, Marchigiam M, Walsh T et al. A double-blind comparison of empirical oral and intravenous antibiotic therapy for low-risk febrile patients with neutropenia during cancer chemotherapy. N Engl J Med 1999; 341:305–11. 74. Kern WV, Cometta A, DeBoeck R et al. Oral versus intravenous empiric antimicrobial therapy for fever in patients with granulocytopenia who are receiving cancer chemotherapy. N Engl J Med 1999; 341:313–18.

61 Symptom management in the older person Robert Anderson, Walter B Forman Introduction Symptoms related to the malignancy and its site of origin and spread are often a difficult experience for the cancer patient because of their adverse effect on quality of life. Each malignancy can have its own associated symptoms (e.g. lung cancer and dyspnea, and multiple myeloma and bone pain), as well as symptoms that are common to people with cancer (e.g. weight loss, fatigue, and depression). Polypharmacy adds to the difficulty in dealing with this complex situation in the elderly. When prescribing medications for symptom control, the primary practitioner must be aware of these issues and further, be informed of all over-the-counter medications and herbs that the patient is taking. Thus, with the goal of optimizing quality of life for patients with cancer, a clear history of the symptom(s), as well as the patients’ medication history, must be carefully obtained. With this in mind, we shall, in this chapter, address some of the common symptoms and therapies faced by patients, their families, and the healthcare professional. Symptoms in older persons with cancer A symptom represents the condition that accompanies a disease state. We have expanded the word in medical jargon to include conditions that may result from treatment as well. In this chapter, the word ‘symptom’ is used to designate a condition that is a result of the illness or its treatment. For example, nausea and vomiting can result from the stomach’s inability to expand during eating as a direct result of the cancer occupying the space that would have been utilized for this purpose or as a side-effect of chemotherapy. Our concentration will be toward the former, a discipline known as palliative medicine. Palliative medicine is formally defined as ‘the study and management of patients with active, progressive, far advanced disease for which the prognosis is limited and the focus of care is quality of life’.1 In palliative medicine, a thorough understanding of the pathophysiology that causes a symptom is required in order that the appropriate treatment regimen be selected. However, the reader should be aware that a holistic approach requires the healthcare provider to consider other issues, such as psychosocial factors and spiritual concerns for the individual reaching the end of life. In patients with advanced cancer, the illness can be associated with symptoms related to the tumor itself, its therapy, on the debility that is often associated with it (for the case of pain symptoms, see Table 61.1 below). Thus, the clinician must distinguish the cause of a symptom in order to treat it effectively.

Comprehensive Geriatric Oncology

1436

There is an emerging database indicating that symptoms are critical in determining survival.2 Similar symptoms can be associated with major differences in terms of prognosis (e.g. constipation secondary to opioids versus that due to bowel obstruction). On the other hand, some symptoms (e.g. pain, fatigue, and weight loss) can be associated with all phases of the illness and not necessarily with prognosis. In this case, the clinician is faced with one of the most difficult problems in cancer: Does the symptom help in predicting survival? Most experienced clinicians will utilize the stage of the disease and performance status of the patient to arrive at a ‘prognosis’. It is becoming clearer, however, that the symptom complex associated with the malignancy is of importance in this area, as well as the stage and performance status. For further information on the subject of symptoms and their role in prognosis, the reader is referred to Chang’s excellent review.3 Although some of the information presented in this chapter can be applied to all patients with cancer, the reader should appreciate that we are addressing, in the main, persons for whom cure is no longer possible. Assessing the symptom(s) In general, we are dealing here with knowing the history of the illness, both past and present. The clinician, especially in caring for the older person, might find this ‘timeconsuming’, since the older person, more often than the younger person, will not be as forthcoming. This has been attributed to a wish not to interfere with the Doctor’s busy day or a belief that the symptom is simply part of the aging process and of no particular clinical importance. Therefore, it is our practice to utilize a simple symptom assessment form that the person can complete in the waiting room. When the patient is brought into the consultation office, the healthcare provider has available to them the major concerns of the patient for this visit. The clinician can quickly begin to explore these problems, evaluate them, and prescribe treatment. We have modified the validated Edmonton Symptom Assessment Score4 to fit our needs. At the Senior Health Center at The University of New Mexico Health Sciences Center, we have been able to demonstrate its usefulness.5 The 10 symptoms assessed are pain, constipation, mood, shortness of breath, activity, nausea, appetite, sleep, anxiety, and quality of life. The patient marks on a 0–10 scoreline (where 0 is none and 10 is the worst) a level at which they consider a particular symptom is affecting them. We have shown that these symptoms, as in other studies of individuals with cancer, appear to be the most common symptoms that need to be addressed.6,7 The ‘score’ is measured by a paramedical person and recorded on the patients’ symptom assessment score (SAS), which is similar to a vital sign graphic. Pain The issue of pain in the older person can be divided into not only the types of pain but also the condition of the individual with regard to their mental and social status.8 When living independently, pain is usually noted more frequently in patients over the age of 60.9 When one examines the long-term care facilities where one might anticipate more infirmed people, the prevalence of pain is even greater, ranging from 45% to 80%.10 It

Symptom management in the older patient

1437

should be clear that as pain increases, it interferes with activities of daily living, especially in individuals with cancer. Yet professionals are seemingly unaware of this problem. When surveyed, a third of nurses believed that pain and discomfort were unavoidable consequences of aging. Further, in a study of oncologists, pain assessment was the greatest barrier to effective cancer pain management.11,12 Brescia et al,13 in a chart survey of patients admitted to Calvary Hospital (an inpatient hospice/palliative care facility), noted that 73% of patients reported pain to be a problem. In our studies in rural New Mexico, the incidence of pain as a major symptom was exactly the same. Mental status is of great importance in pain assessment.14 A variety of assessment tools are available; however, not all have been tested in the older patient population. Patients with cognitive abnormalities housed in long-term care facilities may fare poorly when these tools are utilized. When the person cannot communicate their pain, it can be easily ignored and misinterpreted by others.15 Other factors that interfere with pain assessment include psychological issues, particularly depression, the individual’s quality of life, and physically challenged persons. Although we cannot in this chapter address the mechanism(s) that lead to pain syndromes, the reader should review the article by Lipman and Gauthier.16 Three types of pain presentations are recognized: somatic, visceral (nociceptive), and neuropathic. Somatic pain is characterized by the individual as stabbing, throbbing, aching, dull, sharp, or cramping. It is well localized and is a result of the stimulation of nociceptive receptors. This type of pain is associated with bone metastases, soft tissue infiltration, and postoperative pain. Visceral pain associated with abdominal complaints is often described as a constant ache, occasionally cramping, is poorly localized, and is often associated with nausea. Primary or metastatic tumors (e.g. liver metastases) tend to distend, infiltrate, compress, or stretch the thoracic or abdominal viscera. Visceral pain is often projected to other areas of the body. For example, left shoulder pain may occur when the left hemidiaphragm is irritated. Neuropathic pain is diagnosed by the unusual symptom(s) of intermittent burning, lancinating, tingling, and/or shooting pain. Peripheral nerves may also be damaged by trauma, radiation, or during chemotherapy with the vinca alkaloids or cisplatin. Some common causes of pain in the cancer patient are shown in Table 61.1. Non-pharmacologic techniques of pain control Various non-pharmacologic techniques, including relaxation, distraction, imagery, music, assistance with positioning, mobility, and touch, have been used with some success in relieving pain. It has been demonstrated that individuals tend to choose methods based on personal preference as well as choosing physical over cognitive methods.17 Physical methods include cutaneous stimulation (e.g. massage), thermal manipulation, vibration, pressure, exercises, immobilization, transcutaneous electrical nerve stimulation (TENS), and acupuncture. Cutaneous stimulation is utilized for pain that involves muscle tension, exercise is reliant on physical stamina, and TENS and acupuncture are counterstimulation techniques. Psychological techniques are aimed at coping skills to deal with the pain so that the person gains a sense of control over the pain.

Comprehensive Geriatric Oncology

1438

Pharmacologic approaches to pain control Before beginning therapy, the clinician must consider the factors that affect drug metabolism in the elderly. These

Table 61.1 Common etiologies of pain associated with cancer Unrelated to the cancer For example, spinal stenosis Directly initiated by the cancer Infiltmtion of an organ •

Bone—aching, localized

•

Peripheral nerve (can also compress)—burning, electrical, intermittent

•

Soft tissue—aching, throbbing, localized

•

Hollow viscus—colic, vague, dot-localized

•

Solid organ—capsule stretch (e.g. hepatic metastasis)

Remote effects •

Neuropathies

•

Myopathies

Resulting from treatment Radiation therapy •

Fibrosis

•

Neuropathy—brachial plexus

•

Lymphedema

•

Inflammation of parietal surfaces—pericardial

Surgery •

Incisional

•

Neuropathic—thoracic nerve interruption

•

Phantom limb

Chemotherapy •

Polyarthritis

•

Aseptic necrosis of femoral head

•

Neuropathies

Symptom management in the older patient

•

1439

Inflammation of parietal surfaces—pleura

include age-related physiologic changes in drug metabolism, polypharmacy, increased incidence of side-effects, and the presence of multiple chronic illnesses. As noted earlier, it is important to know what over-the-counter medications and home remedies are being employed. The prescriber should always keep the medication regimen simple and the number of medications at a minimum, use the simplest dosage schedule, and employ the least invasive pain management. Oral medications are preferred because of convenience and cost, and in general smaller doses are able to produce the desired therapeutic response in the older person.18 Opioids In the setting of chronic pain, only the pure opioid agonists (e.g. morphine, oxycodone, hydromorphone, fentanyl, and methadone) should be considered. For mild to moderate pain, an opioid plus a non-opioid is recommended.1 If pain is severe (i.e. >6/10), a strong opioid such as morphine or oxycodone should be initiated. For patients who are elderly and for whom the multiple factors listed above are not clear, the use of an immediate release (IR) preparation should be employed. Within 24–48 hours, the total 24-hour dose of the IR preparation can be determined and converted to the sustained release preparation, if appropriate. Opioids have no ceiling effect; therefore, it is appropriate to titrate the dose upwards to pain relief or unacceptable toxicity. In the clinical situation of opioid-responsive pain where there is inadequate pain relief together with toxicity, switching to another opioid (opioid rotation) is advised.19 Table 61.2 lists suggested equianalgesic conversions for these situations. In some situations, the person might experience a sudden increase in pain, known as ‘breakthrough pain’. In this clinical situation, one should prescribe an opioid dose approximately 10% of the total daily opioid dosage. It is prescribed as needed at a dosing interval of 1–4 hours; no longer than the half-life of the agent used. Meperidine and propoxyphene are not recommended agents, since both have toxic metabolites (normeperidine and norpropoxyphene) that can accumulate, leading to central nervous system toxicity in the form of tremors, confusion, and seizures. Methadone can be a difficult agent in the elderly because it has a very long half-life (12–120 hours) and is cleared by renal mechanisms. However, as a ‘broad-spectrum’ pain reliever that acts with additive mechanisms to opioid receptor activation, it can be a very useful medication when employed properly. The most distressing problems noted in the elderly when the opioids are utilized to treat severe pain include sedation and constipation. Sedation is often associated

Table 61.2 Equianalgesic dosing of opioid agonists Opioid

Equianalgesic dose

Morphine

60 mg (p.o.)

Methadone

6–20 mg (p.o.)

Potency related to Ratio to convert oral to morphine parenteral dose

Half-life (hours)

1

3:1

2–4

3–10

1:1

12–120

Comprehensive Geriatric Oncology

Hydromorphone 12 mg (p.o.)

1440

5

3:1

2–3

Oxycodone

30–60 mg (p.o.)

1–2

N/A

3–4

Fentanyl

25 |ig (transdermal)

100

N/A

0.5

with sleep deprivation secondary to pain, and will gradually decrease over several days. In the setting of refractory sedation, rotation to another opioid or the use of an adjuvant stimulant can prove beneficial. Constipation, on the other hand, does not diminish, and (if not contraindicated) a laxative regimen should be initiated with opioid therapy.12 This situation and its treatment are discussed below. Adjuvant drugs Adjuvant drugs are used to enhance the analgesic efficacy of opioids, treat concurrent symptoms that exacerbate pain (e.g. increased intracranial pressure), as well as to provide independent analgesia for specific types of pain. Non-steroidal anti-inflammatory drugs (NSAIDs) NSAIDs are effective in a variety of pain situations, including pain due to bone metastases, soft tissue infiltration, hypertrophic pulmonary osteoarthropathy, arthritis, serositis, and acute postoperative pain.20,21 These pain situations are mediated by prostaglandin production, which in turn sensitizes nociceptive receptors, causing the pain response. NSAIDs interfere with prostaglandin synthesis and do not activate opioid receptors. Thus, the combination of NSAIDs and opioids is often synergistic and allows for the use of a reduced dose of opioids. NSAIDs have a ceiling effect, i.e. a maximum dose at which further increases result only in toxicity with no increase in analgesic effect. In the elderly, multiple adverse side-effects to the NSAIDs have been demonstrated.12 Gastrointestinal intolerance occurs in over half of elderly patients, manifest as dyspepsia and duodenal and gastric ulceration. The H2-receptor antagonists (e.g. ranitidine) are adequate for the treatment of dyspepsia; however, prophylaxis or treatment of ulceration will require a proton pump inhibitor (e.g. omeprazole) or the mucosal protective agent misoprostol.22 In the elderly patient with a history of ulcerative disease, NSAID doses should be decreased or, if possible, therapy should be discontinued.23 This also holds true for the patient with congestive heart failure, dehydration, a history of renal disease, hypertension, or female gender, and those on diuretic therapy, since there can be a significant increase in side-effects. NSAID/steroid combinations should be avoided, since their gastrointestinal toxicity is extremely high. Because the non-acetylated salicylates (salsalate, sodium salicylate and choline magnesium trisalicylate) have minimal effects on platelet aggregation and do not alter bleeding time, they are to be considered the NSAIDs of clinical choice in the elder patient.24 Acetaminophen (paracetamol), although often used, has little anti-inflammatory activity.

Symptom management in the older patient

1441

Other adjuvant agents Corticosteroids are among the most commonly used adjuvant drugs. They are potent antiinflammatory agents and can enhance both mood and appetite. In pain treatment, they work best in the setting of acute nerve entrapment, increased intracranial pressure, visceral distention, and soft tissue infiltration. In addition to the usual complications when using steroids, patients on long-term use can develop a severe proximal myopathy. Neuropathic pain that is associated with nerve compression, entrapment, or infiltration can be initially treated with the tricyclic antidepressants amitriptyline, desipramine or, in the elderly, nortriptyline. Tricyclic antidepressants may cause orthostatic hypertension and clumsiness in the elderly. Treatment regimens should begin with small doses (10–25 mg at bedtime) and increased by 10–25 mg every 2–4 days toward a maximum dose of 150mg. Lancinating pain responds to anticonvulsants such as carbamazepine, sodium phenytoin or gabapentin. Nerve blocks can be very effective in relieving neuropathic pain, particularly in a single dermatome distribution. Portenoy25 has given a complete review of this subject. Fatigue (weakness) Fatigue is a common and extremely distressing symptom for the patient with advanced cancer, and is a very difficult symptom to diagnosis and treat. Further, a paucity of comprehensive assessment tools increase the complexity and decrease the validity of the clinical decision-making process. Two validated assessment instruments used for fatigue include the multidimensional Piper Fatigue Self-Report Scale and the Functional Assessment of Cancer Therapy, a general tool for assessing quality of life, which contains a specific fatigue scale.26 It is generally accepted that fatigue is a multidimensional phenomenon involving biochemical, behavioral, psychological, and pathophysiologic components. Some probable etiologies of fatigue or processes that may intensify fatigue in the patient with advanced cancer are listed in Table 61.3. The appropriate management of fatigue must include correcting and/or treating these causes whenever possible. Several non-pharmacologic approaches may be used to manage fatigue. Some patients will benefit from education about the process of fatigue.27 Care must be taken to individualize the educational encounter to each patient. A patient diary that chronicles fatigue will often provide important information for both the patient and the clinician.26 The gradual institution of an exercise program may provide significant relief. This approach is often enhanced with involvement by rehabilitation medicine, which can help insure that proper education and an individualized

Table 61.3 Potential causes of fatigue in the elderly cancer patient • The underlying disease • Treatment of the disease (e.g. chemotherapy, immunotherapy, radiotherapy, surgery)

Comprehensive Geriatric Oncology

1442

• Medications (centrally acting agents, e.g. opioids, tricyclic antidepressants) • Anemia (resulting from the disease or from its therapy) • Metabolic disorders (e.g. hypercalcemia) and/or dehydration • Sleep disorders • Anxiety or depression • Coping difficulties with the disease or its therapy • Chronic pain • Immobility and lack of exercise • Concurrent morbidity (e.g. infection, pulmonary dysfunction, renal/hepatic dysfunction, heart failure) • Malnutrition

program be established for each patient. The assessment of sleep hygiene and the establishment of routine sleep patterns may also relieve fatigue.28 Behavioral medicine may provide stress management techniques or cognitive therapies that help alleviate fatigue. Finally, proper nutrition and hydration should be addressed with a referral to a dietician.29 The pharmacologic approach to fatigue in the elderly patient should first be tied to the cause if determined. Chronic pain, anemia, anxiety, and depression are examples of potential causes in which fatigue may be positively influenced with appropriate medication. When the specific cause cannot be determined or when pharmacologic treatment of suspected causes fails to relieve fatigue, psychostimulants provide an ofteneffective approach. Psychostimulants This class of agents, including methylphenidate, pemoline, and dextroamphetamine, have demonstrated efficacy in the setting of opioid-related sedation and depression in the elderly cancer patient.30 While no controlled trials exist for cancer-related fatigue, empiric use may be beneficial for some patients. These agents have slightly different mechanisms of action, so the use of one following failure by another is rational therapy. Initial doses of methylphenidate and dextroamphetamine begin at 5 mg every morning, with a second dose at noon if needed. Total daily doses of 40–60 mg are generally sufficient, although higher doses have been used. Pemoline is generally initiated at 18.75 mg/day, titrated to 75 mg/day, administered as one daily dose in the morning. One advantage of pemoline is its availability as a chewable tablet that is absorbed through the buccal mucosa. However, a clear disadvantage is the rare occurrence of liver failure; thus, pemoline should be reserved as a final option. In an effort to prevent interference with normal sleep, these agents should not be dosed after noon. Adverse events associated with these agents include anxiety, anorexia, tremulousness, insomnia, delirium, and tachycardia. Slow and careful titration to optimal effect may help diminish potential sideeffects.31

Symptom management in the older patient

1443

Anorexia/cachexia Anorexia is a common problem for the elderly cancer patient, and is characterized by the loss of their desire to eat. The primary consequence of anorexia is weight loss. Given the social nature of eating and the effect of weight loss, anorexia can have a profound negative impact on the patient’s quality of life. Potential causes of anorexia, such as pain, nausea and/or vomiting, dysmotility, and depression, should be targeted with appropriate treatment. When the etiology of anorexia is less well defined, good mouth care, nutritional assessment, and appetite stimulants play a major therapeutic role. Cachexia is a more complex syndrome, of which anorexia is one component. In addition to metabolic and hormonal changes, cytokine abnormalities, primarily involving tumor necrosis factor, interleukins-1 and -6, and interferon-α, appear to be necessary for cachexia to occur.32,33 The complexity of the interaction between tumor and host that results in cachexia makes this syndrome extremely difficult to treat. Chronic nausea, asthenia, constipation, further loss of lean body mass, and altered carbohydrate and lipid metabolism further complicate attempts to palliate cachexia. Nutritional supplementation with enteral or parenteral feeding is controversial. Several clinical trials examining aggressive nutritional support have failed to show any significant nutritional improvement or lengthening of survival.33 At present, nutritional support should be reserved for the malnourished patient scheduled for surgery or other antineoplastic therapy. If nutritional support is appropriate, enteral feeding should be used first, with parenteral feeding reserved for the patient with good performance status and good appetite who cannot swallow. Good mouth care is important for maintaining a good appetite. Poor oral hygiene can result in infections, such as Candida (which can cause a metallic taste), and lesions to the mucosa (which can lead to decreased food intake).34 Patients actively being treated with chemotherapy may be at increased risk for mucositis and may also develop aversions to certain foods. Some helpful suggestions for appetite and nourishment are found in Table 61.4. Not all suggestions will be suitable for all patients—individualize the selection to each patient. Some patients may have relatively minor problems with appetite but significant

Table 61.4 Recommendations to patients for appetite and nourishment • Take as much nourishment as possible when your appetite is good. Find ways of encouraging good eating when your appetite is diminished; for example, eat with friends, listen to music while eating, serve foods that look and smell good, and eat small portions • Take advantage of uptime, eat when you feel better; appetite is often better in the morning; put on weight when you can, since it may be lost later • Supplement your diet with high-calorie/high-protein foods, enriched butter, cream, dressings, mayonnaise, whipped cream, milkshakes, dried fruits, hot chocolate, sour cream, gravy, ice cream, cream soups, enriched protein drinks, and instant breakfast shakes • Use double-strength milk—add a cup of non-fat dry milk powder per quart of whole milk and use any time milk is used, for example with hot or cold cereal or instant breakfast shakes

Comprehensive Geriatric Oncology

1444

• Prepare and freeze meals for times when you don’t feel like cooking • Keep high-protein snacks and drinks on hand • If food tastes bad, avoid red meat, which can have a bitter taste; substitute fish or fowl • Use eggs and dairy products to supplement protein intake • Put meat in casseroles or soup to mask the flavor • For swallowing problems, use tender, chopped cuts of meat, put gravy or sauces on meat to make the chewing easier, use pureed meats, vegetables, or even baby foods • For dry mouth, use soft foods, drink plenty of fluids, use pureed foods, add gravy, margarine, or butter. Avoid acidic, salty, and coarse (e.g. toast, cookies, and cakes) foods • Use bland, moist, soft foods if mouth sores are present • Eat small, frequent meals when feeling queasy or nauseated. Sipping small amounts of liquid slowly through a straw can sometimes help queasiness. Eat slowly to avoid ingestion of air, and avoid gassy foods (onions, green pepper, and beans)

problems with taste. For these patients, a trial of 100mg elemental zinc three times daily may provide a benefit. Megestrol acetate Several clinical trials have demonstrated the nutritional benefits of megestrol acetate in patients with advanced cancer.35 This agent has been shown to improve appetite, caloric intake, and nutritional status, and to increase the deposition of fat. It has further been shown to improve other symptoms, including reducing fatigue, providing a sense of wellbeing, and thus enhancing quality of life. Megesterol acetate can be given as a single morning dose, starting at 200 mg/day and titrating to effect with 200 mg every 3–5 days to a maximum of 800 mg/day. Medroxyprogesterone is another progestational drug used to enhance appetite. The liabilities of the progestogens are their high cost and side-effects such as thromboembolic phenomena, edema, and impotence. Corticosteroids While corticosteroids can improve anorexia, they do not generally improve caloric intake or nutritional status.33 Their effects are usually limited to 3–4 weeks, and thus should be reserved for appropriate clinical situations. Patients with dyspnea, bronchospasm, bone pain, spinal cord metastases, or cerebral metastases may show added benefit with the use of corticosteroids. Representative agents include prednisone (30mg/day) and dexamethasone (4–8 mg/day). Initial dosing should begin with a 1-week trial and be continued if the patient responds. The daily dose should be administered in the morning with breakfast to decrease hypothalamic-pituitary-adrenal axis suppression and to reduce the potential for insomnia. A proton pump inhibitor or an H2-receptor antagonist should be prescribed concurrently with the corticosteroid to minimize gastrointestinal complications. Side-effects will increase with therapy longer than 3–4 weeks or as the cumulative dose exceeds 400mg (dexamethasone).

Symptom management in the older patient

1445

Other agents ∆9-Tetrahydrocannabinol (THC) has been shown to enhance appetite and reduce nausea in cancer patients at doses of 2.5–5 mg administered two or three times daily.33 Sideeffects include dizziness, somnolence, dysphoria, and euphoria. Anabolic steroids (nandrolone and oxandrolone) have been shown to enhance appetite, but in at least one large clinical trial were shown to be inferior to dexamethasone or megestrol acetate.36 Studies of these agents are contradictory, and their efficacy may depend on both food intake and physical activity, limiting their use in the elderly cancer patient. Agents currently being investigated include growth hormone, melatonin, eicosapentaenoic acid, and thalidomide. Depression Depression is not a ‘normal response’ to the diagnosis of cancer. It should be perceived as a physiologic disorder, treatable with appropriate intervention (both psychological and pharmacologic), and not confused with sadness.37 Accurately diagnosing depression is a difficult task; however, identifying and treating depression is crucial to reducing the suffering and increasing the quality of remaining life for these patients. Depression may be defined as a loss of interest and/or pleasure in all or many of the usual activities of daily living. Many of the criteria used to help make a diagnosis of depression are those

Table 61.5 Characteristics of possible depression in the cancer patient Medical •

Refusal of treatment or leaving the hospital against medical advice

•

Poor relationship with the physician or other caregivers

•

Poorly controlled physical symptoms, especially pain and insomnia

•

Unwelcome effects of medical or surgical procedures

•

Advanced disease

Social •

Expression of suicidal ideation or wishes to harm others

•

Loss of self-esteem for an extended period of time

•

Excessive guilt for an extended period of time

•

Concern over practical issues (work, finances, housing)

•

Lack of support from family or friends (real or perceived)

History •

Absence of social group affiliations, especially religious

•

Absence of marital and/or family harmony

Comprehensive Geriatric Oncology

•

Prior or current drug and/or alcohol abuse

•

Prior psychiatric illness

1446

already seen in the elderly cancer patient, for example poor appetite or weight loss, sleep disturbances, fatigue, and changes in sexual interest, psychomotor activity, and mental concentration. These characteristic changes may result from the neoplastic disease itself, from symptoms such as pain, nausea, or dyspnea, from medications such as clonidine, propranolol, steroids, anticonvulsants, and phenothiazines, and from other medical or psychological conditions. Thus, for cancer patients, it may be useful to define criteria that may suggest a more serious depression. Table 61.5 lists such criteria. Tricyclic antidepressants Representative agents in this class include amitriptyline, imipramine, nortriptyline, and desipramine. In general, these are not advisable agents unless other symptoms may benefit from their use, since they may precipitate life-threatening cardiovascular events or cause significant central nervous system (CNS) disturbances.38 Their anticholinergic activity produces such side-effects as sedation and dry mouth that may decrease the quality of life for the elderly cancer patient. Lower doses (25–75 mg/day) of the more anticholinergic amitriptyline may benefit the patient with insomnia as comparable doses of the less anticholinergic desipramine or nortriptyline may benefit the patient with neuropathic pain. However, depression often requires higher doses and may take 2–6 weeks for therapeutic effect. Further, these medications potentiate certain side-effects of opioids and may be intolerable in those using opioids for pain control. Selective serotonin reuptake inhibitors (SSRIs) SSRIs have few anticholinergic effects, are non-sedating, and are safe for use in the elderly cancer patient.38 However, they may cause nausea, anorexia, diarrhea, headache, and anxiety. They demonstrate a prolonged half-life in the elderly and have a slow onset of action, often taking 2 weeks to show effect. Agents in this class include fluoxetine, paroxetine, and sertraline. A related agent, mirtazepine, has a more rapid onset of action—often within a few days. It further exhibits sedative (antihistaminic) and antiemetic (5-HT3-antagonist) properties. A predominant side-effect that may be used to benefit is appetite stimulation and weight gain. Psychostimulants Psychostimulants are rapidly becoming the agents of choice for treating depression associated with terminal illness.31,39 They have a rapid onset of action, with responses usually being seen within 2–3 days. Their additive benefits of improving fatigue sedation, arousal and ability to attend and concentrate, and their ability to improve cognitive function combine to increase the quality of life for the patient with terminal cancer. The primary agents in this class are methylphenidate and dextroamphetamine. Initial therapy should begin with the smallest dose (2.5–5 mg) administered in the morning and at noon.

Symptom management in the older patient

1447

Doses should not be given in the afternoon, to prevent interference with sleep. Doses may be titrated every 3–5 days in 5 mg increments to a maximum of 40mg/day. Therapy should be discontinued if there is no response after 2 weeks or there are significant adverse effects. The principal side-effects of these medications include insomnia, anorexia, dry mouth, nausea, and tremor. Other less common side-effects include cardiovascular events (arrhythmias, hypertension, palpitations, and tachycardia), and CNS events (dizziness, euphoria, headache, and nervousness). Dyspnea The palliation of respiratory symptoms in the elderly cancer patient is of importance because of the great fear that shortness of breath and a feeling of suffocation can elicit.40 The causes of dyspnea in the cancer patient are listed in Table 61.6. If the dyspnea is not treatable, then palliative intervention is important to relieve what can cause a significant decrease in quality of life. There are many non-pharmacologic interventions that may provide relief from dyspnea and associated anxiety. These management techniques often have a role as adjuncts when pharmacologic therapy

Table 61.6 Causes of dyspnea in the cancer patient Cancer-related •

Pleural or pericardial effusion

•

Superior vena cava obstruction

•

Pneumothorax

•

Broncho-esophageal fistula

•

Tumor compression of the bronchi or trachea

•

Pathologic rib fracture

•

Atelectasis

•

Hepatomegaly

•

Ascites

•

Lymphangitis

•

Infection

•

Anemia

•

Gastrointestinal bleeding

•

Pulmonary emboli

Treatment-related •

Surgery (e.g. pneumonectomy)

•

Radiation-induced pneumonitis or fibrosis

Comprehensive Geriatric Oncology

1448

•

Drug-induced pneumonitis or fibrosis (e.g. bleomycin, methotrexate)

•

Radiotherapy- or chemotherapy-induced cardiomyopathy

Concurrent Illness •

Chronic obstructive pulmonary disease

•

Congestive heart failure

•

Myocardial infarction

•

Pneumothorax

•

Bronchospasm

•

Phrenic nerve dysfunction

is required. General measures include reassurance, modification of daily activity, reducing the work of breathing and coughing, facial cooling, home humidifiers, and teaching of patient relaxation and positioning techniques. When hypoxia results in dyspnea, oxygen therapy may be of value. Low-dose supplementation should be humidified and delivered via nasal prongs. The patient should be weaned off oxygen if successful pharmacologic management is achieved. Morphine Morphine acts to relieve dyspnea in several ways. It may act to reduce excessive respiratory drive and rate, reduce anxiety, alter cardiac preload, and relieve pain. Although the exact mode of action is unknown, the medical literature is replete with citations confirming the value of systemic opioid therapy for dyspnea.40 The initial starting dose for the opioid-naive patient is 5mg every 4 hours of immediate release morphine. Sustained release preparations may be substituted after titration to an effective dose. For patients on opioid therapy for pain, general guidelines suggest a 25% increase in dose. Nebulized opioids have been recommended; however, the data are contradictory.40,41 Systemic uptake of opioids following nebulized therapy is reported to be low (4–8%), which may provide benefit to the patient who cannot tolerate further increases in systemic opioid therapy. Initial dosing is 5–10 mg of parenteral morphine inhaled via nebulizer every 4 hours as needed. Anxiolytics and tranquilizers Dyspnea is a very frightening experience that can be palliated with benzodiazepines (e.g. diazepam 2mg every 8 hours) or other medications such as chlorpromazine (25–100 mg every 8 hours) or haloperidol (2–5 mg every 12 hours). Haloperidol has advantages in the patient sedated from other concurrent medication.

Symptom management in the older patient

1449

Corticosteroids Prednisone (10–20 mg three times daily) or dexamethasone (8–12 mg every morning) are effective in treating dyspnea due to underlying inflammatory processes such as obstruction by tumor swelling, bronchospasm associated with asthma, lymphangitis, and sometimes superior vena cava syndrome. Corticosteroids may be inhaled if appropriate to the clinical situation. Other agents Nebulized albuterol (a β-agonist) or nebulized bupivacaine (2 ml of a 0.25% solution) have been reported as efficacious in treating dyspnea. Any nebulized agent, however, can result in bronchospasm. Theophylline may be used with inhaled β-agonists when chronic bronchodilation is required, but is generally not recommended because of the need to monitor blood levels. If excessive secretions are present as the underlying cause of dyspnea, then agents such as scopolamine (0.4 mg subcutaneously every 3–4 hours as needed), octreotide (50–100 µg subcutaneously every 8 hours as needed) or glycopyrrolate (1–2mg orally every 8–12 hours) are reasonable therapeutic alternatives. Constipation Constipation may be defined as a decrease in the frequency of the passage of formed stools and characterized by stools that are hard with a sensation of incomplete, prolonged, and difficult evacuation. It is a frequent health concern for older individuals, who may have unique factors predisposing them to constipation. The decreased physical mobility of the elderly may present a problem in getting to the toilet or commode, resulting in their avoiding it. Further, a lack of privacy or the need for

Table 61.7 Causes of constipation Cancer-associated • Hypercalcemia and other electrolyte imbalances • Spinal cord compression • Cauda equina syndrome • Depression • Colorectal tumors Debility-associated • Weakness or fatigue • Inactivity or confinement to bed • Poor nutrition and/or fluid intake

Comprehensive Geriatric Oncology

1450

• Confusion • Inability to reach the toilet • Lack of privacy Treatment-associated • Medications (e.g. opioids, anticholinergics, antidepressants, aluminum salts, iron, calcium channel blockers, non-steroidal anti-inflammatory drugs, 5-HT3 antagonist antiemetics, vinca alkaloid antineoplastics) • Radiotherapy insult Concurrent disorders • Hemorrhoids • Anal fissures • Perianal ulceration • Neurologic/psychiatric disorders • Endocrine disorders

nurse or caregiver help in toileting can exacerbate constipation. Physical changes, such as loss of colonic cells, may cause the bowels to function improperly. In the geriatric cancer patient, these factors enhance potential constipation from a variety of other causes (Table 61.7). A thorough assessment of constipation is crucial to effective management, especially in the elderly. An accurate history is important to establish how the present pattern of bowel movements differs from the patient’s normal pattern. This history should investigate the patient’s frequency and consistency of stools, the presence of nausea and/or vomiting, abdominal pain, and other symptoms, the patient’s access to a toilet, mobility, privacy, and diet, and a general observation of abdominal distention, visible peristalsis, and/or borborygmi, which can suggest an obstruction. A digital rectal examination is essential if constipation is suspected. This will reveal the presence of hard stool, tumor masses, or distinct concomitant disease. A plain X-ray of the abdomen is helpful when the diagnosis remains unclear. The effective management of constipation in the elderly must include, in addition to pharmacologic intervention, attention to symptoms (especially pain), increasing physical activity, insuring the availability of proper toileting facilities, advice on diet and fluid intake, and the establishment of a routine for bowel evacuation. While these nonpharmacologic interventions are often insufficient for the constipation encountered in the geriatric oncology patient, they will aid in achieving a positive outcome from laxative therapy, and their use should generally be encouraged. Physical activity is important because it increases the motility of the stool through the gastrointestinal tract. The activity need not be strenuous—the simple exercise of walking is often sufficient. Increasing fluid intake to eight 8-oz glasses per day will help moisten and soften the stool. Dietary fiber (e.g. unrefined bran, vegetable and fruit fiber, and whole grain) functions to increase the volume and bulk of the stool and thereby promote easier

Symptom management in the older patient

1451

evacuation. The gradual introduction of fiber into the diet may aid in preventing the flatulence, gaseousness, and abdominal discomfort that may occur during the first few weeks of therapy. Contraindications to the use of fiber include the bedridden or debilitated patient or those with intestinal stricture (where its use may lead to obstruction). Bran may also interfere with the absorption of calcium and iron, and should be avoided in patients prone to those deficiencies. Addressing the availability of appropriate toileting facilities for the bedridden or debilitated patient and of privacy concerns for all patients is essential for the establishment of a good routine for bowel evacuation. Patients should be encouraged to follow their established routine even when constipated or in the absence of the urge to defecate. The pharmacologic management of constipation involves the use of laxatives, which are generally classified according to their activity in the gut. The goal of laxative therapy is comfortable defecation—not an arbitrary frequency of bowel movements. While the choice of laxative is often dependent on the etiology of the constipation and patient preference, whenever possible oral laxatives should be used.42 Bulk-forming laxatives These agents, which include psyllium mucilloid, plantago, methylcellulose, and carboxymethylcellulose, are non-digestible crude fiber that acts by absorbing water to produce bulk in the intestine.43 Therefore, it is essential that adequate fluid intake (at least 250ml) be maintained to avoid potential fecal impaction or intestinal obstruction. They are not true laxatives, since they do not act on stool present in the colon or rectum, but rather promote prevention of constipation and normalization of bowel evacuation. The onset of action is usually 18–24 hours; however, in the elderly patient, activity may not be seen for as long as 3 days. These agents should be avoided in patients who are bedridden or debilitated, have difficulty drinking fluids or ambulating, are incontinent, or have decreased intestinal motility. Care must also be taken to insure that the sodium or sugar content, which may be high in some preparations, is not a contraindication for elderly patients with congestive heart failure or diabetes. Lubricants Lubricating agents ease passage by coating the stool and preventing the absorption of water from the colon. The onset of action is generally 6–8 hours. Mineral oil is the prototype medication, but is not recommended for the elderly. In addition to its unpleasant taste, long-term use can result in perianal irritation and decreased absorption of the fat-soluble vitamins A, D, E, and K. Further, use in bedridden patients or administration at bedtime may precipitate aspiration and cause lipoidal pneumonia. Saline laxatives Saline laxatives draw fluid into the bowel, resulting in a strong, sometimes undesirable, purgative action. This action increases luminal pressure, resulting in a mechanical stimulus that increases bowel motility. Their onset of action ranges from 30 minutes to 3 hours. Agents in this class include the citrate, hydroxide, and sulfate salts of magnesium

Comprehensive Geriatric Oncology

1452

and various phosphate salts of sodium. Overuse of these medications, especially in the elderly, may place patients at risk for fluid and electrolyte imbalances. The magnesium preparations should be avoided in patients with decreased renal function (creatinine clearance <20ml/min) and the phosphate salts must be used with caution in patients with congestive heart failure, hypertension, or edema. Further, the phosphate preparations may lead to phosphorus and calcium abnormalities. Osmotic laxatives Osmotic laxatives include lactulose, sorbitol, GoLYTELY, and glycerin suppositories. Similar to the saline agents, they act by increasing intraluminal pressure and stimulating peristalsis. The most commonly used agent is lactulose, which may take up to 3 days for onset of action. Lactulose is a non-absorbable semisynthetic disaccharide that is generally safe and effective for the elderly patient and may be dosed on a once-a-day schedule for constipation.44 Compliance and quality of life may be compromised owing to flatulence, nausea, and the sweet taste of lactulose. Therefore, it is not a first-line agent, but rather a good adjunct to stimulant/stool softener therapy. Sorbitol is more cost-effective and may produce less nausea; however, it has a similarly sweet taste. Both lactulose and sorbitol use should be accompanied with increased fluid intake. Glycerin suppositories have an onset of action of about 30 minutes when used to soften hard stool in the rectum. Routine use, however, can cause rectal irritation and are of little value in the elderly patient with decreased anorectal sensation. GoLYTELY is a polyethylene glycol-saline solution used for colonic lavage in preparation for colonic procedures. It has recently been formulated as a laxative. Stool softener laxatives Stool softeners are anionic detergents that act as surfactants to increase water penetration and thus soften the stool for easier passage. Representative agents include the sodium, calcium, and potassium salts of docusate and dioctyl sodium sulfosuccinate. Their onset of action ranges from 12 to 72 hours. They do not promote peristalsis, and therefore are often used in combination with stimulant laxatives. They are safe and effective for use in the elderly for the short-term management of constipation, especially when straining at evacuation should be avoided (e.g. following rectal surgery or after myocardial infarction). Stimulant laxatives These drugs induce defecation by directly stimulating the myenteric plexus to induce peristalsis, by local irritation on the mucosa, and by altering fluid and electrolyte absorption, producing net intestinal fluid accumulation and laxation. These agents are particularly useful for opioid-induced constipation. Opioids cause constipation by increasing smooth muscle tone, suppressing forward peristalsis, and reducing sensitivity to rectal distention. In addition to the delay in fecal passage, there is an increased absorption of water and electrolytes in the gut. By enhancing fluid secretion and

Symptom management in the older patient

1453

improving stool consistency, stimulants directly counteract these actions of the opioids. Their onset of action is approximately 6–12 hours. Stimulant laxatives are divided into three classes: castor oil, diphenylmethanes, and anthraquinones. Castor oil can cause fluid and electrolyte imbalances along with damage to the gastric mucosa. This agent should not be used to treat chronic constipation, and, indeed (given the surplus of more appropriate laxatives), castor oil use should not be considered in any situation. Phenolphthalein, a diphenylmethane, has recently been removed from the commercial market and should never be used in the elderly. Of interest, prunes, a natural remedy for constipation, contain phenolphthalein. Ingestion of prunes has been reported to produce cathartic colon, and cessation following daily use of prunes has resulted in constipation. Bisacodyl is a diphenylmethane laxative available in both an oral and rectal formulation. Frequent use of suppositories can result in rectal irritation; however, their occasional use for the removal of soft stool from a lax rectum is often beneficial. Oral bisacodyl is an enteric-coated tablet that should not be crushed, chewed, or taken with antacids. The most commonly used stimulants are in the anthraquinone class, which includes senna, cascara sagrada and its extract casanthranol, and aloe. This class of stimulants is the mildest, with the exception of aloe and its derivative aloin, which are reportedly very irritating. Senna and casanthranol are commercially available in combination with stool softeners—products that are highly effective for opioid-induced constipation.45 The dosage should be titrated carefully to effect, and lower doses in combination with other types of laxatives should be considered if colic or abdominal cramping becomes problematic. Enemas An appropriate oral laxative regimen should always accompany the use of rectal laxatives. Enemas, and sometimes suppositories, are appropriate for the treatment of fecal impaction; however, they should not be part of the daily treatment for the elderly cancer patient with constipation.46 Most patients, family, and caregivers consider the therapy undignified, inconvenient, and difficult, resulting in a decreased quality of life for all involved. Hydrogen peroxide enemas, milk and molasses enemas, and particularly soap suds enemas (which carry the risk of soap colitis), should be avoided in the elderly. Commercially available enemas (e.g. Fleets) are considered safe and effective for use in the geriatric patient. Oil retention enemas are used to soften very hard stool or for an impaction high up the colon, and are then followed with saline preparations if necessary. Diarrhea Diarrhea can be defined as a change in the frequency, fluidity, or volume of stool. Diarrhea can be highly debilitating in the elderly patient, since it can lead to severe dehydration and electrolyte abnormalities, resulting in weakness and fatigue.42 Chronic diarrhea often involves weight loss, anorexia, and chronic weakness. Replacement of fluid and electrolytes is essential—orally if the patient can tolerate it, otherwise intravenously. Further, concern with soiling and the effort involved in repeated trips to

Comprehensive Geriatric Oncology

1454

the toilet have a significant and negative impact on quality of life. The most common cause of diarrhea in the elderly cancer patient is the use of laxatives. A careful history of

Table 61.8 Causes of diarrhea in patients with cancer • Drugs: laxatives, antibiotics, antacids, chemotherapy (5-flourouracil, irinotecan) • Radiotherapy • Intestinal obstruction: including fecal impaction • Concurrent disease: e.g. inflammatory bowel disease • Diet • Infection • Malabsorption: pancreatic cancer, gastrectomy, ileal resection, colectomy • Tumor: colorectal, carcinoid, pancreatic, pelvic, fistulae

laxative use is essential to insure that inappropriate laxative use is not the cause of the diarrhea (e.g. rebound diarrhea from erratic use of laxatives for constipation). Patientdescribed diarrhea from overflow associated with fecal impaction is also commonly reported. Teaching appropriate laxative use and therapy for impaction are required; antidiarrheal therapy is not appropriate in this situation. Other causes of diarrhea that should be gleaned from a careful history include recently prescribed medications (especially antibiotic use), recent travel, the presence of a food or lactose intolerance, and colon cancer or other colorectal disease. Table 61.8 illustrates possible causes of diarrhea in the elderly patient with cancer. Acute diarrhea (episodes that usually resolve within 72 hours), is generally selflimiting and is treated symptomatically with non-specific antidiarrheal agents. Loperamide is the agent of choice for the elderly. This drug has a more favorable sideeffect profile than the opioid derivatives such as diphenoxylate, codeine, and camphorated tincture of opium. The significant adverse effects of the opioid preparations on the CNS generally preclude their use in the elderly patient. Loperamide is generally dosed 2–4 mg initially and 2mg after each loose stool to a maximum of 16mg daily. However, high-dose loperamide (up to 28mg/day) has been used safely in the setting of chemotherapy-induced diarrhea. Adsorbents used to treat diarrhea include kaolin, pectin, and polycarbophil. The effectiveness of kaolin and pectin is questionable; however, polycarbophil, an agent that can absorb approximately 60 times its weight in water, has been proven an effective antidiarrheal. Its side-effects include flatulence and epigastric pain. The tablets must be chewed, which can be problematic for the elderly patient with poor dentition. Anticholinergic agents should be avoided in the elderly because of their significant adverse event profile (dry mouth, urinary retention, blurred vision, and confusion). However, short-term use of atropine or hyoscine butylbromide may be of benefit for cholinergic-mediated diarrhea. Combination of agents should be avoided to prevent the delivery of subtherapeutic doses. Subcutaneous octreotide, at starting doses of 50–100 µg escalating to 500µg every 8 hours, has shown efficacy in the clinical setting of intractable diarrhea.47 Cholestyramine is effective for diarrhea caused by increased bile

Symptom management in the older patient

1455

salts in the setting of bowel resection. Other agents used in specific clinical situations include cyproheptadine for carcinoid syndrome, NSAIDs for diarrhea caused by inflammatory bowel syndrome, and clonidine for diarrhea associated with bronchogenic carcinoma. Nausea and vomiting Severe or protracted nausea and vomiting are distressing and potentially medically significant symptoms in the

Table 61.9 Potential causes of nausea and vomiting in patients with advanced cancer • Drugs: opioids, chemotherapy, non-steroidal anti-inflammatory agents, digoxin, anticholinergics, antibiotics • Migraine headache • Intestinal obstruction, gastroparesis, constipation, irritable bowel syndrome • Carcinoma: especially hepatic, gastric, colon, pancreatic • Visceral pain: e.g. myocardial infarction, colic (renal, biliary, or small bowel) • Infection • Metabolic and endocrine abnormalities: e.g. hypercalcemia, ketoacidosis, uremia, hyperparathyroidism • Pelvic or abdominal radiotherapy • Anxiety or other psychological factors (emotions, sights, smells, tastes) • Vestibular inflammation or other disturbances, motion sickness, Meniere’s syndrome • Elevated intracranial pressure: e.g. from metastasis to the brain

elderly patient with advanced cancer. Medical complications include dehydration, malnutrition, metabolic disturbances (e.g. alkalosis, hyponatremia, hypochloremia, and hypokalemia), and aspiration pneumonia (especially in sedated patients or those with decreased level of consciousness), and, in susceptible patients, repeated severe vomiting may cause pathologic fracture or tears of the gastroesophageal junction (Mallory-Weiss syndrome). Regulated through a complex reflex arc, nausea and vomiting may be activated at many sites; thus, a variety of etiologies exist (Table 61.9).48 Primary therapy should revolve around the determination and subsequent correction of the underlying cause if possible. Dopamine antagonists Prochlorperazine, haloperidol, and metoclopramide are examples of the dopamine antagonists. Dopamine appears to be active at afferent impulses from the periphery and at

Comprehensive Geriatric Oncology

1456

the chemoreceptor trigger zone,49 making these agents beneficial for nausea and vomiting of drug-induced, obstructive, and metabolic etiologies. Metoclopramide, dosed at 10–20 mg every 6 hours, can be especially effective in the setting of gastroparesis, where gastric motility stimulation relieves the nausea and vomiting resulting from gastric stasis. Haloperidol has added benefit for the patient with delirium. Initial doses of 1–2 mg every 8 hours may be titrated up to 5mg as required. Although these are very useful medications, anticholinergic, cardiovascular, and extrapyramidal side-effects coupled with sedation require close monitoring, especially wheri used in the elderly or frail patient. Corticosteroids The mechanism of action of these agents is unknown; however, their appetite-enhancing and mild euphoric effects (improved mood and sense of well-being) may help relieve nausea and vomiting. Dexamethasone, dosed at 4–20 mg per day, is compatible with many other symptom control medications (e.g. opioids and metoclopramide), and thus may be used in combination for subcutaneous or intravenous delivery. Vestibular disturbances The antihistamines (e.g. meclizine and dimenhydrinate) and the anticholinergics (e.g. scopolamine) are effective for the nausea and vomiting associated with vestibular disturbances. Scopolamine is more effective than the antihistamines for motion sickness; however, sedation and other anticholinergic side-effects can limit its usefulness, especially in the elderly. This side-effect profile has been improved with the transdermal formulation, which provides an effective blood level of medication over a prolonged period of time. The primary side-effects seen with this formulation are dry mouth, blurred vision, and drowsiness. 5-HT3 (serotonin receptor) antagonists Ondansetron, granisetron, and dolasetron are antiemetics approved for use in the setting of chemotherapy- or radiation-induced and postoperative nausea and vomiting.50 In general, they do not have significant efficacy if used on a PRN (as needed) basis, are more effective in preventing emesis than nausea, and in the chemotherapy setting are more effective for the acute phase (first 24 hours) than for the delayed phase. Their primary side-effects include headache and constipation. Acetaminophen therapy is usually adequate to treat this headache; however, although very rare, severe headache may require rotation to another serotonin antagonist. Their use in nausea and vomiting from other causes should follow the failure of the other antiemetic agents, since their efficacy has not been established and their cost is significantly higher.

Symptom management in the older patient

1457

Cough Therapy is targeted at defining the underlying cause of the cough and then selecting the appropriate treatment (Table 61.10).51 Cough has a negative impact on quality of life by disturbing sleep, and increasing dyspnea, pain, and anxiety. Non-drug therapies for persistent dry cough include humidifying room air, keeping the mouth moist with increased fluid intake, evaluation of positional factors, and the use of chest

Table 61.10 Common causes and treatment of cough Cause

Treatment

Respiratory infection

Antibiotics

Postnasal drip

Antihistamines, decongestants

Asthma

Bronchodilators

Gastroesophageal reflux

Elevating the head of the bed, antacids, H2-receptor antagonists, proton pump inhibitors

Bronchial tumor

Beclomethasone inhaler, oral steroids, opioids, local anesthetics

Drugs (e.g. angiotensin inhibitors)

Change therapy if possible

Chronic bronchitis

Removal of irritant (e.g. smoking)

physiotherapy. Non-drug therapies such as humidity, herbal remedies and even sour lemon candy can prove useful. Drug therapy for cough is primarily the use of opioids. The prescribing of local anesthetics, anticholinergics, and steroids may play a role in specific clinical circumstances. Opioids 52

All opioids have antitussive activity. For the cancer patient receiving opioids for pain, tolerance to the antitussive effect may exist. Although this tolerance has not been investigated experimentally, cross-tolerance between opioids regarding analgesia and side-effect profiles is known to be incomplete; therefore, it is reasonable to try a small antitussive dose of an alternative opioid. For example, for a patient whose pain is well controlled on significant doses of morphine, a trial of hydrocodone 5–15 mg every 4–6 hours for cough may be effective.

Comprehensive Geriatric Oncology

1458

Local anesthetics Lidocaine, bupivacaine, and benzonatate are local anesthetic agents that have been used in the control of refractory cough.53 Lidocaine is nebulized at 2–5 ml of a 2% solution every 4–6 hours as needed. Bupivacaine is an alternative agent used at a dose of 5ml of a 0.25% solution every 4 hours. Owing to the short-term loss of the gag reflex, care must be taken to prevent the ingestion of food or liquid 30 minutes prior to and 2 hours after treatment. The clinician is cautioned that any nebulized agent may result in a bronchospastic adverse response. Lidocaine has also been used as a single spray to the back of the throat in a 10% solution. Benzonatate is a local anesthetic that has been used for dry cough at one or two capsules every 8 hours as needed. Miscellaneous agents Cough caused by bronchospasm will often respond to inhaled steroids or bronchodilators. Oral corticosteroids may benefit patients with lymphangitic carcinomatosis or other inflammatory components. Whenever aspiration of saliva or excess secretions play a role in cough, anticholinergics such as glycopyrrolate may be of benefit. Caution with the use of both corticosteroids and anticholinergics in the elderly must be exercised because of their significant side-effect profile. Hiccup (hiccough, singultus) Hiccup that is benign and self-limiting may be caused by a variety of conditions that stimulate some component of the hiccup reflex arc. These episodes are often precipitated by food, liquid, or air-induced gastric distention. Table 61.11 lists causes associated with intractable hiccup.

Table 61.11 Causes of intractable hiccup Central nervous system, diaphragmatic, vagus nerve •

Structural lesions

•

Trauma

•

Inflammation

•

Vascular lesions

•

Infection

Toxic, metabolic •

Uremia

•

Hypokalemia

•

Hyponatremia

Symptom management in the older patient

•

Hypocalcemia

•

Hyperventilation

•

Alcohol

•

Gout

•

Fever

•

Diabetes mellitus

•

Insulin shock therapy

1459

Surgical •

General anesthesia

•

Thoracotomy

•

Craniotomy

•

Laparotomy

•

Prostatic and urinary tract surgery

Drug-induced •

Sulfonamides

•

Steroids (especially high-dose)

•

Methyldopa

•

Diazepam

•

Short-acting barbiturates

•

Chlordiazepoxide

•

Analeptic agents

•

Chemotherapy (cisplatin)

Table 61.12 Non-drug therapy for intractable hiccup Mechanism of action

Therapy

Relief of gastric distention

Gastric lavage, nasogastric aspiration

Counterirritation

Vagus nerve: apply pressure on eyeballs, rectal massage, irritate tympanic membrane Diaphragm: chest compression (leaning forward or by pulling knees to chest), mustard plaster

Stimulation or interruption of

Hyperventilation; rebreathing into a paper bag of breathing 5% carbon dioxide; induced sneezing; valsalva maneuver; sudden fright (induced

Comprehensive Geriatric Oncology

respiration

1460

gasping); breath holding; compress thyroid cartilage

Irritation of Gargling; pineapple juice; sipping ice water; drinking a mixture of honey nasopharynx or uvula and vinegar; granulated sugar swallowed dry; 1–2 tablespoons heavy syrup in fruit cocktail (or similar can of fruit); use of ammonia, ether, or other noxious stimulants; forcible tongue retraction

The management of intractable hiccup is approached with both drug and non-drug therapy. Non-drug therapy is based primarily on interrupting the hiccup reflex via pharyngeal stimulation or providing counterirritation or blockade of vagal or phrenic nerve impulses. Other non-drug therapies include prayer, hypnosis, and the use of behavioral modification techniques. A list of selected non-drug therapies and their mechanism of action is given in Table 61.12. A trial of one or more of these treatments is preferable to the initial use of drug therapy, especially in the elderly, where drug sideeffects can be troublesome. Drug therapy is based on the same mechanisms as non-drug therapy, namely, counterirritation, nerve impulse blockade, or direct action on the cause. The data for drug therapy is derived almost exclusively from case reports. Only one agent, chlorpromazine, has been approved by the US Food and Drug Administration (FDA) for use in the setting of intractable hiccup.54 As with almost all drug use in the elderly, the lowest possible dose should be initiated and slowly titrated to effect. Dopamine-related agents Chlorpromazine is thought to act by antagonizing dopamine in the hypothalamus. It is dosed at 25–50 mg every 6–8 hours. If the hiccups persist beyond 4–5 days, the drug may be administered parenterally in the same dose. Care should be taken to monitor the blood pressure of the patient and to watch for undesirable anticholinergic side-effects. Common adverse reactions associated with chlorpromazine include drowsiness, blurred vision, dry mouth, constipation, dermatologic reactions, and orthostatic hypotension. Prolonged use may lead to extrapyramidal reactions, tardive dyskinesias, and disruption of the hypothalamic thermoregulatory center. Agents with similar mechanisms of action and similar side-effect profiles include metoclopramide (10–20 mg orally every 6 hours or parenterally every 8 hours), haloperidol (1–5 mg orally every 12 hours), and amitriptyline (25–90 mg orally at bedtime). Metoclopramide, a gastric motility agent, is particularly useful in the clinical setting of gastric stasis or squashed stomach syndrome. Additional agents that are dopamine-related include amantadine, amphetamines, methylphenidate, ephedrine, and cocaine. Baclofen Baclofen is postulated to activate inhibitory neurotransmitters, which in turn act to block the hiccup reflex. It is also a centrally acting striated muscle relaxant, which may account for its action. The drug is dosed at 5 mg every 8 hours, titrated to a maximum of 60mg/day. Its primary side-effects include CNS effects (drowsiness, weakness, dizziness, headache, confusion, insomnia, and lethargy), and gastrointestinal (GI) effects

Symptom management in the older patient

1461

(nausea/vomiting and constipation). The drug may also cause hypotension and urinary frequency, and has been implicated in the exacerbation of psychotic disorders. Membrane-stabilizing agents Nifedipine is a membrane-stabilizing agent that acts by blocking calcium channels. Initial doses of 10mg increased to 20mg every 6–8 hours have been used.55 One case report successfully used 160 mg for intractable hiccup; however, fludrocortisone was required to maintain blood pressure. Blood pressure should be monitored regularly: every 2–3 days for the first 2 weeks, then weekly thereafter. Side-effects include dizziness, lightheadedness, headache, hypotension, palpitations, nausea, weakness, peripheral edema, and flushing. Carbamazepine (200–400 mg orally every 8–12 hours) and phenytoin are sodium-channel blockers that act to stabilize synaptic membranes. Valproic acid Similar to baclofen, this agent is thought to act on inhibitory neurons, resulting in blockade of the hiccup reflex. Initial dosage is 15mg/kg/day, titrated up by 250mg every 2 weeks until hiccup is relieved or side-effects become intolerable. Adverse events include CNS effects (sedation, tremor, headache, dizziness, and nystagmus), GI effects (indigestion, nausea, vomiting, and hepatotoxicity), photosensitivity, and psychiatric changes. Nebulized lidocaine Inhaled lidocaine is thought to act by anesthetizing sensory or irritated afferents involved in the hiccup reflex arc. Lidocaine is usually nebulized at 3 ml of a 4% solution daily for 3 days. Owing to the short-term loss of the gag reflex, care must be taken to prevent the ingestion of food or liquid 30 minutes prior to and 2 hours after treatment. The loss of protective lung reflexes may also precipitate bronchoconstriction, especially in the asthmatic patient. Gargling lidocaine should be discouraged, since it may be aspirated during a hiccup. Benzonatate, at one or two capsules every 8 hours as needed, is another local anesthetic that has been used for refractory hiccup. Midazolam Midazolam may relieve hiccup by its action as a centrally acting skeletal muscle relaxant or via inhibition of nerves involved in the hiccup reflex. Despite reports of diazepam and midazolam causing or intensifying hiccup, case reports suggest that midazolam can be used in the setting of persistent hiccup when sedation is acceptable.56 An initial 5–10 mg intravenous bolus is followed with a 60–120 mg continuous subcutaneous infusion. Its principal side-effect is sedation; however, it can also depress respiration, alter blood pressure and heart rate (usually decreases), and cause nausea and/or vomiting. This agent must be used with caution, especially in the elderly, and is best reserved for use in terminal agitation associated with the dying patient.

Comprehensive Geriatric Oncology

1462

Bowel obstruction Bowel obstruction is a relatively frequent clinical complication in patients with advanced malignancy of the abdomen or pelvis.57 Obstruction may have mechanical and/or functional causes, and it may occur at single or multiple sites. Externally, tumor compression, malignant or surgical adhesions, postirradiation fibrosis, and omental or mesenteric masses may result in obstruction. Within the lumen, obstruction can occur owing to annular tumor or polyploid lesions. Finally, tumor infiltration into the mesentery or bowel muscle may lead to motility disorders that result in obstruction (pseudoobstruction). Intestinal colic, abdominal pain, and vomiting are nearly universal symptoms associated with bowel obstruction. Other common presenting symptoms include anorexia, intermittent borborygmi, abdominal distention, and visible peristalsis.58 Significant sequelae of bowel obstruction include potential life-threatening perforation, intravascular volume depletion, and sepsis. Treatment is aimed primarily at relieving the obstruction by a surgical procedure. Surgery, however, is often contraindicated in the elderly person or in those who have had previous surgery to relieve this problem. If surgery is not appropriate or is contraindicated, a determination of alternative treatment to nasogastric suction should be made expeditiously. Percutaneous gastrostomy involves the insertion of a tube into the stomach, through the abdominal wall. The procedure allows for continuous decompression of the stomach and/or intestine that relieves the symptoms of the obstruction. Patients can be safely cared for at home with appropriate nursing support. Percutaneous gastrostomy is generally reserved for patients in whom medical intervention has produced unsatisfactory results. The pharmacologic management of bowel obstruction involves the use of analgesic, antiemetic, and antisecretory drugs. These agents may be used individually or in combination, as called for by the clinical situation. They are generally delivered by continuous subcutaneous (preferred) or intravenous infusion, and most of the medication combinations are compatible, which allows for a single injection site. Analgesics Strong opioids are the primary analgesic agents used for bowel obstruction. The two agents most commonly employed are morphine and hydromorphone. Dosing is individualized, starting low and titrating to effect. These agents are compatible with most other drugs used to treat this condition. Antiemetics The centrally acting antiemetics haloperidol and prochlorperazine are most commonly used for the nausea and vomiting associated with obstruction. They are used despite their relatively poor activity in this setting, especially when employed as single agents. They are much more effective when used in combination with antisecretory agents. The use of agents that promote gastric motility is controversial. Agents such as metoclopramide have a good effect on nausea and vomiting; however, they can exacerbate colicky pain. Again,

Symptom management in the older patient

1463

dosing should be individualized, starting with the lowest possible dose and titrating slowly to effect. Antisecretory agents The anticholinergic agent scopolamine (hyoscine) hydro-bromide has been used with success in the setting of bowel obstruction. An initial starting dose of 0.5–1.0 mg/day can be escalated to 2–3 mg/day based on antiemetic and antisecretive effect, with careful observation for adverse effects. The primary side-effects include dry mouth, blurred vision, drowsiness, confusion, and urinary retention. Careful attention to dosing must be exercised, since these symptoms are often present in the elderly as the result of age, disease, and concurrent medication. The antisecretory agent octreotide has been shown to improve the symptoms associated with bowel obstruction.59 The reductions in nausea and vomiting, abdominal pain, bloating, and anorexia improve the quality of life and wellbeing of the patient. The known side-effects of octreotide (abdominal pain, bloating, and dry mouth) occur rarely in this setting and rarely persist. The major disadvantage is the cost. However, this cost should be weighed against the suffering and distress of the patient, the family, and the caregiver. Initial starting doses are 150–300 µg/day, escalating to 600 µg/day. Higher doses do not appear to add efficacy, although, if necessary, they have been shown to be safe and effective.60 Corticosteroids have been used in the attempt to reduce peritumoral inflammatory edema in an effort to improve intestinal passage. Dosing is not standardized; however, various clinicians have suggested dexamethasone in the range of 8–60 mg/day. Given their side-effect profile and the available alternative agents, corticosteroids should probably be reserved for those patients with concomitant symptoms that would benefit from steroid administration. Summary The control of symptoms associated with cancer is necessary if one anticipates maximizing quality of life. In this chapter, we have highlighted those problems most often encountered clinically in the elderly person with advanced cancer. For further information, there are journals, textbooks, and a variety of websites61 that will allow the reader to remain current in this area. References 1. World Health Organization. Cancer Pain Relief and Palliative Care: a Report ofa WHO Expert Committee. Geneva: World Health Organization, 1990. 2. Laussaniere J, Vinant P. Prognostic factors, survival and advanced cancer. J Palliat Care 1992; 8:52–4. 3. Chang V. The value of symptoms in prognosis of cancer patients. In: Topics in Palliative Care, Vol 4 (Portenoy RK, Bruera E, eds). Oxford: Oxford University Press, 2000:23–53. 4. Bruera E, Kuehn N, Miller M et al. Symptom Assessment System (ESAS): a simplified method for the assessment of palliative care patients. J Palliat Care 1991; 7:6–9.

Comprehensive Geriatric Oncology

1464

5. Findley J, Rhyne R, Forman WB. The use of the Modified Edmonton Symptom Assessment Form. In preparation. 6. Forman WB, Birkholtz G, Gibson J. The hospice experience: symptom experiences in a rural state. The New Mexico experience. In preparation. 7. Coyle N, Adelhardt J, Foley KM, Portenoy RK. Character of terminal illness in the advanced cancer patient: pain and other symptoms during the last 4 weeks of life. J Pain Sympt Manage 1990; 5:83–93. 8. Ferrell BA. Pain management in elderly people. J Am Geriatr Soc 1990; 39:64–9. 9. Crook J, Rideout E, Browne G. The prevalence of pain complaints among a general population. Pain 1984; 18:299–302. 10. Herr KA, Mobily PR. Pain management for the elderly in alternate care settings. In: Pain in the Elderly (Ferrell BR, Ferrell BA, eds). Seattle: IASP Press, 1996:110–11. 11. Von Roenn JH, Cleeland CS, Gonin R et al. Physician attitude and practice in cancer pain management: a survey from ECOG. Ann Intern Med 1993; 119:121–125. 12. AGS Panel on Chronic Pain in Older Persons. The management of chronic pain in older persons. J Am Geriatr Soc 1998; 46:635–651. 13. Brescia F, Adler D, Gray G et al. Hospitalized advanced cancer patients: a profile. J Pain Sympt Manage 1990; 5:221–4. 14. Stein WM, Ferrell BA. Pain in the nursing home. Clin Geriatr Med 1996; 12:601–15. 15. Cohen-Mansfield J, Marx MS. Pain and depression in the nursing home. Corroborating results. J Gerentol 1993; 48:906–7. 16. Lipman AG, Gauthier ME. Pharmacology of opioid drugs: basic principles. In: Topics in Palliative Care, Vol 1 (Portenoy RK, Bruera E, eds). Oxford: Oxford University Press, 2000:137–63. 17. Sorkin BA, Rudy TE, Hanlon RB et al. Chronic pain in old and young patients: differences appear less important than similarities. J Gerontol 1990; 45:64–70. 18. Vigano A, Bruera E, Suarez-Almazor ME. Age, pain intensity, and opioid dose in patients with advanced cancer. Cancer 1998; 83: 1244–50. 19. Mercadante S. Opioid rotation for cancer pain. Cancer 1999; 86: 1856–66. 20. Pace V. Use of nonsteroidal anti-inflammatory drugs in cancer. Palliat Med 1995; 9:273–86. 21. Eisenberg E, Berkey CS, Carr DB et al. Efficacy and safety of non-steroidal anti-inflammatory drugs for cancer pain: a meta-analysis. J Clin Oncol 1994; 12:2756–65. 22. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med 1999; 340: 1888–99. 23. Hernandez-Diaz S, Rodriguez LAG. Association between nonsteroidal anti-inflammatory drugs and upper gastrointestinal tract bleeding/perforation. Arch Intern Med 2000; 160:2093–9. 24. Nuki G. Pain control and the use of non-steroidal analgesic anti-inflammatory drugs. Br Med Bull 1990; 46:262–78. 25. Portenoy RK. Adjuvant analgesics in pain management. In: Oxford Textbook of Palliative Medicine, 2nd edn (Doyle D, Hanks GWC, MacDonald N, eds). Oxford: Oxford University Press, 1998:361–90. 26. Winningham ML. Fatigue. In: Cancer Symptom Management (Groenwald SL, Frogge MH, Goodman M et al, eds). Boston: Jones and Bartlett, 1996:42–58. 27. Schwartz AL. Patterns of exercise and fatigue in physically active cancer survivors. Oncol Nurs Forum 1998; 25:485–91. 28. Yellen SB, Dyonzak JV. Sleep disturbances. In: Cancer Symptom Management (Groenwald SL, Frogge MH, Goodman M et al, eds). Boston: Jones and Bartlett, 1996:151–68. 29. Dalakas MC, Mock V, Hawkins MJ. Fatigue: definitions, mechanisms, and paradigm for study. Semin Oncol 1998:25(Suppl 1): 48–53. 30. Bruera E, Brenneis C, Patterson AH et al. Use of methylphenidate as an adjuvant to narcotic analgesics in patients with advanced cancer. J Pain Sympt Manage 1989; 4:3–6.

Symptom management in the older patient

1465

31. Homsi J, Walsh D, Nelson K. Psychostimulants in supportive care. Support Care Cancer 2000; 8:385–97. 32. Tisdale MJ. Biology of cachexia. J Natl Cancerlnst 1997; 89:1763–73. 33. Puccio M, Nathanson L. The cancer cachexia syndrome. Semin Oncol 1997; 24:277–87. 34. Sweeney MP, Bagg J. The mouth and palliative care. Am J Hosp Palliat Care 2000; 17:118–24. 35. Ottery FD, Walsh D, Strawford A. Pharmacologic management of anorexia/cachexia. Semin Oncol 1998; 25(Suppl 6): 35–44. 36. Loprinzi CL, Kugler JW, Sloan JA et al. Randomized comparison of megesterol acetate versus dexamethasone versus fluoxymesterone for the treatment of cancer anorexia/cachexia. J Clin Oncol 1999; 17: 3299–306. 37. Breitbart W, Chochinov HM, Passik S. Psychiatric aspects of palliative care. In: Oxford Textbook of Palliative Medicine, 2nd edn (Doyle D, Hanks GWC, MacDonald N, eds). Oxford: Oxford University Press, 1998:933–54. 38. Berney A, Stiefel F, Mazzocato C et al. Psychopharmacology in supportive care of cancer: a review for the clinician. III Antidepressants. Support Care Cancer 2000; 8:278–86. 39. Homsi J, Walsh D, Nelson K et al. Methylphenidate for depression in hospice practice: a case series. Am J Hosp Palliat Care 2000; 17:393–8. 40. Ripamonte C. Management of dyspnea in advanced cancer patients. Support Care Cancer 1999; 7:233–43. 41. Davis CL, Hardy JR. Current issues in cancer. Palliative medicine. BMJ 1994; 308:1359–62. 42. Fallon M, O’Neill B. ABC of palliative care. Constipation and diarrhoea. BMJ 1997; 315:1293– 6. 43. Cheskin LJ, Kamal N, Crowell MD et al. Mechanisms of constipation in older persons and effects of fiber compared to placebo. J Am Geriatr Soc 1995; 43:666–9. 44. Kot TV, Pettit-Young NA. Lactulose in the management of constipation: a current review. Ann Pharmacother 1992; 26:1277–82. 45. Passmore AP, Wilson-Davies K, Stoker C et al. Chronic constipation in long stay elderly patients: a comparison of lactulose and a senna-fibre combination. BMJ 1993; 307:769–71. 46. McMillan SC. Assessing and managing narcotic-induced constipation in adults with cancer. JMCC 1999; 6:198–204. 47. Wadler S, Benson AB III, Engelking C et al. Recommended guidelines for the treatment of chemotherapy-induced diarrhea. J Clin Oncol 1998; 16:3169–78. 48. Baines MJ. Nausea, vomiting, and intestinal obstruction. ABC of palliative care. BMJ 1997; 315:1148–50. 49. Grunberg SM, Hesketh PJ. Control of chemotherapy-induced emesis. N Engl J Med 1993; 329:1790–6. 50. ASHP Committee on Therapeutics. ASHP therapeutic guidelines on the pharmacologic management of nausea and vomiting in adult and pediatric patients receiving chemotherapy or radiation therapy or undergoing surgery. Am J Health Syst Pharm 1999; 56:729–64. 51. Davis CL. Breathlessness, cough, and other respiratory problems. ABC of palliative care. BMJ 1997; 315:931–4. 52. Hagen N. An approach to cough in cancer patients. J Pain Sympt Manage 1992; 6:257–62. 53. Coucher K, Hanks G. Long term management of respiratory symptoms in advanced cancer. J Pain Sympt Manage 1990; 5:320–30. 54. Chlorpromazine (Thorazine®), Manufacturer’s Package Insert, SmithKline Beecham Pharmaceuticals. In: Physicians Desk Reference, 57th edn. Montvale, NJ: Thomson Healthcare, 2003. 55. Quigley C. Nifedipine for Hiccups. J Pain Sympt Manage 1997; 13: 313. 56. Wilcock A, Twycross R. Midazolam for intractable hiccup. J Pain Sympt Manage 1996; 12:59– 61. 57. Ripamonte C. Malignant bowel obstruction in advanced and terminal cancer patients. Eur J Palliat Care 1994; 1:16–18.

Comprehensive Geriatric Oncology

1466

58. Baines MJ. The pathophysiology and management of malignant intestinal obstruction. In: Oxford Textbook of Palliative Medicine, 2nd edn (Doyle D, Hanks GWC, MacDonald N, eds). Oxford: Oxford University Press, 1998:526–34. 59. Mercadante S. Octreotide in relieving gastrointestinal symptoms due to bowel obstruction. Palliat Med 1993; 7:295–9. 60. Riley J, Fallon MT. Octreotide in terminal malignant obstruction of the gastrointestinal tract. Eur J Palliat Care 1994; 1:23–5. 61. Raj A, Gopal A, Bruera E. The role of the internet in palliative care. Prog Palliat Care 2000; 8:271–5.

62 Oncological rehabilitation of the elderly Dario Dini, Alberto Gozza Introduction The main goals of cancer research and cancer treatment are cure of cancer, and, when cure is not achievable, meaningful prolongation of patient survival. The cure rate has improved over the past decade for numerous adult malignancies, including some forms of acute leukemia, lymphomas, breast cancer, germ cell tumors, epithelial carcinoma of the ovaries, lung cancer, and colorectal cancer. For many more malignancies, disease-free survival has been substantially prolonged by aggressive systemic therapy. In these cases, restoration and preservation of the functions that may be impaired by cancer and by its treatment alike allows the patient to resume the activity of life prior to the diagnosis of cancer. Yet, in many cases, neither cure or disease-free survival can be obtained. In these cases, the practitioner can mainly offer comfort to the dying patient, by relieving the most vexing symptoms of the disease. Rehabilitative and supportive care frequently interface and thus are best discussed together. Over the past two decades, impressive advances in supportive care and rehabilitation have improved the quality of life of most cancer patients. Better symptom control has allowed terminal patients to enjoy fully the limited time left to them. Effective rehabilitation has allowed patients who had undergone major surgery, or were debilitated by aggressive chemotherapy and radiotherapy, to resume their regular activities. A major tenet of the practice of oncology is that, whatever the prognosis, the quality of life of the cancer patient must be preserved with all available means. Based on these principles, the management of the cancer patient is becoming more and more a multidisciplinary endeavor, aimed at providing pain control, nutritional therapy, social support, emotional care, and functional rehabilitation, in addition to specific antineoplastic treatment. Supportive care and rehabilitative interventions are particularly important for the older person with cancer. In frail patients, supportive care may also play a life-prolonging role. The management of older cancer patients is becoming more and more common for two reasons. First, the prevalence of most malignancies increases with the age of the population and approximately 50% of cancers occur in patients over 65.1 Second, older people are often affected by concomitant illnesses, functional restrictions, social isolation, and economic limitations. Any treatment plans for older persons with cancer must take these issues into account.2

Comprehensive Geriatric Oncology

1468

The meaning of oncological rehabilitation The rehabilitation of the cancer patient must address physical and functional damages caused either by progression of cancer or by cancer treatment, and requires a highly individualized approach, accounting for variations in the course of the disease and in treatment plans. The rehabilitation of the aged is further complicated by age-related disabilities and comorbid conditions, whose effects may be superimposed on those of the cancer and its treatment. The rehabilitation program cannot follow rigid guidelines, but needs to be continuously molded to the evolving clinical picture.3 The rehabilitation team members require a general knowledge of oncology, physiatrics, and geriatrics; the qualities of sympathy and understanding are necessary to help both patients and their families. Whenever possible, patients must be helped and encouraged to resume their usual lifestyle and independence.4 For the older patient, the possibility of recovery is contingent not only on resolution of cancer-related disabilities, but also on pre-existing physical disabilities and on comorbidities (cardiovascular, pulmonary, and renal insufficiency, diabetes, and neurological and rheumatological diseases) and on the patient’s ability to follow the treatment plan. These conditions compel us, when planning rehabilitation for an elderly patient, to evaluate the limitations on autonomy imposed by impaired physical function(s). Reversal of these impairments and restoration of some degree of autonomy are the first steps toward further rehabilitation. The improve-ment of physical function is essential to motivate the older person to achieve and to maintain independence, whenever possible. Cancer rehabilitation team The team operating in an oncological rehabilitation department is composed of physicians expert in oncology, physiatrics, and geriatrics, physiotherapists and occupational therapists, stoma care nurses, primary nurses, and medical social workers (Table 62.1). The efforts of the rehabilitation team are coordinated with those of the nutrition and teams and with the practitioner providing primary oncological care (Figure 62.1). Proper pain control and nutritional support are essential to successful rehabilitation. It is essential to enroll the support of family members, whenever possible, and to instruct them on rehabilitative interventions that may be carried out at home. Frequently, the intervention of family members is the most effective, since it involves personal knowledge of the patient, lifelong trust, emotional support, and encouragement. The cooperation of various team members with the patient’s primary caregiver guarantees the most successful rehabilitative outcome.3 A common problem in dealing with the family of elderly cancer patients in need of homecare is pre-existing family dynamics. Underlying conflicts may be exacerbated by a serious disease in the

Oncological rehabilitation of the elderly

1469

Table 62.1 Members of the rehabilitation team and their respective functions Physician •

Diagnosis

•

Medical treatment

•

Prescription of physical and instrumental therapy

Physiotherapist •

Physical and instrumental therapy

•

Application of prosthesis

•

Patient and family education

Stoma care specialist Instructions related to: •

Stoma management

•

Bowel irrigation

•

Stoma appliances

Primary nurse •

Management of medical treatment

•

General assistance to patient and family

Social worker •

Emotional support of patient and family

•

Management of social and financial issues

Comprehensive Geriatric Oncology

1470

Figure 62.1 Pain relief and nutritional support are essential to enable functional rehabilitation. family; different family members may use the patient to promote their different and sometimes antagonistic agendas. When such a dynamic is allowed to surface, the patient’s care may be seriously compromised as the patient is caught in the middle of a battlefield. It is very important that the social worker in the rehabilitation team assess the family dynamics and promote the resolution of conflicts through meetings involving different family members. During these meetings, the proposal of a common goal targeted to the rehabilitation of the patient, and the definition of specific roles for each family member, may promote harmony within the family, which could otherwise be torn apart. The identification of a primary caregiver, i.e. of a family member responsible for coordinating the efforts of all other members, is the key to successful homecare in both functional and dysfunctional families. The primary caregiver, who is frequently an adult daughter of the patient, must have the trust of all family members. The dedication of this person to the patient and the absence of any plan of secondary gain must be clear to everybody and beyond suspicion. A person who has already proven him/herself a leader of the family in previous times of distress is the most natural choice for primary

Oncological rehabilitation of the elderly

1471

caregiver. The primary caregiver must be knowledgeable about the patient’s daily progress, must establish realistic short-term objectives of patient care, must control the performance of each family member, and must prevent ‘role blurring’, which may cause new conflicts between family members. Cancer-related damage In oncological rehabilitation, it is useful to classify organ damage leading to disabilities according to the main etiology (Table 62.2). Thus, we recognize iatrogenic damage, due to cancer treatment, pathological damage, due to the effects of cancer, and immobility damage, which are a consequence of prolonged bed rest and immobilization. In the following discussion, we shall examine the pathogenesis and management of each condition. In Table 62.3 we summarize the principles, indications, advantages, and disadvantages of common rehabilitative techniques.

Table 62.2 Types of organ damage leading to disability in older cancer patients latrogenic damage Surgery-related • Scar pathology • Nerve injury • Muscle injury • Lymphedema • Cutaneous stomas • Limb amputations Radiotherapy-related damage • Early complications • Late complications –

Contractures

–

Pulmonary fibrosis

–

Osteoporosis and fractures

–

Myelitis

–

Plexopathy and neuropathy

Chemothempy-related damage • Extravasation of drugs • Central and peripheral neuropathies

Comprehensive Geriatric Oncology

1472

Pathological damage Skeletal metastases • Pain • Pathological fractures Central nervous system metastases • Disturbances of motility, speech, consciousness, sensations, and vegetative functions Peripheral nervous system metastases • Muscular weakness • Paresthesias • Neuropathic pain Skin and lymph node metastases • Lymphedema Immobility damage • Respiratory problems • Deep vein thrombosis • Pressure sores • Muscle atrophy • Contractures • Bone loss

Iatrogenic damage Surgery, radiotherapy, and chemotherapy may cause numerous and frequent disabling effects. The organ damage may be permanent or temporary, depending on the seriousness and the duration of the injury. Some iatrogenic complications, such as lymphedema from lymph node dissection, radiation neuropathy, and anthracyclineinduced cardiomyopathy, may become evident months or years after the treatment has been discontinued. The most common iatrogenic lesions seen at the National Cancer Research Institute, Genoa during 1998 in cancer patients over 65 are summarized in Table 62.4. Surgery-related damage Scar pathology Adhesions and retractions are common after cervical, axillary, or inguinal dissection. These complications may cause lymphatic stasis and lymphedema, and paresthesias and

Oncological rehabilitation of the elderly

1473

weakness from nerve entrapment, and may limit the range of motion of the limbs and neck. The management of these conditions involves massage, lymphatic drainage, and vacuum therapy. Soft massage and vacuum therapy are useful to reduce the adhesion of the tissues, to prevent the formation of scar retraction, and to preserve the range of motion. Lymphatic drainage is important to minimize the lymph stasis around the scar, which facilitates scar formation. Nerve injury Injury to a visceral nerve may lead to derangements of visceral function. In head and neck surgery, nerve injury may cause dysarthria, dysphagia, and disturbances of mastication. In pelvic surgery, nerve injury may cause urinary and/or fecal incontinence and erectile dysfunction.

Figure 62.2 Winged scapula. Table 62.3 Common techniques of oncological rehabilitation Acupuncture Mechanism of action unknown Indications Most forms of pain and fatigue Advantages Low cost; short time involved (one or two weekly sessions of 30 minutes each, for 2–3 months); low technology; does not require patient’s active participation

Comprehensive Geriatric Oncology

1474

Disadvantages Unpredictable effectiveness; needs specifically trained personnel Electrically stimulated lymphatic drainage The lymphatic flow is stimulated by electric impulses starting from the most proximal portion of the limbs Indications Lymphedema, both from obliteration of regional lymph nodes and from tumor recurrences Advantages Can be used for tumor recurrences; does not require patient’s active participation; safe; inexpensive Disadvantages Time-consuming (three treatments per year, each involving 10 daily sessions lasting 60 minutes each); limited effectiveness Edemacenthesis Multiple punctures of the hardest part of the edematous limb with 25-gauge needles. After many punctures, the limb is gently massaged to promote the outflow of third-space fluid. Heparin (5000 U) and normal saline (10 ml) are added to the dressing to prevent early coagulation of the drainage. Thorough disinfection of the limb before and after the procedure is mandatory Indications Refractory edema Advantages Effective; inexpensive Disadvantages Painful; high risk of infections. Should be reserved for a few selected cases Facilitating techniques Methods of muscular rehabilitation based on stimulation of peripheral receptors, both extero- and proprioceptors. As an example, the Kabat facilitating technique is based on a scheme of movement involving groups of muscles that are functionally connected. Exercises are performed along the spiral and diagonal axes, starting from the greatest muscle elongation. Exercises against resistance exploit the phenomenon of ‘irradiation’, i.e. the possibility of spreading the voluntary efforts of healthy muscles to weaker muscles belonging to the same muscular scheme Indications Muscle weakness from peripheral or central nervous injury Advantages Low technology; low cost Disadvantages Time-consuming; requires patient’s active participation; requires normal joints, intact proprioception, and intact posterior columns Laser therapy (low-level) The mechanism of action involves increased intracellular concentration of ATP and stimulation of prostaglandin synthesis Indications Management of pain, fibrosis, soft tissue ulcers from drug extravasation; wounds Advantages High effectiveness; safety; does not require patient’s active participation Disadvantages Time-consuming; expensive; requires high technology and trained personnel Pressotherapy

Oncological rehabilitation of the elderly

1475

For many years has been considered the standard treatment of lymphedema. The mechanism of action consists in ‘pressing’ the third-space fluid into the lymphatic and venous capillaries. A special form of pressotherapy that has recently been introduced is intermittent gradient therapy, which facilitates proximal drainage of the lymphedema fluid Indications Lymphedema of the extremities, from obliteration of regional lymph nodes due to surgery or irradiation. Not indicated for tumor recurrence Advantages Effective and safe; may be used for home therapy Disadvantages Costly, especially the intermittent gradient form; may require some degree of patient participation in the case of home care Transcutaneous electrical nerve stimulation (TENS) This technique is based on the ‘Gate theory’ of pain, which holds that counterstimulation of the nervous system may decrease the perception of pain. It requires a stimulator connected with electrodes applied to the skin Indications Most forms of localized pain, especially neuropathic pain manifested as hyperesthesia, dysesthesia, and allodynia Advantages Low cost; easy management, even for older patients Disadvantages Low effectiveness in severe pain Ultrasound therapy Mechanism of action includes increased blood flow, increased extensibility of collagen, thermal effect, mast cell degranulation, increased intracellular calcium levels, increased fibroblast protein synthesis, increased vascular permeability, increased angiogenesis, and increased tensile strength of collagen Indications Muscle retractions; joint contractures; delayed healing of wounds and ulcers Advantages Low cost; safety; does not require specialized training or active patient’s active participation Disadvantages Time-consuming; unpredictable results

Surgical damage to a motor nerve causes paresis or palsy of a muscle or of a group of muscles. A typical example of this sort of complications is the winged scapula (Figure 62.2) due to injury of the thoracic long nerve, which may limit abduction of the arm.5 A frequent symptom of sensory nerve injury is neuropathic pain that presents the characteristics of deafferentation pain: shooting of electrical shock-like pain on a background of burning, constricting sensations. These symptoms are reported as dysesthesia and hyperesthesia, and are accompanied by allodynia of significant degree on examination.6 Frequent clinical manifestations of nerve

Comprehensive Geriatric Oncology

1476

Figure 62.3 Acupuncture. injury are postmastectomy, post-thoracotomy and stump pairi. The treatment of motor disability involves physical therapy and facilitating techniques (Table 62.3), which exploit the neurogenic interactions of muscles within the same muscle district. For the success of these techniques, it is important that some of the muscles of the district not be injured. The treatment of neuropathic pain may benefit from transcutaneous electrical nerve stimulation (TENS) (Table 62.3),7,8 topical application of anesthetics or capsaicin,9,10 antidepressant and antiepileptic drugs, and acupuncture (Table 62.3 and Figure 62.3). In older individuals, who are particularly sensitive to the side-effects of antidepressant medications, capsaicin may have a primary role. Capsaicin is the pungent principle of red pepper and similar plants,

Table 62.4 latrogenic lesions in 168 patients over 65 seen at the National Cancer Research Institute, Genoa during 1998 Muscle retractions

45%

Nerve injuries

38%

Pain

30%

Abdominal stomas

20%

Lymphedema

18%

Drug extravasation

9%

Oncological rehabilitation of the elderly

1477

Scar pathology

4%

Tissue fibrosis

4%

The total is >100% because several patients presented more than one lesion.

and is supposed to interrupt nociceptive transmission by depleting substance P from the endings of unmyelinated fibers. Capsaicin causes a burning sensation at the site of application, which may be prevented by lidocaine ointment, and is otherwise devoid of side-effects. In concentrations of 0.025%, capsaicin may be applied three or four times daily for at least 2 months. Another advantage of capsaicin its low cost. In outpatients, we try capsaicin first, TENS and acupuncture thereafter, or a combination of these techniques prior to instituting treatment with amitriptyline, nortriptyline, or carbamazepine. Muscle injury Muscle injury includes muscular retractions, a frequent finding during functional assessment for rehabilitative purposes. Muscle retractions are a result of soft tissue tumor surgery, and may be worsened by radiotherapy. Retractions may also be originated by a defense reflex11 that makes the muscle shorter in response to the trauma of a surgical procedure; this outcome is a common complication of axillary dissection. Physical therapy is the main form of prevention of muscle injury. Adjuvant therapy with ultrasound or laser (Table 62.3) is indicated in the cases in which muscle retraction is likely or when the patient is unable or unwilling to cooperate with physical therapy. Adjuvant therapy with ultrasound or low-level laser energy is particularly helpful in the case of older patients with pre-existing cognitive or physical impairments that interfere with physical therapy. Adjuvant treatment may be continued until the maximal rehabilitative effects have been obtained. With the proper combinations of these techniques, satisfactory results are obtained in the large majority of patients. Lymphedema Lymphedema is one of the most frequent issues in oncological rehabilitation. Commonly, lymphedema complicates radical dissection of important lymph node chains. Lymphedema is a common complication of iliac or lumbar dissection. Its occurrence is more unpredictable after axillary or femoral dissection. A number of external factors may increase the risk and worsen the severity of lymphedema. These include radiotherapy, infections (cellulitis and lymphangitis), venous obstruction, prolonged exposure to heat, and excessive exercise of the limb, especially isometric exercise. These factors may aggravate pre-existing problems of lymphatic drainage, by obliterating the remaining superficial lymphatic vessels of the skin and subcutaneous tissue. Lymphedema may also signal recurrent disease (secondary lymphedema), and as such it pertains to pathological damages.

Comprehensive Geriatric Oncology

1478

Figure 62.4 Electrically stimulated limb drainage. There is almost universal consensus that both iatrogenic and pathological lymphedema may be controlled, but may not be completely reversed.12–14 Nevertheless, pressotherapy or electrical drainage (Table 62.3) and the use of compressive garments (elastic bandages or sleeves) effectively reduce the edema of the extremities. Manual lymphodrainage has produced the best results in postsurgical edema.15–17 Pharmacological therapy, including diuretics, vasoconstrictors, and, occasionally, anticoagulants,18 has been effective in decreasing the sense of tension of the arm and in partially maintaining the result of compressive therapies. The management of lymphedema varies with its seriousness and age. Manual lymphodrainage is the most effective treatment of lymphedema of recent onset and small volume. The first course of lymphodrainage consist of 15 sessions; the following courses are repeated every 6 months and consist of 10 sessions. Each session lasts approximately 1¼ hours. Elastic bandages should be worn continuously. Pressotherapy and electrically stimulated drainage (Figure 62.4) are used mainly for inveterate lymphedema. Cutaneous stomas Cutaneous stomas are the end-results of radical surgery involving the larynx, bladder, or rectum. Stomas affect both the physical and the emotional welfare of the patient. Often, they may cause a chronic dependence of the patient on the caregiver, and may result in strain within interpersonal relationships.19 For this reason, counseling should be seriously considered for all patients destined to have a permanent colostomy and for their caregivers. A realistic outline of the function and of the possible complications of a stoma

Oncological rehabilitation of the elderly

1479

may defuse the anxiety related to the stoma. It may also be useful to allow the patient and his/her caregiver to express their feelings related to the new situation and to work out mutually satisfactory solutions. Detailed instructions on stoma management should be conveyed to patients and family members in order to avoid common cutaneous complications, such as maceration and abrasion.20 Periodic bowel irrigation allows those with a definitive colostomy for colorectal cancer to recover an intermittent intestinal function and to control fecal excretion, and thus to maintain their quality of life.21,22 Limb amputations Limb amputations may represent the end-result of the management of melanomas or sarcomas of the extremities. Limb amputation may have serious physical, social, and emotional implications.3 The rehabilitative plan aims to rebuild the balance among the remaining muscle, to maintain strength, to promote circulation, and to prepare the patient to use a prosthesis.23 Pain and phantom sensations are managed by TENS and medications.6 Radiotherapy-related damage The functional complications of radiotherapy may be divided into early and late complications.24 Acute radiation-induced injuries are related to damage to surface epithelial cells, and may delay the completion of treatment and the institution of other forms of treatment such as chemotherapy. This damage is usually reversed in a few weeks. Early complications include erythema, moist desquamation, and ulceration. Their treatment is based on the topical application of substances that promote healing and prevent further lesions.25 Late complications have more serious rehabilitative implications. They occur months or years after completion of treatment, and are due to a progressive compromise of the small blood vessels (endarteritis obliterans with chronic alteration of connective and nervous tissues). The most frequent conditions include joint or muscle contractures, subcutaneous fibrosis, pulmonary fibrosis, spontaneous bone fractures, myelitis, and brachial/lumbar plexopathies. Xerostomia is a symptom that frequently affects patients treated with radiotherapy for head and neck cancers. The seriousness of the clinical picture depends on the site of irradiation, on the dosage, and on the time since completion of treatment.26 The management of late complications includes segmental physiotherapy for muscular lesions, pulmonary physiotherapy for lung lesions, and support devices able to stabilize fractures and to sustain paralyzed limbs. Neuropathic pain is a common sequela of peripheral nerve damage, and is managed with TENS, local application of anesthetics or capsaicin, and antidepressants. To prevent xerostomia, it is essential to observe strict oral hygiene and to use any means to maintain adequate salivary secretion: ice cubes, vitamin C, or pieces of pineapple. If radiotherapy has involved the whole parotid gland, no salivary flow can be produced; in this case, salivary substitutes and oral pilocarpine (5 mg three times a day) can be of some utility.

Comprehensive Geriatric Oncology

1480

Outcomes of chemotherapy Chemotherapy is associated with numerous side-effects: nausea and vomiting, hair loss, visceral dysfunction, peripheral neuropathy, and local tissue damage following drug extravasation. Of these complications, peripheral neuropathy and contractures from drug extravasation are susceptible to rehabilitative intervention. Peripheral neuropathy is a common consequence of treatment with cisplatin, vinca alkaloids, podophyllotoxins, and taxanes.27,28 Impairment of sensations (paresthesia and numbness, or sensory ataxia) may make the patient susceptible to skin injuries and Charcot’s joints, while neuropathic pain and loss of tendon reflexes may

Oncological rehabilitation of the elderly

1481

Figure 62.5 Laser therapy of a cutaneous ulcer due to extravasation of cancer chemotherapy. hinder the patient’s motility. Even if chemotherapy is discontinued as soon as the first neuropathic signs and symptoms become apparent, the neuropathy may continue to develop, and spontaneous regression is slow and incomplete; similarly to other neurological disorders, rehabilitative management with electrical stimulation and

Comprehensive Geriatric Oncology

1482

physiotherapy is necessary in order to reduce the consequences of peripheral nerve involvement. Inadvertent extravasation of antitumor agents during intravenous administration is a potential complication of cancer chemotherapy; it can cause local tissue reactions ranging from minor erythema, acute pain, and swelling in the area of vesicant infiltration, to severe necrosis.29,30 The list of vesicant drugs includes anthracyclines, alkylating agents, and plant alkaloids. The appropriate management of these iatrogenic accidents, including their prevention, as a part of supportive care in the elderly has been addressed by several experimental and clinical studies; they demonstrate the usefulness of combined management—medical, surgical, and rehabilitative—in the appropriate care of extravasation.30,31 Topical dimethylsulfoxide (DMSO) has shown great effectiveness in preventing cutaneous ulcers, while laser therapy may facilitate ulcer healing (Figure 62.5).32 Pathological damage More demanding for the rehabilitation team is the management of elderly patients affected by the disabling outcomes of cancer progression. Needless to say, in elderly cancer patients, progression of disease can lead to further deterioration in pre-existing pathological situations such as incontinence, restricted mobility, impaired cognition, and communication. A multidisciplinary approach associating antineoplastic treatment with emotional support and appropriate therapy of specific dysfunctions is the key to successful rehabilitation of elderly patients with advanced cancer. Bone metastases Bone metastases are frequent and cause considerable suffering and disability. Skeletal involvement results from many types of tumors, including breast, lung, kidney, and prostate. It may also represent the site of a primary bone lesion. Vertebral metastases may lead to vertebral collapse and spinal cord compression. Long bones bearing lytic metastatic lesions are subject to spontaneous fractures. In the elderly, the risk of vertebral collapse or weight-bearing long bone fracture is increased from coexisting osteoporosis. Pain is almost universal in bone metastases and may further limit a patient’s motility. Painful bony metastases likely enhance the dependence of elderly patients on the assistance of family members. The rehabilitative approach must be coordinated with other forms of treatment, such as surgery, radiotherapy, and chemotherapy. The initial rehabilitative step is aimed to reduce the risk of vertebral collapse and of bone fractures with orthotic devices that tend to reduce the load on the affected bone and permit a partial recovery of mobility.3 Pharmacological management of pain in the elderly must avoid dangerous complications of analgesic drugs such as non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and antidepressants. Bisphosphonates, however, seem to be well tolerated by the aged, but produce effective pain control in only 20–25% of cases.33 Bisphosphonates (etidronate, clodronate, and pamidronate) inhibit osteoclastic

Oncological rehabilitation of the elderly

1483

bone reabsorption and decrease both neoplastic and age-related bone loss. They seem to prevent fractures and to ameliorate bone pain, but clinical studies of these drugs are still ongoing. Persisting clinical problems include differences in activity between firstgeneration bisphosphonates and newer drugs (alendronate, tiludronate, and risedronate), the optimal duration of treatment, the optimal dosage, and the long-term risks and benefits. In general, corticosteroids and NSAIDs are the first-line management of bone pain from metastases, but in older patients the complications of these drugs may be substantial and bisphosphonates may be safer and more effectively used as front-line treatment. The following case illustrates the effects of bisphosphonates in older persons with bone metastases: • An 85-year-old woman with breast cancer metastatic to the bone since 1989 was seen by us in 1993. Her tumor had progressed with tamoxifen, aminogluthetimide, progestins, and estrogen at high doses. She had pain in her left femur, and a radiograph showed a 3cm lytic lesion, which was surgically stabilized with an intramedullary rod. She received several 6-week courses of vinorelbine intravenously at 20mg/m2, but myelotoxicity caused delay of treatment on three occasions. Her CA15–3 level increased in the meantime from 80ng/dl to 154ng/dl, and her bone pain progressed. She refused further chemotherapy, and we initiated treatment with pamidronate 60mg intravenously over 3 hours every 3 weeks, and oral calcium. The patient experienced immediate relief of pain that was maintained for 4 months. Central and peripheral nervous system recurrences The disabling effects of tumors on the nervous system vary in intensity from minimal to severe. The location and the extent of the lesion determine the functional effects. Neoplastic involvement of the central nervous system (CNS) may cause abnormality in cognitive (language, cognition, memory, and personality), motor, and sensory functions. Patients with CNS lesions are often dependent on caregivers.34–36 The involvement of cranial nerves, as seen in recurrences of head and neck cancer and in neoplastic meningitis, may affect important visceral functions such as swallowing, respiration, and speech.37,38 The rehabilitation program involves physiotherapy, and is aimed at minimizing the patient’s disability and allowing the patient to recover some degree of autonomy. One mainstay of recovery is maintenance of strength and function of non-paralyzed muscles. The patient is taught to use orthotic devices and to become self-supporting as much as possible. To assure the comfort of the patient at home in a familiar environment, it is important to enlist the cooperation of family members and to instruct all potential caregivers in the family in the use of orthotic devices. Skin and lymph node recurrences Skin and lymph node recurrences generate similar clinical pictures. The most frequent symptoms are pain (which often presents the characteristics of deafferentation pain), decreased range of motion of certain muscular groups, and secondary lymphedema. This lymphedema differs from that following surgery. Secondary lymphedema generally presents a rapid onset, with dramatic enlargement of the limb volume and hardening of

Comprehensive Geriatric Oncology

1484

soft tissues. There is often a widespread redness of the limb, which presents some telangiectasias at its root due to venous compression. The treatment of secondary lymphedema is palliative and quite different from that of surgical lymphedema. Treatment involves edemacentesis (Table 62.3 and Figure 62.6), low-compression pressotherapy,

Figure 62.6 Edemacentesis. electrical lymphatic drainage, pharmacological therapy with steroids, diuretics, and anticoagulants, and active and passive limb mobilization. Generally, high-compression pressotherapy and lymphatic drainage have been considered to be contraindicated in secondary lymphedema because of the possibility of dislodgement and distant spreading of tumor cells. It should be underlined, however, that this risk is more theoretical than real. Also, when dealing with recurrent and generally widely metastatic cancer, further spreading may have only a limited impact on survival or quality of life. Although effective, edemacentesis should be limited to the most refractory and most discomforting forms of lymphedema. This technique is painful and may cause serious infections. The most effective rehabilitation of secondary lymphedema is effective antineoplastic treatment. Palliative measures, when successful, may improve the quality of life of patients with metastatic cancer. Consequences of immobility Elderly patients with cancer often require prolonged bed rest. This may follow prolonged and difficult surgical procedures or be due to debilitation from cancer and from antineoplastic treatment. This enforced immobility has a number of important

Oncological rehabilitation of the elderly

1485

consequences.39 Aging processes, concomitant illnesses, and functional restrictions are risk factors that cause common complications of immobility more frequently in older than in younger adults. Metabolic and physiological changes associated with bed rest may compromise the patient’s medical and functional recovery.3 Respiratory problems Respiratory complications are likely to develop after general anesthesia. The patient may present difficulties in breathing and coughing from retained secretions, reduced thoracic expansion, and fear of pain. In elderly people, physiotherapy is performed both before and soon after surgery to prevent further complications such as atelectasis, postoperative pneumonia, and aspiration pneumonia. Deep breathing exercises should be taught preoperatively to obtain the patient’s utmost collaboration immediately after recovery from anesthesia. After the operation, the physiotherapist should teach the patient to cough effectively and with as little pain as possible in order to facilitate the removal of secretions. Deep vein thrombosis Advanced age and malignancies are both risk factors for deep vein thrombosis (DVT), which occurs more frequently in the lower extremities. Often pain and edema signal the presence of DVT, but a silent presentation of this complication is not uncommon. Compression devices and physical therapy may prevent DVT in older patients bedridden for prolonged periods of time. Active exercises of the lower extremities and deep breathing exercises should be practiced several times daily during both the preoperative and the postoperative periods. Patients at high risk of DVT should also be treated with anticoagulants. If a DVT does develop, active exercises can usually be continued while the patient is receiving anticoagulant therapy. Elastic bandages may control swelling and aid venous return. Pressure sores Pressure sores can be superficial or deep. Superficial sores involve the skin and present a shallow, painful ulcer. Deep pressure sores involve the subcutaneous tissues. Malnutrition is a major risk factor for both pressure sores and delayed wound healing. The most common sites of pressure ulcers are the heels, malleoli, great trochanter, sacrum, and elbows, where continued pressure induces the occlusion of blood vessels and deprives the tissues of nutrition. Other causes of pressure ulcers are ill-fitting splints, friction from rough sheets, and persistent soaking of the skin with urine secondary to incontinence. Prevention of pressure sores involves changing position every 2 hours. Sheepskin is often used under paralyzed or heavy patients to prevent friction. Air- and waterbeds are very expensive devices, but are very effective in reducing the risk of pressure sores. They may be indicated for patients subject to prolonged immobilization. Treatment of pressure ulcers involves debridement of the necrotic tissue, accurate cleansing, application of cicatrizing ointments, and laser therapy.

Comprehensive Geriatric Oncology

1486

Muscle atrophy Prolonged bed rest leads to atrophy and hypotonia of muscles; the most remarkable effect of this is alteration in posture and difficulty in walking. Muscle atrophy may be avoided with active movement either in the form of active exercises or as static (isometric) work. Contractures These complications are a particular concern to the elderly, since they lead to serious limitation of the range of motion and to pain. They are caused by shortening of muscles, tendons, and ligaments due to prolonged bed rest resulting in loss of joint motion. To prevent contractures, the patient should perform stretching exercises once or twice daily. Other preventive modalities include ultra-sound and laser therapy. Bone loss Osteoporosis due to immobility is more common in older than in younger patients. Pathological fractures may complicate osteoporosis. Frequent mobilization and oral biphosphonates are the mainstay treatment of this complication. Rehabilitative assessment A large body of literature deals with functional and quality of life assessment in disabled cancer patients. The various methods of assessment may differ in methodology according to pathology and patient characteristics. Irrespective of the method of assessment, maintenance of the patient’s autonomy and preservation of meaningful social relationships are major rehabilitative goals for the elderly.40 Thus, it is important to define impairment, disability, and handicap in a framework of reference to assess older individuals with cancer who present potentially disabling conditions.41 • impairment: loss or abnormality of physiological or anatomical structure or function (e.g. restricted gait); • disability: restriction or lack of ability to perform an activity (e.g. inability to write due to loss of hand movements or to dyslexia); • handicap: disadvantage suffered by individuals as a result of ill-health due to inability to fulfil a role that is normal for someone of their age, sex, and culture. The concept of quality of life in rehabilitation is connected with impairment of function, overall autonomy, and social relationships. The definition of quality of life lacks full consensus and an unambiguous method of evaluation.42–45 Nevertheless, there seems to be general agreement on some of the components of quality of life in persons with disease (health-related quality of life). These include physical function, emotional or psychological function, social function, and symptoms related to the disease or to its treatment.

Oncological rehabilitation of the elderly

1487

The rehabilitative assessment of elderly cancer patients is a dynamic process that begins at diagnosis and continues throughout the course of the illness. Although the methods of assessment may vary with the condition of the patient and the course of the disease, the focus of the assessment is always the same, namely to measure the impact of an anatomical or functional impairment on the patient’s overall well-being. In the evaluation of elderly cancer patients, we make a distinction between patients with metastatic cancer and those without metastases. This distinction stems from our experience. In general, full functional recovery may be obtained in the absence of metastases. In patients with metastatic cancer, the chances of full functional recovery are poorer and the main goals of rehabilitation are to ameliorate functional impairment and to delay the development of new dysfunctions and disabilities. We subscribe to the classification of rehabilitative outcome of elderly cancer patients proposed by Rustmeyer.46 This author envisioned three different situations: • Complete recovery: patients with favorable prognosis for whom we can predict a full recovery from the damage or an incomplete recovery that is still adequate to preserve previous autonomy and social relationship. • Incomplete recovery: patients who are still able to maintain some degree of autonomy and some meaningful social life, but at a poorer level than that preceding the disabling event. • Palliative treatment: patients affected by serious and irreversible motor or functional impairments for whom treatment aims to prevent further deterioration and to relieve the symptoms related to the disease. The different stages of disease and differences in functional impairment lead us to assume a distinct approach also in assessing the quality of life of patients with or without metastases. In this, we agree with authors who maintain that quality of life can only be defined by patients themselves according to their current situation. Young and Longmann47 define quality of life as the degree of satisfaction with present life circumstances. For Gerson,48 quality of life is measured by the degree to which an individual succeeds in accomplishing his/her desires, despite the constraints imposed upon him/her by a hostile or indifferent nature, God, or social order. Lewis49 emphasizes the psychological impact of disease on quality of life and measures quality of life from self-esteem, the presence of a purpose in life, and the degree of anxiety. Clearly, irrespective of the definition, cancer and cancer treatment have a substantial impact on the quality of life of each person.50 Assessment of patients without metastases The rehabilitative assessment is performed about 1 month after hospital discharge or completion of treatment, when the patient is aware of the treatment outcome and of the implications related to autonomy and social relationship. The first step is the assessment of voluntary motility of the muscle districts involved by surgery or radiotherapy. Oncological treatment can impair one or more of the following voluntary functions: swallowing, moving and speaking capabilities, urinary and fecal continence, and motor functions of the face, spine, and upper and lower extremities. The second and third steps evaluate how far the impairment of segmental voluntary motility affects overall

Comprehensive Geriatric Oncology

1488

autonomy (in feeding, dressing, providing for personal hygiene, and standing up/lying down) and social relationships (working occupation, leisure activities, and use of means of transport). Assessment of patients with metastases The rehabilitation team, when faced with an elderly patient with metastases, goes beyond the traditional concepts of psychiatric evaluation and focuses on the influence of progression of disease and of treatment on quality of life. This includes physical, psychological, and social dimensions, in addition to symptoms related to the cancer and its treatment. An essential part of the examination involves activities of daily living (ADL), which pertain to functional autonomy, instrumental activities of daily living (IADL), which pertain to personal autonomy, and advanced activities of daily living (AADL), which pertain to enjoyment of one’s life. It is extremely important to realize that some AADLs may be maintained and preserved even when ADLs and IADLs are lost. For example, we saw a mildly demented 72-year-old man with metastatic transitional cell carcinoma of the bladder who needed assistance in grooming and feeding and was unable to manage his own affairs, but still enjoyed his morning game of golf. Cytotoxic chemotherapy produced a marked relief of bone pain from bone metastases and allowed him to play golf for 6 additional months after diagnosis of his disease. The most frequent and disabling symptoms of metastatic cancer include pain, asthenia, sleeping abnormalities (with reversal of the daytime sleeping pattern), depression, and anxiety. It is important to weigh the capacity of the family to support the needs of the patient in the home environment. Conclusions The rehabilitation of elderly cancer patients is a multidisciplinary endeavor that may involve strict coordination with the work of other treatment teams. In particular, control of disabling problems, such as pain and malnutrition, is the first step toward successful rehabilitation. The support and cooperation of the patient’s family is essential to provide effective homecare in both functional and dysfunctional families. The recognition of a primary caregiver within the family is critical to the success of the rehabilitative effort. Family education should be incorporated in all rehabilitative plans involving patients who may spend a substantial amount of time at home. The focus of all rehabilitative efforts is improvement and preservation of the quality of life of the older cancer patient. This goal may be reached with different modalities in different cases. For patients with a substantial chance of cure or prolonged disease control, it is reasonable to attempt to restore the level of function that existed before the diagnosis of cancer. For patients with advanced and incurable malignancies, the main objective is control of discomfort due to cancer symptoms.

Oncological rehabilitation of the elderly

1489

Age itself does not impair rehabilitative efforts. Treatment plans for older patients should be continuously reviewed in the light of progression of the cancer and of other coexisting conditions. The rehabilitation of the older patient with cancer is an open area of continuous research to improve present outcomes. Rehabilitation is probably the youngest field of oncology, born from the continuous improvements in cancer treatment and the increasingly prolonged survival of cancer patients. Rresearch in this field is still in its initial phases. We should like to propose the following priorities for research related to oncological rehabilitation of the older patient: 1. Uniform evaluation, definition, and quantification of rehabilitative outcome. 2. Correlation between rehabilitation and quality of life. 3. Social rehabilitation. 4. Continuous exploration of new rehabilitative techniques, such as laser therapy, which appear to be very effective and to require minimal active participation from the patient.

References 1. Fentiman IS, Tirelli U, Monfardini S et al. Cancer in the elderly: why so badly treated? Lancet 1990; 335:1020–2. 2. Balducci L, Ades T, Carbone P et al. Issues in treatment. Cancer 1991; 68:2527–9. 3. Gerber L, Levinson S, Hicks JE et al. Evaluation and management of disability: rehabilitation aspects of cancer. In: Cancer: Principles and Practice of Oncology, 4th edn (DeVita VT, Hellman S, Rosemberg SA, eds). Philadelphia: JB Lippincott, 1993:2538–69. 4. Raven RW. Rehabilitation and Continuing Care in Cancer. Carnforth, UK: UICG/Parthenon, 1986. 5. Tish Knobf MK. Primary breast cancer: physical consequences and rehabilitation. Semin Oncol Nurs 1985; 1:214–24. 6. Foley KM. Pain assessment and cancer pain syndromes. In: Oxford Textbook of Palliative Medicine. (Doyle D, Hanks GWC, MacDonald N, eds). Oxford: Oxford University Press, 1993:148–65. 7. Mannheimer JS, Lampe GN. Clinical Transcutaneous Electrical Nerve Stimulation. Philadelphia: FA Davis, 1984. 8. Thompson JW, Filshie J. Transcutaneous electrical nerve stimulation (TENS) and acupuncture. In: Oxford Textbook of Palliative Medicine (Doyle D, Hanks GWC, MacDonald N, eds). Oxford: Oxford University Press, 1993:229–44. 9. Dini D, Bertelli G, Gozza A et al. Treatment of the post mastectomy pain syndrome with topical capsaicin. Pain 1993; 54:223–6. 10. Watson CP, Evans R. The post mastectomy pain syndrome and topical capsaicin: a randomized trial. Pain 1992; 51:375–9. 11. Sherrington CS. The Integrative Action ofthe Nervous System. New York: Scribner, 1906 (2nd edn New Haven: Yale University Press, 1947). 12. Foldi E, Foldi M, Clodius L. The lymphedema caos: a lancet. Ann Plast Surg 1988; 22:505–15. 13. Bertelli G, Venturini M, Forno G et al. Conservative treatment of postmastectomy lymphedema: a controlled, randomized trial. Ann Oncol 1991; 2:575–8. 14. Petrek JA, Pressman P, Smith R. Lymphedema: corrent issues in research and management. CA Cancer J Clin 2000; 50:292–307.

Comprehensive Geriatric Oncology

1490

15. Zanolla R, Monzeglio C, Balzarini A, Martino G. Evaluation of the results of three different methods of postmastectomy lymphedema treatment. J Surg Oncol 1984; 26:210–13. 16. Swedborg I. Effects of treatment with an elastic sleeve and intermittent pneumatic compression in postmastectomy patients with lymphoedema of the arm. Scand J Rehab Med 1984:16:35–41. 17. Mirolo BR, Bunce IH, Chapman M et al. Psychosocial benefits of postmastectomy lymphedema therapy. Cancer 1995; 18:197–205. 18. Casley-Smith JR, Morgan RG, Piller NB. Treatment of lymphedema of the arms and legs with 5,6-benzo-α-pyrone. N Engl J Med 1993; 329:1158–63. 19. Costello AM. Supporting the patient with problems relating to body image. In: Proceedings of the National Conference on Cancer Nursing. Chicago: American Cancer Society, 1974:36–40. 20. Kunrtzman SH, Gardner B, Kellner WS. Rehabilitation of the cancer patient. Am J Surg 1988; 155:791–803. 21. Venturini M, Bertelli G, Forno G et al. Colostomy irrigation in the elderly. Dis Colon Rectum 1990; 33:1031–3. 22. Dini D, Venturini M, Forno G et al. Irrigation for colostomized patients: a rational approach. Int J Colorectal Dis 1991; 6:9–11. 23. Davis BC. Amputations. In: Cash’s Textbook of Physiotherapy in Some Surgical Conditions (Downie PA, ed). London: Faber & Faber, 1979: 133–60. 24. Bentzen SM, Overgaard M. Early and late normal tissue injury after postmastectomy radiotherapy. Rec Res Cancer Res 1993; 130:59–78. 25. Dini D, Macchia R, Gozza A et al. Management of acute radiodermatitis. Canc Nurs 1993; 16:366–70. 26. Dutreix J. Human skin: early and late reactions in relation to dose and its time distribution. Br J Radiol 1986; 59:23. 27. Kaplan RS, Wiernik PH. Neurotoxicity of antineoplastic drugs. Semin Oncol 1982; 9:103. 28. Hildebrand J. Neurological Adverse Reactions to Anticancer Drugs. Berlin: Springer-Verlag, 1991. 29. Gallina EJ. Practical guide to chemotherapy administration for physicians and oncology nurses. In: Cancer: Principles and Practice of Oncology, 4th edn (DeVita VT, Hellman S, Rosemberg SA, eds): Philadelphia: JB Lippincott, 1993:2570–80. 30. Dorr RT. Antidotes to vesicant chemotherapy exstravasations. Blood Rev 1990; 4:41–60. 31. Bertelli G, Gozza A, Forno GB et al. Topical dimethylsulfoxide (DMSO) for the prevention of soft tissue injury after extravasation of vesicant cytotoxic drugs: a prospective clinical study. J Clin Oncol 1995; 13:2851–5. 32. Kitcher SS, Partridge CJ. A review of low level laser therapy. Physiotherapy 1991; 77:161–8. 33. Portenoy RK. Adjuvant analgesics in pain management. In: Oxford Textbook of Palliative Medicine, 2nd edn (Doyle D, Hanks GWC, MacDonald N, eds). Oxford: Oxford University Press, 1998:361–90. 34. Zochodne DW, Cairncross JG. Metastasis to the central nervous system. Cancer Growth Prog 989; 8:32. 35. Black PM. Brain tumors (I). N Engl J Med 1991; 324:1471–6. 36. Black PM. Brain tumors (II) N Engl J Med 1991; 324:1555–64. 37. Dudgeon B, DeLisa L, Miller R. Head and neck cancer: a rehabilitative approach. Am J Occup Ther 1980; 34:243. 38. Mathog RH. Rehabilitation of head and neck cancer patients: consensus on recommendations from the International Conference on Rehabilitation of the Head and Neck Cancer Patient. Head Neck 1991; 1–2. 39. Thompson KM. Complications following surgery. In: Cash’s Textbook of Physiotherapy in Some Surgical Conditions (Downie PA, ed). London: Faber & Faber, 1979. 40. Simpson JM, Forster A. Assessing elderly people. Should we all use the same scales? Physiotherapy 1993; 79:836–42.

Oncological rehabilitation of the elderly

1491

41. Ebrahim S. Measurement of impairment, disability and handicap. In: Measuring Outcomes of Medical Care (Hopkins A, Costain D, eds). London: Royal College of Physicians, 1990. 42. Forer S, Granger C et al. Functional Independence Measure. Buffalo, NY: The Buffalo General Hospital, State University of New York at Buffalo, 1987. 43. Donovan K, Sanson-Fisher RW, Redman S. Measuring quality of life in cancer patients. J Clin Oncol 1989; 7:959–68. 44. Cella DF, Tulsky DS, Gray G et al. The functional assessment of cancer therapy scale: development and validation of the general measure. J Clin Oncol 1993; 11:570–9. 45. Linacre JM, Heinemann AW, Wright BD et al. The structure and stability of the functional independence measure. Arch Phys Med Rehab 1994; 75:127–32. 46. Rustmeyer J. Rehabilitation. Physical and clinical aspects. In: Geriatrics (Platt D, ed). Berlin: Springer-Verlag, 1993. 47. Young K, Longmann A. Quality of life and persons with melanoma: a pilot study. Cancer Nurs 1983; 6:219–25. 48. Gerson E. On the quality of life. Am Soc Rev 1976; 41:793–806. 49. Lewis F. Experienced personal control and quality of life in late-stage cancer patients. Nurs Res 1982; 31:113–19. 50. Glaus A. Quality of life. A measure of the quality of nursing care. Support Care Cancer 1993; 1:119–23.

63 Family caregiving for older cancer patients William E Haley, Allison M Burton, Laurie A LaMonde, Ronald S Schonwetter Introduction Family caregiving for older adults is receiving increasing attention as an issue central to research, clinical care, and policy related to chronic illness.1 Caregiving research has grown dramatically as a result of several demographic changes.2 Increasing lifeexpectancy, with a resulting higher prevalence of a number of chronic illnesses, have led to more older people unable to care for themselves. Families commonly prefer to care for disabled relatives themselves, and older adults are usually highly motivated to remain in their homes, even with illness and disability. There are additional pressures for families to provide caregiving owing to the limits of community services, and the high financial burden associated with hospital and nursing home care. These changes have resulted in more families, particularly spouses and adult daughters, assuming the role of caregivers. Cancer causes changes in the family’s identity, roles, and daily functioning, and the effect of such changes may be profound and long-lasting, regardless of the outcome of the disease.3 Despite the benefits of homecare in cost-saving and convenience, family caregivers must deal with many unfamiliar situations and unexpected demands throughout the treatment and progression of the disease.4 Caregiving may lead to ‘hidden’ costs of care that are borne by family members, such as negative effects on psychological, social, or physical health functioning.5,6 Since caregivers may experience adverse effects, attention to caregiving issues is important in understanding how this major, unpaid segment of the healthcare and long-term care system works and what can be done to minimize the burdens of caregiving. While a variety of chronic conditions precipitate families into the caregiving role, the majority of research within this area has focused on caregivers of elderly patients with Alzheimer’s disease (AD) and other forms of dementia.2,6–8 This is unfortunate, because policy, practice, and research have neglected special caregiving issues associated with other illnesses. Cancer is highly prevalent and a leading cause of death in late life, with age emerging as a primary risk for the subsequent diagnosis of cancer.9 Compared with men and women in their mid-40s to mid-60s, the incidence of cancer quadruples among elderly men and doubles among elderly women.9 By 2030, cancer prevalence in the USA is projected at over six million elderly adults.9 The rising rate of cancer among this increasing population will affect the number of families assuming responsibility for these family members. This trend is apparent in the growing number of articles concerning family caregiving issues, and recently cancer caregivers have been studied using more methodologically sound research.

Family caregiving issues for older cancer patients

1493

Until recently, most psychosocial work in oncology focused on the patient, rather than the caregiver.10 Although some caregiving stressors may be similar between AD and cancer, there are likely to be several vastly different stressors that heighten the danger of overgeneralizing from one illness to another. In general, research suggests that dementia caregiving leads to greater ill effects for the caregiver,11,12 or equivalent effects.13–15 However, given the various forms of cancer, and the greatly differing issues faced by caregivers at varying stages of cancer, it would be premature to assume that cancer has a lesser impact on family members. Family cancer caregivers expressed unmet needs for social, volunteer, and professional support as their own physical and emotional health suffered.16 More research is needed to evaluate the specific issues involved in family caregiving for older cancer patients. This chapter will provide an overview of the field of caregiving research, emphasizing a stress process model as an organizing theme. Variations in the caregiver role, based upon differences by race/ethnicity, gender, and relationship to the patient, will be discussed. General findings from the field of caregiving research will be presented, including available information on issues specific to caregiving for older cancer patients. A number of issues that have received considerable attention in the literature on caregiving, such as the stresses of caregiving, possible mediators within the stress process model, mental and physical health outcomes of caregiving, interventions for caregivers, and issues around bereavement, will also be addressed, to provide direction for future work on cancer caregiving. Diversity and family caregiving Caregivers are often discussed as a homogeneous group, but caregiving varies greatly, depending upon such issues as relationship to the patient, gender, and race/ethnicity. One factor that has received considerable attention is differences between spouses and other family members as caregivers. Spousal caregivers often have extremely strong commitments to providing care for the patient, and may be especially vulnerable because of their own age, health, and willingness to sacrifice themselves for the care of their partner. The average number of hours spent in the caregiving role per week by a spouse is substantially greater than for an adult child, and spouses are shown to provide this care for a much longer period of time.17 Spousal caregivers in the USA, both AfricanAmerican and White, have been shown to be in poorer health than non-caregivers, yet they have no greater number of social supports to assist them in their caregiving roles.18 Spousal caregivers report more fatigue, less energy, and more sleep difficulty than nonspousal caregivers.19 Race and ethnicity are increasingly recognized as important in caregiving because of diverse cultural values and supports. Few studies have addressed racial/ethnic diversity in cancer caregivers, but in studies of dementia care, African-American caregivers have been shown to have much higher levels of overall coping mastery ability than White caregivers in a number of different studies.20–22 Research indicates that while adult children are a major source of care for both older Whites and African-Americans, the latter are more likely to be cared for by a member of their extended family than Whites.22 It is important to note that the differences in culture and family structure may account for

Comprehensive Geriatric Oncology

1494

the differences in the two races, and further studies are needed to investigate racial/ethnic differences among cancer caregivers. With societal changes in marital status and number of children per family, there are an increasing number of friends who are becoming caregivers in later life. The majority of these cases are older, never-married women who care for another older woman, and the number of these cases is likely to increase in the upcoming years.23 One possible explanation for the friend caregiver is that women who never marry are more likely to develop strong social support outside of their families, which increases the likelihood of both receiving care from non-family members and providing such care themselves. The quality of the relationship between the caregiver and the care recipient is an important aspect in the long-term effects of caregiving. Better relationship quality is directly related to lower levels of depression and decreased sense of role captivity for the caregiver.24 The stress Process model of caregiving Drawing from broader investigations in the field of stress and coping,25 family caregiving for chronically ill relatives has been viewed as an example of a major life stress to which individuals adjust with a variety of coping mechanisms. Stress process models of caregiving, widely applied to AD caregiving, typically focus on the specific stressors produced by the patient’s illness, the caregiver’s appraisals of these stressors, how the caregiver copes with these stressors, the extent and perceived quality of their social support system, and how the caregiver is affected by these stressors.2,7,8,26 In addition, factors such as perceived burden and the degree of resentment that this causes, caregiver optimism, level of negative social interaction, and restriction of activities due to the caregiving role affect the degree to which a caregiver is affected both mentally and physically by the demands of caregiving.4 Much current research on cancer caregiving has been atheoretical or focused on a specific aspect of the stress process, rather than utilizing a comprehensive stress process model. However, a comprehensive theoretical model of caregiving has been presented by Weitzner et al,4 demonstrating the impact of caregiver stressors on caregiver well-being. Fundamental to this stress process model is that there are marked individual differences in reactions to caregiving. Some caregivers react with depression or poor health, or feel a substantial burden, while other families show little or no negative impact (and may even report benefits from caregiving). Within a stress process model, common caregiving stressors include caring for the disabilities that accompany illness, or coordinating medical regimens. Objective measures of caregiving stressors’ severity are commonly found to predict surprisingly little variance in caregiver well-being, suggesting that mediating variables deserve attention.5,7,8 Appraisals, another component of this model, include the caregiver’s subjective perceptions of the patient’s problems and the acceptability of recent changes in the caregiver’s life due to the demands of caregiving.4,7,8,27,28 Another element of this model includes the coping responses of the caregiver. These can include such efforts as problem solving, emotional discharge, and seeking information.29 Social support is another widely studied potential moderator of caregiving stress, with the premise that a larger and more supportive social network would assist caregivers.30 Other potential

Family caregiving issues for older cancer patients

1495

individual difference variables affecting caregiver stress have also been described, including financial resources, distress appraisal, personality variables, relationship variables, and the availability of formal and informal help. Studies assessing the outcome of caregiving commonly include an assessment of the caregiver’s well-being, including outcomes such as the caregiver’s mental and physical health. More recent work on caregiving has also examined positive outcomes of caregiving, including improvement on measures of the caregiver’s level of mastery, satisfaction, marital communication,31 and other perceived benefits of caregiving. These factors within the stress process model will now be reviewed. Where possible, we highlight knowledge about caregiving specific to cancer; when necessary, we emphasize research drawn from other areas and suggest future directions for research in cancer caregiving. The stressors It is difficult to make general statements about the requirements of cancer caregiving because of the diversity of cancer in later life and the diversity of impairments that are experienced by caregivers. There are tremendous variations in the amounts and kinds of care required by the primary caregiver. For family caregivers of some cancer patients, minimal assistance with activities of daily living and emotional support for the older adult who is facing the illness are the daily requirements. However, families of patients with end-stage lung cancer may provide extensive assistance with medical care and activities of daily living. In a recent study, female caregivers of hospice patients with lung cancer reported spending an average of 127 hours per week in the caregiving role, and males reported an average of 105 hours per week.15 Caregivers who are highly stressed may be unable to continue to provide care, and the problems of caregivers appear to have a significant impact on subsequent problems during bereavement.32 Primary stressors of caregiving include those that directly relate to caregiving tasks, such as assisting the patient with daily dependencies, managing the patient’s symptoms, including their treatment-related side-effects, and handling the behavioral problems or emotional reactions of the patient. As noted by Sales et al,33 researchers studying cancer caregiving have used a variety of indices to estimate the severity of caregiving stressors, including stage of illness, prognosis, demands of caregiving, duration of illness, site of cancer, and patient distress.33 Greater caregiver distress has generally been found to be associated with more advanced cancer, higher caregiving demands, and elevated patient distress. However, few existing projects have included a number of desirable methodological features, such as a longitudinal follow-up of caregiving families through the progression of cancer symptoms and caregiving. Another limitation of this work is that it is unclear what mechanisms might be involved with a given stressor; for example, prognosis may be a marker for the caregiver having more caregiving tasks, versus an indication of anticipatory grieving. One method used to study caregiving stressors includes identifying specific caregiving tasks or patient behaviors and then evaluating the prevalence of these demands. For example, having the caregivers report the number of activities for which the patient requires assistance is one measure of primary stressors. Typically, these measures include the Activities of Daily Living (ADL), which include tasks such as dressing and bathing,

Comprehensive Geriatric Oncology

1496

and the Instrumental Activities of Daily Living (IADL), which include tasks such as shopping and meal preparation.34,35 Many studies that have examined the burdens faced by cancer caregivers combine patients with different cancer diagnoses, even though these self-care behaviors may vary greatly for patients with varying disease stages (e.g. metastasized cancer often entails more management due to the possibility of multiple organs being impaired). According to the review by Sales et al,33 the literature supports the notion that greater psychosocial problems, such as an increased sense of being overwhelmed, more impaired family relations, and greater mood disturbances, arise when cancer metastasizes. A major primary stressor is the patients’ disruptive behavioral problems, which can stem from treatment-related effects, disease-related effects, or pain, and can emerge or worsen as the illness progresses.5 Although behavioral problems were less common in one cancer caregiving project, these problems were described as the most difficult, upsetting, tiring, and hardest to manage among caregivers of terminally ill elderly patients.36 In general, this research suggests that the severity of patient self-care impairments has relatively little direct relationship to caregivers’ well-being, but that patients’ behavioral problems are more likely to be related to caregiver depression and burden.5,37 Kurtz et al38 reported that cancer patients’ symptoms indirectly predict caregivers’ depression, mediated by patient depression, again suggesting that the provision of physical care is less important in predicting caregivers’ distress than the potential ‘emotional contagion’5 of assisting a distressed relative. A few studies assessing the impact of cancer on caregivers have shown that certain stressor factors place caregivers at risk for adverse effects. For example, Jensen and Given39 found that caregivers experience greater fatigue when their schedules become more burdened (the demands and expectations placed upon them have increased). Other researchers have also found that relatives of cancer patients have poorer psychological well-being (high anxiety levels, mood disturbance, and overall mental health) during palliative care than active treatment or follow-up periods.40,41 Palliative care is typically associated with impending bereavement, aimed at comforting the patient rather than battling the cancer. Older cancer patients may have self-care impairments that increase the need for caregiving assistance, but they rarely display the disruptive behavioral problems that are seen in dementia patients unless additionally burdened with cognitive impairment or delirium. However, cancer caregivers face a number of other stressors that are extremely difficult, but have not been systematically characterized. Many of these occur because cancer patients may be undergoing aggressive treatment regimens aimed at palliative care, cure, or remission of cancer. For example, depending on the type of cancer, family caregivers may coordinate and witness complex medical regimens, such as chemotherapy, in an ambulatory or home setting. Family caregivers may also be responsible for escorting their loved one to radiation or chemotherapy sessions, and must assist the patient in coping with treatment-related side-effects, such as nausea and vomiting. Caregivers also face increasing stressors related to newer treatments such as infusion therapy in the home, given that they may face exposure to toxic drugs that represent a biological hazard.42 These diverse stressors need to be systematically studied in order to understand the role that primary stressors may have upon caregivers’ mental and physical health outcomes.

Family caregiving issues for older cancer patients

1497

Terminal care provides other unique stressors. Family caregivers must deal not only with special in-home care tasks, but also with managing the death of their relative, including such sensitive aspects as closing the eyes upon death or dealing with material expelled upon death.43 Most of the published reports that do examine possible stressors of cancer caregiving are descriptive and lack a measure that quantifies the broad range of caregiving stressors that are involved in cancer care. Existing research suggests that assisting with self-care tasks, managing patients’ symptoms44 and the treatment regime,45 and witnessing the suffering of the relative with cancer46 are major stressors identified by cancer caregivers. Future research that could better quantify common caregiving stressors faced by families of older cancer patients would be quite valuable in providing an objective measurement of the daily caregiving stressors faced by these families. Finally, caregiving can also lead to secondary stressors such as role strain, strains on finances and employment, changes in family structure and other areas due to providing care to the patient, and intrapsychic strains, or changes in the caregiver’s self-concept.2 These are ‘spillover’ effects that can occur, but may not universally do so. Contextual stressors include the difficulties to which the caregiver is exposed in the environment, independent of caregiving. As Aneshensel et al47 note, the difficulties faced by caregivers do not occur in a vacuum. Existing reports support that finances, managing the household, alterations in roles, employment changes, disrupted schedule, lack of family support, and loss of physical strength43,44,48 are secondary stressors identified as problems by cancer caregivers. Appraisals of stress There has been some effort to study cancer caregivers’ appraisals of their general circumstances. Stetz,45 using a measure of caregivers’ general appraisal of the demands of caregiving, found that female cancer caregivers appraised greater strain than did male caregivers. Oberst et al49 found that cancer caregivers appraised the challenges of caregiving (i.e. meeting responsibilities, managing problems, and creating solutions) as the most stressful area of caregiving on the Appraisal of Caregiving Scale (ACS). Carey et al50 reported that a negative appraisal of the caregiving situation mediated the relationship between caregiver burden and patient dependency; however, most caregivers in their study appraised caregiving as challenging, benign, or beneficial rather than as negative. Families also report that patient depression is highly stressful to the caregiver.51 In general, subjective appraisals of caregiving stressors have been found to be more predictive of caregiver burden and depression than objective severity of patient illness.52 Little is known about the role of appraising specific stressors in caregiving for older patients with cancer. While some primary stressors, including patient ADL and IADL impairment, and patient depression, are common to AD and cancer caregiving, the different problems specific to cancer deserve greater attention. As noted above, the development of measures of primary caregiving stressors in cancer is quite important, and these could include assessments of caregiver appraisals as well. For example, an instrument that could assess the prevalence and appraised stressfulness of cancer caregiving stressors would be valuable.

Comprehensive Geriatric Oncology

1498

Social support and activity Extensive literature has suggested that social supports are valuable in coping with a variety of life stresses.30 Research on AD caregiving has shown that being a caregiver does not diminish the objective size of the social support network, but significantly reduces caregivers’ perceived satisfaction with their levels of social support.20,53 Caregiving in AD also leads to a clear reduction in social activities for the caregiver, including visiting others outside of the home, lowered church attendance, and decreased formal social activities.20,53 In turn, smaller numbers of social supports, lower satisfaction with support, and fewer social activities have been found to be predictive of greater caregiver depression.7,52 As caregiving continues over a long period of time, changes in social support may become persistent and resistant to recovery even when caregiving ends.54 Research on cancer caregiving and social support has been surprisingly sparse.55 Most of the research has focused on examining the impact of cancer on the patient’s supportive network, neglecting the caregiver’s social support. The few studies available suggest that family caregivers of cancer patients experience a lack of perceived support from family members and medical staff.41,45,55 Breast cancer patients’ husbands with lower levels of social support had more difficulty adjusting than those with a higher level of social support.56 A longitudinal study found that low levels of perceived social support predicted poor functioning in the caregiver.57 One study found that cancer caregivers with a low level of daily emotional support were more depressed over time.58 Disruption of daily routines and reduced socializing by cancer caregivers has been examined.59 This study suggested that over half of cancer caregivers report disruption of their daily routines, with older caregivers reporting significantly fewer disruptions. Over half of the caregivers also reported reduced socializing with neighbors, friends, and others due to the demands of caregiving. Decreased social activities also produce a sense of interpersonal loss for the caregiver, and are associated with loss of intimacy and affection, increased symptoms of depression, and increased feelings of resentment.60 Caregivers, regardless of race or gender, demonstrate a need for support of their decisions. The earlier the support is received, the more effective is the decision making and the lower the caregiver’s stress.61 There is also some evidence demonstrating that caregivers who plan ahead are more likely to seek advice from others, both support groups and professionals, and to consider more alternatives because they have more information about the availability of community services.61 There is an important need for future cancer caregiving research to better specify the consequences of caregiving on the various dimensions of social activity and social support. For example, the size of the social network, subjective satisfaction with the network, engaging in visits with family and friends, and opportunities for more structured social activities may all be diminished by caregiving. Comparison with non-caregiving groups would also be advantageous in allowing for estimates of the impact of caregiving beyond changes due to other factors, such as aging. It is important to recognize that the patterns of social support established during caregiving may have important implications for subsequent adjustment of the caregiver during bereavement in the case of terminally ill patients.54

Family caregiving issues for older cancer patients

1499

Coping In recognition that life stress does not simply act on passive individuals, stress researchers have characterized the coping responses used in a variety of life stresses. A general taxonomy of coping includes approach coping, or efforts to directly face the stress through such means as seeking out information or problem solving, versus avoidance coping, which includes efforts to ignore problems, or wishful thinking.29 While avoidance coping may be effective in reducing distress in the short run, in general, research finds that caregivers who use approach coping more extensively have better psychological adjustment.25 Several studies have reported the benefits derived from the caregiver’s level of optimism as a coping mechanism. More optimistic caregivers appear less depressed and appraise the caregiving situation as having less of an impact upon their health and schedule than caregivers who scored low on optimism.38 Given et al62 also reported that the caregiver’s disposition of optimism predicted their mental health status and their reactions to caregiving. In other words, optimism appears to play an important role in helping caregivers adapt to the stressors of caregiving, and may play a valuable role in designing interventions.62 A number of studies have identified particular variables that are similar to some aspects of the coping construct; for example, studies have assessed the extent to which prognosis is openly discussed with the patient. Generally, families that communicate more openly with a terminal cancer patient tend to adjust better following bereavement.63,64 A study by Schumacher et al65 reported that the caregiver’s perceived efficacy of coping strategies mediated the relationship between depression and strain, providing support for the stress process model; however, these researchers acknowledge the limitations of having only one item assessing coping strategies. Future research needs to pay greater attention to assessing which caregivers’ coping mechanisms are empirically associated with better caregiving adjustment. Mental and physical health outcomes There is strong evidence that caregiving leads to an increased risk for depression, and conflicting evidence suggesting a risk to the physical health of the caregiver.5,6 Depression has been found to have a higher prevalence in AD caregivers than in noncaregivers or population norms across most studies.5,6 Physical health measures have not yielded consistent results across studies. Several studies suggest that caregivers have poorer health than non-caregivers or normative data,53,66–68 but results have been inconsistent.5 The lack of consistent results in the area of physical health is likely due in part to the difficulty in accurately measuring health through questionnaires, and the diverse groups of caregivers often included in studies. A review,69 examining studies that have used more sophisticated approaches to measure the effects of caregiving on physical health, found that caregiving can lead to lowered immune system functioning,67 altered response to influenza vaccination,70 and slower wound healing.71 This review also found that caregiving can lead to increased blood pressure72 and altered lipid profiles.73 A study by Schulz and Beach74 found evidence that caregivers who feel highly stressed in their roles showed a 63% increase in mortality over

Comprehensive Geriatric Oncology

1500

a 4-year period compared with noncaregivers or caregivers who do not report being highly stressed. An important caveat is that most of this research has been applied to dementia patients. The few studies that have attempted to assess the mental and physical health impact of caregiving for relatives with cancer have not detected marked negative effects. For example, in the review by Sales et al,33 several researchers indicated that most family members do not develop clinically problematic levels of emotional distress when coping with the demands of cancer. However, there are some families that do have difficult handling the impact of cancer. Mor et al59 reported rates of depression in cancer caregivers that are somewhat higher than population norms, but are lower than those found in AD caregivers. However, another study reported substantial levels of depression among cancer caregivers.75 Hinds46 reported that the percentage of families that would benefit from supportive services was greater than 30%. One study comparing dementia caregivers and lung cancer caregivers in hospices found that cancer caregivers reported the same levels of depression as dementia caregivers, but that female caregivers reported higher levels of depression than male caregivers.15 Haley et al15 also found that both lung cancer and dementia caregivers reported lower life satisfaction, lower perceived health, lower physical functioning, and higher levels of depression than non-caregiving controls and normative data. It is of note that this project focused on caregivers of patients who were severely impaired and terminally ill, thus exposing both groups of caregivers to very high levels of stress. Some caregivers do report benefits from the caregiving experience. For example, one study of men who survived testicular cancer found that they and their wives experienced improvements in a number of dimensions of marital outcomes, including increased intimacy, as a result of the experience of coping with cancer.31 Another study found that although caregiving may lead to depression, especially in those experiencing loss of physical strength, caregivers may sustain their quality of life by deriving self-esteem from caregiving.48 Further attention needs to be paid to the positive aspects of caregiving and the perceived benefits, such as satisfaction, that can be derived as a response to caregiving. Interventions for caregivers Because of the widely documented impact of AD caregiving on family members’ depression, a variety of psychosocial interventions have been developed to enhance caregiver adjustment.76 These interventions have included support groups, individual and family interventions, and respite care. Besides descriptive studies of these programs, a good deal of work has provided systematic evaluation of the efficacy of these interventions for AD caregivers on such variables as caregiver well-being, and delaying institutionalization of the patient.77 Support groups, although widely available and commonly very well received by participants, have been found to lead to relatively little objective improvement in caregivers’ mental health.77 Caregivers often report such benefits as gaining information, or satisfaction from knowing that others share their problems, but the typical formats of support groups are not focused or intensive enough to successfully combat caregivers’

Family caregiving issues for older cancer patients

1501

depression. Recent research has shown that group interventions that are more focused on teaching caregivers specific skills, such as anger management or increasing life satisfaction, have a greater impact on caregivers’ well-being.78 Other studies have shown that intensive individualized caregiver interventions not only decrease caregivers’ depression, but also can delay nursing home placement.79 Evaluations of respite care programs have generally found that caregivers are highly satisfied with these programs, but the results have been conflicting. One study indicated that they do not appear to significantly delay institutionalization or decrease caregivers’ depression.80 However a more recent study found that a respite period is likely to mitigate the negative consequences of caregiving if the social support resources are available to facilitate time away from the care receiver that completely frees the caregiver from the regular stressors associated with the caregiver role.81 In a survey assessing primary caregivers’ needs for overnight respite, nearly 60% of primary caregivers reported that the amount of sleep they were getting was inadequate and 70% of all respondents indicated that they would use overnight respite services.82 Another study found that a short length of stay by a cancer patient in an inpatient hospice (less than 8 days) was associated with better psychological well-being for spousal caregivers.83 The authors suggested that caregivers who placed their spouses in an inpatient hospice for longer periods of time may feel that they had abandoned their partners and therefore may have more guilt during the bereavement period. One important need that is expressed by caregivers is for information regarding the disease and its treatment. Family caregivers supporting cancer patients during bone marrow transplantation reported the need for information about preparing for caregiving, managing the care, facing challenges, developing supportive strategies, and discovering unanticipated rewards and benefits.84 Research has also shown that education about cancer pain improves family caregivers’ knowledge about pain and their experience caring for the elderly patient in pain.85 Several studies have evaluated the impact of intervention protocols on the well-being of the cancer caregiver. One individualized intervention that introduced problem-solving skills to aid cancer caregivers did not find greater improvement in the treatment group and the control group on a broad range of psychosocial measures. However, many of the caregivers in this project were found to have relatively low levels of caregiving activities, and the authors suggested that greater benefits of intervention were found among a highly distressed subsample of caregivers.75 Two intervention studies have produced impressive evidence of positive results for the caregiver from innovative interventions targeting both the patient and the caregiver. In the first intervention, specialized oncology homecare services were provided to terminally ill patients with lung cancer and their families in a randomized controlled trial.86 Psychological distress was significantly lower among spouses of patients receiving this intervention than among spouses of those receiving standard home care or office care. A very important aspect of this intervention is that its efficacy was sustained over a 13-month period. The second intervention was a transmural care intervention for terminal cancer patients.87 This study reported that the intervention had a significantly positive effect on the quality of life of the primary caregivers when compared with standard community care. Communication and continuity of care was the emphasis of this intervention, and the effect was evident both 1 week after discharge and 3 months after

Comprehensive Geriatric Oncology

1502

the death of the patient. The enhanced coordination and cooperation between professional caregivers working in intramural and extramural care was the main factor to which the authors attributed the results. This enhanced cooperation leads to improved supportive care for both patients and caregivers. Bereavement issues Since caregiving is highly stressful, some have thought that the end of caregiving might afford family members some relief after what is often a lengthy and highly stressful process. However, the available research suggests that caregivers may experience longterm sequelae after long-standing efforts at caregiving. When caregiving ends with the death of a relative, another major life stress begins: bereavement. The bereavement process may be made more difficult by the depletion of caregivers’ resources, alterations in their social supports and activities, and the lingering reminders of caregiving and loss. In one unique longitudinal project, Bodnar and Kiecolt-Glaser54 found that, even 4 years after the death of a relative with dementia, caregivers as a group reported levels of depression as high as when they had active caregiving responsibilities. Of interest is that two factors were found to be particularly predictive of continued distress: low levels of social support and high levels of rumination (repetitive thinking) about the caregiving situation. In another project, it was found that family strain during caregiving predicted greater subsequent distress after the death of the patient.88 One study has found that people with a ruminative coping style, who tend to focus excessively on their own emotional reactions to a trauma, compared with those without a ruminative coping style, seek more social support, and benefit more from social support, but report receiving less social support.89 Cancer caregiving may also lead to such troublesome problems for bereaved caregivers.90 It appears likely that caregivers who become socially isolated or depressed after lengthy caregiving duties may have similar problems in resolving their grief and resuming an active life. For example, Mullan91 suggested that caregiving can lead to problems during subsequent bereavement when psychological or social resources that could assist with adjustment to bereavement became depleted through the process of caregiving. It is noteworthy that one report found that depression among bereaved spouses commonly begins 6 months before the death of the spouse, which may be related to anticipatory grief or the strains of caregiving.92 Hinton93 reported that cancer patients’ and their caregivers’ level of awareness of death were positively correlated, as well as their levels of acceptance, and that caregivers were more willing to accept death when the patients were over 70, weak, unable to concentrate, and demonstrated low quality of life. A number of interventions have been used to assist families with the grieving process, including support groups, and family support offered through hospice programs. It is important to note that hospices provide grief counseling prior to death and that follow-up contact is made in 100% of those who utilize hospice services, while only 2% of nursing homes reported the availability of these services.94 This same study found that 76% of nursing homes were unable to offer a referral to a counseling or psychiatric professional when bereavement intervention was deemed necessary.94 While such interventions appear promising, future research needs to be more rigorous in assessing the impact of

Family caregiving issues for older cancer patients

1503

interventions on the long-term outcome of bereavement. Clinical experience tends to support the value of hospice bereavement services,95 but these benefits have been difficult to document with objective evidence.96 Of particular interest in the current context is whether psychosocial intervention during caregiving might prevent complications in the bereavement process. Many hospice programs attend to such issues by beginning bereavement counseling before the patient’s actual death.96 The impact of such intervention needs further research. Implications for healthcare delivery Geriatric medical care has been described as differing from the typical care of younger adults because of the common inclusion of a triad of doctor, patient, and caregiver.97 In efforts to focus on the care of older patients with cancer, it is important to realize that the family member is much more than the person who delivers the patient for treatment. With older adults, the family caregiver is often an essential informant about patient status, and is necessary to the implementation of any treatment regimen. Attention to caregivers’ concerns and distress is thus essential to successful comprehensive care of these patients. The American Medical Association Council on Scientific Affairs has strongly urged the formation of partnerships between physicians and family caregivers in the care of older adults.98 While not specific to oncology, this paper outlines a number of specific ways in which physicians and other healthcare providers can improve care for older adults by recognizing the family context of late-life disease. For example, families greatly appreciate such simple assistance as brochures and referrals to information services. Caregivers of older patients often need referrals to community agencies. Family caregivers also value some acknowledgment from healthcare providers of the valuable and often heroic efforts made in caregiving, and attention to the caregiver’s distress. Other recommendations specific to the context of cancer caregiving are provided in another report.” This ideal of viewing the family, rather than just the patient (or their disease), as the target of treatment is currently difficult to attain in many settings, but should be a primary goal in geriatric care. Summary and future directions Family caregivers provide largely hidden care that is essential to the well-being of cancer patients—sometimes at a significant personal cost. More research focusing on the problems of cancer caregivers using stronger methodologies is clearly needed in order to better understand their needs and concerns. Since this is a relatively recent area of exploration, most of the research that has been conducted on cancer caregiving for older patients is limited methodologically, in terms of small, convenient samples collected at one point in time, across various types of cancer, with a primary focus on terminal patients.100 One high priority for future research in this area should be identification of cancer caregivers who are at risk for depression, so that these families can be targeted for services. The literature reviewed above points to factors that are likely to place cancer caregivers at risk: a combination of high levels of caregiving stressors, coupled with

Comprehensive Geriatric Oncology

1504

poorer social supports and/or maladaptive appraisals and coping responses. In terms of intervention, systematic evaluation of the efficacy of caregiver interventions will be important in improving these services, and justifying their existence in a cost-driven system of care. Intervention studies should target cancer caregivers who show evidence of significant depression, or risk factors for depression; previous research has shown that many caregivers cope well without special intervention programs. Attention to family caregivers is important not only because of the potential human costs that caregivers experience, but also because unpaid family caregivers are an essential part of the healthcare system that is being strained by efforts to cut costs, often by increasing demands on family members. Better information on the costs of caregiving, and on factors that help caregivers adjust better to the potentially overwhelming task of caring for a loved one at home, is essential. References 1. Kane RA, Penrod J. Aging and Family Caregiving Policy. Newbury Park: Sage, 1995. 2. Pearlin LI, Mullan JT, Semple SJ, Skaff MM. Caregiving and the stress process: an overview of concepts and their measures. Gerontologist 1990; 30:583–94. 3. Blanchard CG, Albrecht TL, Ruckdeschel JC. The crisis of cancer: psychological impact on family caregivers. Oncology 1997; 11: 189–94. 4. Weitzner MA, Haley WE, Chen H. The family caregiver of the older cancer patient. Hematol Oncol Clin North Am 14:269–81. 5. Schulz R, O’Brien AT, Bookwala J, Fleissner K. Psychiatric and physical morbidity effects of dementia caregiving: prevalence, correlates, and causes. Gerontologist 1995; 35:771–91. 6. Schulz R, Visintainer P, Williamson GM. Psychiatric and physical morbidity effects of caregiving. J Gerontol 1990; 45:181–91. 7. Haley WE, Levine EG, Brown SL, Bartolucci AA. Stress, appraisal, coping, and social support as predictors of adaptational outcome among dementia caregivers. Psychol Aging 1987; 2:323– 30. 8. Gatz M, Bengtson VL, Blum MJ. Caregiving families. In: Handbook of the Psychology of Aging, 3rd edn (Birren JE, Schaie KW, eds). San Diego: Academic Press, 1990:404–26. 9. Schonwetter RS. Geriatric oncology. Cancer Epidemiol Prev Screening 1992; 19:451–63. 10. Cassileth BR, Chou JN. Psychosocial issues in the older patient with cancer. In: Geriatric Oncology (Balducci L, Lyman GH, Ershler WB, eds). Philadelphia: JB Lippincott, 1992:311– 19. 11. Clipp EC, George LK. Dementia and cancer: a comparison of spouse caregivers. Gerontologist 1993; 33:534–41. 12. Krizek-Karlin N, Bell PA. Self-efficacy, affect, and seeking support between caregivers of dementia and non-dementia patients. J Women Aging 1992; 4:59–78. 13. Rabins PV, Fitting MD, Eastham J, Fetting J. The emotional impact of caring for the chronically ill. Psychosomatics 1990; 31:331–6. 14. Stommel M, Wang S, Given CW, Given B. Confirmatory factor analysis (CFA) as a method to assess measurement equivalence. Res Nurs Health 1992; 15:399–405. 15. Haley WE, LaMonde LA, Han B et al. Family caregiving in hospice: effects on psychological and health functioning among spousal caregivers of hospice patients with lung cancer or dementia. Hospice J 2001; 15(4): 1–18. 16. Steele RG, Fitch MI. Needs of family caregivers in patients receiving home hospice care for cancer. Oncol Nurs Forum 1996; 23: 823–8.

Family caregiving issues for older cancer patients

1505

17. Montgomery RJ, Kosloski KA. Longitudinal analysis of nursing home placement for dependent elders cared for by spouses vs adult children. J Gerontol 1994; 49: S62–74. 18. Wallsten SS. Effects of caregiving, gender, and race on the health, mutuality, and social supports of older couples. J Aging Health 2000; 12:90–111. 19. Teel CS, Press AN. Fatigue among elders in caregiving and noncaregiving roles. West J Nurs Res 1999; 21:498–520. 20. Haley WE, West CA, Wadley VG et al. Psychological, social, and health impact of caregiving: a comparison of Black and White dementia family caregivers and noncaregivers. Psychol Aging 1995; 10:540–52. 21. Pickett SA, Vraniak DA, Cook JA, Cohler BJ. Strength in adversity: Blacks bear burden better than Whites. Prof Psychol Res Pract 1993; 24:460–7. 22. Peek MK, Coward RT, Peek CW. Race, aging, and care. Res Aging 2000; 22:117–42. 23. Himes CL, Reidy EB. The role of friends in caregiving. Res Aging 2000; 22:315–36. 24. Lawrence RH, Tennstedt SL, Assmann SF. Quality of the caregivercare recipient relationship: Does it offset negative consequences of caregiving for family caregivers? Psychol Aging 1998; 13:150–8. 25. Lazarus RS, Folkman S. Stress, Appraisal, and Coping. New York: Springer-Verlag, 1984. 26. Vitaliano PP, Russo J, Young HM et al. Predictors of burden in spouse caregivers of individuals with Alzheimer’s disease. Psychol Aging 1991; 6:392–402. 27. Zarit SH. Issues and directions in family intervention research. In: Alzheimer’s Disease Treatment and Family Stress: Directions for Research (Light E, Lebowitz BD, eds). Washington, DC: National Institute of Mental Health, 1989. 28. Niedereche G, Fruge E. Dementia and family dynamics: clinical research issues. J Geriatr Psych 1984; 17:21–56. 29. Moos RH, Cronkite R, Billings A, Finney J. Health and Daily Living Form Manual. Palto Alto: Social Ecology Laboratory, Stanford University and Department of Veterans’ Affairs Medical Centers, 1984. 30. Sarason BR, Sarason IG, Pierce GR (eds). Social Support: An Interactional View. New York: Wiley, 1990. 31. Gritz ER, Wellish DK, Siau J, Wang HJ. Long-term effects of testicular cancer on marital relationships. Psychosomatics 1990; 31: 301–12. 32. Schulz R, Newsom JT, Fleissner K et al. The effects of bereavement after family caregiving. Aging Mental Health 1997; 1:269–82. 33. Sales E, Schulz R, Biegal D. Predictors of strain in families of cancer patients: a review of the literature. J Psychosoc Oncol 1992; 10:1–26. 34. Katz S, Ford AB, Moskowitz RW et al. Studies of illness in the aged. The index of ADL: a standardized measure of biological and psychological function. JAMA 1963; 185:914–19. 35. Lawton M, Brody E. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 1969; 9: 179–86. 36. Yang C, Kirschling JM. Exploration of factors related to direct care and outcomes of caregiving: caregivers of terminally ill older persons. Cancer Nurs 1992; 15:173–81. 37. Miaskowski C, Kragness L, Dibble S et al. Differences in mood states, health status, and caregiver strain between family caregivers of oncology outpatients with and without cancerrelated paint. J Pain Sympt Manage 1997; 13:138–47. 38. Kurtz ME, Kurtz JC, Given CW, Given B. Relationship of caregiver reactions and depression to cancer patients’ symptoms, functional states and depression—a longitudinal view. Soc Sci Med 1995; 40: 837–46. 39. Jensen S, Given BA. Fatigue affecting family caregivers of cancer patients. Cancer Nurs 1991; 14:181–7. 40. Cassileth B, Lusk E, Brown L, Cross P. Psychosocial status of cancer patients and next-of-kin: normative data from POMS. J Psychosoc Oncol 1985; 3:99–105.

Comprehensive Geriatric Oncology

1506

41. Cassileth BR, Lusk E, Strouse T et al. A psychological analysis of cancer patients and their next-of-kin. Cancer 1985; 55:72–6. 42. McNally JC. Home care. In: Cancer Nursing: Principles and Practice (Groenwald SL, Frogge MH, Goodman M, Yarbro CH, eds). Boston: Jones and Bartlett, 1993:1403–31. 43. Hine V. Dying at home: Can families cope? Omega 1979–80; 10: 175–86. 44. Blank JJ, Longman, AJ, Atwood JR. Perceived home care needs of cancer patients and their caregivers. Cancer Nurs 1989; 12:78–84. 45. Stetz KM. Caregiving demands during advanced cancer. Cancer Nurs 1987; 10:260–8. 46. Hinds C. The needs of families who care for patients with cancer at home: Are we meeting them? J Adv Nurs 1985; 10:575–81. 47. Aneshensel CS, Pearlin LI, Mullan JT et al. Profiles in Caregiving: The Unexpected Career. San Diego: Academic Press, 1995. 48. Nijboer C, Triemstra M, Tempelaar R et al. Determinants of caregiving experiences and mental health of partners of cancer patients. Cancer 1999; 86:577–88. 49. Oberst MT, Gass KA, Ward SE. Caregiving demands and appraisal of stress among family caregivers. Cancer Nurs 1989; 12:209–15. 50. Carey PJ, Oberst MT, McCubbin MA, Hughes SH. Appraisal and caregiving burden in family members caring for patients receiving chemotherapy. Oncol Nurs Forum 1991; 18:1341–8. 51. Teri L, Traux P, Logsdon R et al. Assessment of behavioral problems with dementia: the revised memory and behavior problems checklist. Psychol Aging 1992; 185:622–31. 52. Haley WE, Roth DL, Coleton MI et al. Appraisal, coping, and social support as mediators of well-being in Black and White Alzheimer’s family caregivers. J Consult Clin Psychol 1996; 64:121–9. 53. Haley WE, Levine EG, Brown SL et al. Psychological, social, and health consequences of caring for a relative with senile dementia. J Am Geriatr Soc 1987; 35:405–11. 54. Bodnar JC, Kiecolt-Glaser JK. Caregiver depression after bereavement: chronic stress isn’t over when it’s over. Psychol Aging 1994; 9:372–80. 55. Clark JC, Gwin RR. Psychosocial responses of the family. In: Cancer Nursing: Principles and Practice (Groenwald SL, Frogge MH, Goodman M, Yarbro CH, eds). Boston: Jones and Bartlett, 1993: 468–83. 56. Northouse LL. Social support in patients’ and husbands’ adjustment to breast cancer. Nurs Res 1988; 37:91–5. 57. Ell K, Michimoto R, Mantel J et al. Longitudinal analysis of psychosocial adaptation among family members of patients with cancer. J Psychosom Res 1988; 32:429–38. 58. Nijboer C, Tempelaar R, Triemstra M et al. The role of social and psychological resources in caregiving of cancer patients. Cancer 2001; 91:1029–39. 59. Mor V, Allen S, Malin M. The psychosocial impact of cancer on older versus younger patients and their families. Cancer Suppl 1994; 74:2118–27. 60. Williamson GM, Shaffer DR, Schulz R. Activity restriction and prior relationship history as contributors to mental health outcomes among middle-aged and older spousal caregivers. Health Psychol 1998; 17:152–62. 61. Wackerbarth S. Modeling a dynamic decision process: supporting the decisions of family members with dementia. Qual Health Res 1999; 9:294–314. 62. Given CW, Stommel M, Given B et al. The influence of cancer patients’ symptoms and functional states on patients’ depression and family caregivers’ reaction and depression. Health Psychol 12: 277–85. 63. Cohen P, Dizenhuz I, Winget C. Family adaptation to terminal illness and death of a parent. Soc Casework 1977; 58:223–8. 64. Northouse LL, Swain MA. Adjustment of patients and husbands to the initial impact of breast cancer. Nurs Res 1987; 36:221–5. 65. Schumacher KL, Dodd MJ, Paul SM. The stress process in family caregivers of persons receiving chemotherapy. Res Nurs Health 1993; 16:395–404.

Family caregiving issues for older cancer patients

1507

66. Fuller-Jonap F, Haley WE. Mental and physical health of male caregivers of a spouse with Alzheimer’s disease. J Aging Health 1995; 7:99–118. 67. Kiecolt-Glaser JK, Dura JR, Speicher CE et al. Spousal caregivers of dementia victims: longitudinal changes in immunity and health. Psychosom Med 1991; 53:345–62. 68. Pruchno RA, Potashnik SL. Caregiving spouses: physical and mental health in perspective. J Am Geriatr Soc 1990; 45:697–705. 69. Haley WE. The family caregiver’s role in Alzheimer’s disease. Neurology 1997; 48(S6): S25– 9. 70. Kiecolt-Glaser JK, Glaser R, Gravenstein S et al. Chronic stress alters the immune response to influenza virus vaccine in older adults. Proc Natl Acad Sci USA 1996; 93:3043–7. 71. Kiecolt-Glaser JK, Marucha PT, Malarkey WB et al. Slowing of wound healing by psychological stress. Lancet 1995; 346:1194–6. 72. King AC, Oka RK, Young DR. Ambulatory blood pressure and heart rate responses to the stress of work and caregiving in older women. J Gerontol 1994; 49: M239–45. 73. Vitaliano PP, Russo J, Niaura R. Plasma lipids and their relationships with psychosocial factors in older adults. J Gerontol 1995; 50: P18–24. 74. Schulz R, Beach SR. Caregiving as a risk factor for mortality: the caregiver health effects study. JAMA 1999; 282:2215–19. 75. Toseland RW, Blanchard CG, McCallion P. A problem solving intervention for caregivers of cancer patients. Soc Sci Med 1995; 40: 517–28. 76. Zarit SH, Orr NK, Zarit JM. The Hidden Victims of Alzheimer’s Disease: Families Under Stress. New York: New York University Press, 1985. 77. Knight BG, Lutzky SM, Macofsky-Urban F. A meta-analytic review of interventions for caregiver distress: recommendations for future research. Gerontologist 1993; 33:240–8. 78. Gallagher-Thompson D, DeVries H. ‘Coping with frustration’ classes: development and preliminary outcomes with women who care for relatives with dementia. Gerontologist 1994; 34:548–52. 79. Mittelman MS, Ferris SH, Steinberg G et al. An intervention that delays institutionalization of Alzheimer’s disease patients: treatment of spouse-caregivers. Gerontologist 1993; 33:730–40. 80. Lawton MP, Brody EM, Saperstein AR. Respite for Caregivers of Alzheimer’s Patients: Research and Practice. New York: Springer-Verlag, 1991. 81. Strang VR, Haughey M. Respite—a coping strategy for family caregivers. West J Nurs Res 1999; 21:450–71. 82. Bramwell L, MacKenzie J, Laschinger H et al. Need for overnight respite for primary caregivers of hospice clients. Cancer Nurs 1995; 18:337–43. 83. Gilbar O. Does length of stay at a hospice affect psychological adjustment to the loss of the spouse? J Palliat Care 1998; 14: 16–20. 84. Stetz KM, McDonald JC, Compton K. Needs and experiences of family caregivers during marrow transplantation. Oncol Nurs Forum 1996; 23:1422–7. 85. Ferrell BR, Grant M, Chan J et al. The impact of cancer pain education on family caregivers of elderly patients. Oncol Nurs Forum 1995; 22:1211–18. 86. McCorkle R, Yost LS, Jepson C et al. The effects of home nursing care for patients during terminal illness on the bereaved’s psychological distress. Nurs Res 1998; 47:2–10. 87. Smeenk FW, de Witte LP, van Haasregt JC et al. Transmural care of terminal cancer patients: effects on the quality of life of direct caregivers. Nurs Res 1998; 47:129–36. 88. Bass DM, Bowman K. The transition from caregiving to bereavement: the relationship of carerelated strain and adjustment to death. Gerontologist 1990; 30:35–42. 89. Nolen-Hoeksema S, Davis CG. ‘Thanks for sharing that’: ruminators and their social support networks. J Pers Soc Psych 1999; 17:801–14. 90. McHorney CA, Mor V. Predictors of bereavement depression and its health services consequences. Med Care 1988; 26:882–93.

Comprehensive Geriatric Oncology

1508

91. Mullan JT. The bereaved caregiver: a prospective study of changes in well-being. Gerontologist 1992; 32:673–83. 92. Lichtenstein P, Gatz M, Pedersen NL et al. A Cotwin-control study of response to widowhood. J Gerontol 1996; 51: P279–89. 93. Hinton J. The progress of awareness and acceptance of dying assessed in cancer patients and their caring relatives. Palliat Med 1999; 13:19–35. 94. Murphy K, Hanrahan P, Luchins D. A survey of grief and bereavement in nursing homes: the importance of hospice grief and bereavement for the end-stage Alzheimer’s disease patient and family. J Am Geriatr Soc 1997; 45:1104–7. 95. Longman AJ. Effectiveness of a hospice community bereavement program. Omega 1993; 27:165–75. 96. Hayslip B Jr, Leon J. Hospice Care. Newbury Park: Sage, 1992. 97. Silliman RA. Caring for the frail older patient: the doctor-patient-family caregiver relationship. J Gen Intern Med 1989; 4:237–41. 98. Council on Scientific Affairs American Medical Association. Physicians and family caregivers: a model for partnership. JAMA 1993; 269:1282–4. 99. Northouse LL, Peters-Golden H. Cancer and the family: strategies to assist spouses. Semin Oncol Nurs 1993; 9:74–82. 100. Biegel DE, Sales E, Schulz R. Family Caregiving in Chronic Illness. Newbury Park: Sage, 1991.

64 Interdisciplinary teams in geriatric oncology Janine Overcash Introduction The number of people aged 75 and over in North America is increasing. Statistics from the US Centers for Disease Control in Atlanta (CDC) suggest that people over 75 made up 5.6% of the population in 1995 and will increase to 9.3% in 2030.1 Most seniors are very healthy and active; however, with respect to those diagnosed with a malignancy, 35% of cancer deaths in men and 46% in women occur at age 75 or older.2 According to Repetto et al,3 deaths associated with cardiovascular disease are declining as compared with cancer-related deaths, which are increasing. In response to the issues of aging and cancer, the development of a Geriatric Oncology Program (GOP) may help meet the health needs of the older person with cancer. The intention of this chapter is to consider the definition of a Multidisciplinary Geriatric Program (MGP), the disciplines that are generally included, the use of assessment instruments, advantages of a geriatric program, and the target populations of seniors that may most benefit. The definition of a geriatric oncology program (GOP) A GOP is a dynamic construct that can be molded to meet of needs of various older populations, or more specifically, individual seniors. The factor that is crucial to a GOP is the multidisciplinary team component. Health professionals working together for the common goal of meeting the individual needs of a senior patient is a reasonable characterization of a GOP. Various facilities may include disciplines that other facilities do not. For example, for populations where seniors are transient (such as Florida), the addition of a pharmacist may be effective in evaluating the many medications prescribed by different healthcare providers. Providers who practice where many seniors are likely to have mobility limitations (such as a veterans hospital) may choose to provide a physical therapist as part of the GOP. The composition of disciplines can vary, but the goal of the program remains essentially to keep seniors as functional as possible. Why are multiple disciplines included in a GOP? This is a valid question, and one that many healthcare institutions and those in private practice may pose. Issues such as the expense of hiring, reimbursement issues, and occupying an outpatient clinic room for several hours may be huge hurdles for those considering formulating a GOP. The answer is that many seniors present with many comorbidities. Fried et al4 suggested that people 76 and over have approximately five comorbidities. Conversely, a single complaint is

Comprehensive Geriatric Oncology

1510

likely to be motivated by several of these comorbid conditions.5 With that dimensionality in mind, each separate discipline can assess, control, or detect the various confounding diseases that may have an effect on cancer treatment. The combination of disciplines such as nursing, medicine, and social work is fairly standard in the design of an GOP. The needs of the population for which the GOP is directed should dictate how the program is constructed. The basic multidisciplinary make-up of a GOP is fairly similar among institutions with respect to medicine, nursing, and social work (Table 64.1). Specialties such as a geriatrician/oncologist and a geriatric nurse practitioner offer expertise that typically is not included in other cancer treatment teams. Pharmacokinetic changes associated with reduced renal excretion and reduced intracellular catabolism of drugs will have an effect on cancer treatment. Moreover, older people are likely to experience prolonged myelosuppression, mucositis, and the potential for cardiomyopathy and neuropathy from cancer therapy, which should be of consideration when treating the senior with cancer.6 Geriatric-oriented knowledge can prevent complications that can arise from cancer therapy. Other disciplines such as a dietitian for the assessment of nutritional requirements while an older person is undergoing cancer therapy can provide some proactive health maintenance interventions. Consults from disciplines such as psychology can provide interventions for those who screen positive for depression or experience coping issues associated with their diagnosis.

Table 64.1 Disciplines that are frequently included in a Geriatric Oncology Program (GOP) • Nurse practitioner • Primary care nurse • Oncologist/geriatrician • Dietitian • Pharmacist • Social worker

Each team member performs a discipline-specific assessment and reports to the central person who is formulating each intervention into a plan of care. Communication among the GOP is essential to the compilation of the individual components detected subsequent plan of care. The Comprehensive Geriatric Assessment (CGA) The assessment used by each member of the GOP contributes to a Comprehensive Geriatric Assessment CGA. This is a tool addressing a variety of multidisciplinary issues that contribute to a total health picture of the patient and family or support person. The CGA is an assessment instrument used primarily in geriatrics. It looks not only at the physical assessment, but also at functionality, emotional issues, social support issues,

Interdisciplinary teams in geriatric oncology

1511

economic concerns, dementia, and other components vital to the healthcare needs of the older individual (Table 64.2). Like the make-up of a GOP, a CGA is geared to a specific population. Some GOPs may elect to assess quality of life, or locus of control, while others may focus on functional independence or depression. A multitude of tools are available for any one of the constructs deemed necessary to assess. The purpose of the CGA is to act as a guide in collecting multifocused assessment information in order to make a medical diagnosis, to provide cancer treatment, and as a measure of treatment outcome. Both inpatients and outpatients benefit from a CGA.7–11 The American Geriatrics Society developed criteria to establish a target

Table 64.2 Components of a Comprehensive Geriatric Assessment (CGA) • History and physical examination • Functional assessment • Depression • Cognition screening instrument • Nutritional assessment • Medications • Psychosocial support

demographic of patients that may benefit from a CGA.12 It was determined that patients with potentially treatable problems that are medical, functional, or psychosocial and that impair independent living are those that should be targeted for a CGA. These problems include: • confusion; • polypharmacy; • failure to thrive; • abusive home situation. The outpatients who were found to benefit from a CGA were those with: • decreased functional status; • falls; • confusion; • incontinence; • death of a spouse; • polypharmacy; • failure to thrive; • use of in-home assistive services; • use of adult daycare. Inpatients who tend not to benefit from a CGA are those with a terminal illness or severe dementia and those patients without an alternative to nursing home placement. Outpatients who are not likely to benefit are those in need of urgent hospitalization and

Comprehensive Geriatric Oncology

1512

those without any significant functional impairment. Some general characteristics of patients who benefit from a CGA are those of frailty; these are people who are entering a nursing home, undergoing repeated hospitalizations, or with comorbid conditions, functional dependencies, and psychosocial issues.13 Geriatric syndromes such as falls, incontinence, malnutrition, and polypharmacy are other indications of those who would benefit from a CGA. The CGA can be a basis for formulating a medical treatment plan. Predicting treatment tolerance and determining cytotoxic therapy are important functions of a CGA.6 Through the use of a CGA, it may be determined that a person who has experienced a decline in functional status over the administration of two courses of chemotherapy may not endure large amounts of chemotherapeutic agents. Another function would be to provide follow-up data on seniors as they proceed through their cancer treatment. For cognitive deficits, the use of a CGA provided by a GOP found patients who had delirium to experience shorter duration, less severity and a higher degree of general physical functioning compared to those who did not encounter a CGA.14 The initial CGA can act as a baseline, whereas subsequent assessments can detail health status throughout cancer treatment. This ongoing assessment may help recognize toxicities before they become largely symptomatic.

Table 64.3 Benefits of a Geriatric Oncology Program (GOP) • Provision of cancer care specific to the older person • Provision of a Comprehensive Geriatric Assessment (CGA) • Motivates clinical research • Enhances social support • Develops a comprehensive plan of treatment • Provides ongoing follow-up care

Why is a GOP helpful? Cancer develops differently in older people. Large cell non-Hodgkin lymphoma may be more aggressive in older people (see Chapter 48 of this volume15). Conversely, breast cancer may tend to be less aggressive in older women (see Chapter 51 of this volume16). These differences can be proactively anticipated by a GOP and interventions implemented to help seniors cope with cancer and cancer therapy. A thorough CGA conducted by a GOP can detect problems before they become crises. Casting the assessment net over a range of issues brings forth physical, social, and emotional considerations integral to maintaining independence. Being proactive is key to geriatrics, because older people have less functional reserve.17 Older people can be less likely to bounce back from health insults owing to the occurrence of comorbidities. Table 64.3 depicts some of the benefits of a GOP. The development of clinical trials geared to the older person is another function of the GOP. Often older people are not included in clinical trials.5 Motivating research that

Interdisciplinary teams in geriatric oncology

1513

focuses on understanding how chemotherapeutic agents react in the older person, physical limitations caused by the agents, and any possible interventions that may benefit patients and their families may greatly enhance the care of the older person with cancer. It has been shown that patients participating in clinical trials tend to receive more aggressive therapy, medication either free or at a reduced price, and frequent diagnostic evaluations.18 In addition to clinical research, which is often quantitative in nature, a GOP creates an ample ground for qualitative research. A GOP can facilitate the collection of narratives to understand the personal situations that older people with cancer may endure. Narrative research is also a congruent method for studying seniors. The use of a personal interview without instrumentation may be more comfortable for people who have poor eyesight or other comorbidities that limit the completion of a questionnaire. The stories derived from the interviews can help repair the physical and mental damage that illness has done to the body.19 Serious illness also provides the substance to compose a story for the purpose of telling friends and family the events associated with medical care.20 Not only are stories beneficial to people experiencing illness, but also to clinicians who collect health histories on which to develop medical interventions. Many older people have a reduced social support system. One of the prime intentions of the GOP is to assess and work with the patient with the intention of providing the social support necessary while undergoing cancer therapy. Economic problems associated with medication costs can be addressed so that the patient can obtain the necessary products. Problems with transportation may be solved with community transportation, or by working with the patient to identify neighbors and/or friends who may provide this service. Transportation is one of the major barriers to treatment of cancer in older people, and, by exploring possible options to satisfy this problem, the patient may experience optimal treatment outcome.21 An adequate social support environment has been associated with enhanced postmastectomy self-esteem and reduced mortality in women with breast cancer.22,23 Social support has been suggested to be usefiil to the cancer patient by helping to moderate anxiety and fears associated with the diagnosis and treatment of cancer and by reducing distress throughout rehabilitation.24 Lack of access to social support has been shown to be greatest for older women, minorities, and individuals with a low socioeconomic status.25 A GOP can identify some of the social issues that are problematic and can aid in work to try to solve some of the challenges that can hinder cancer treatment. Often the caregiver is the recipient of a large amount of responsibility. Details of daily care, cooking, cleaning and transportation may become additional responsibilities to the caregiver. Caregiver stress can be a prominent problem in the care of the patient. Parr and Overcash26 suggested that caregiver stress has more to do with the stress of the patient than the patient’s own physical health. A GOP can work to provide respite programs and other interventions that can give some relief. Gearing interventions toward the patient and the support person will enhance overall care. The comprehensive plan of care resulting from the CGA is another benefit of developing a GOP. Cancer treatment options, diagnostic evaluations, and follow-up care, in addition to the myriad of functional, malnutrition, and polypharmacy elements, are included within a plan of care. A reasonable plan of care should entail actual and

Comprehensive Geriatric Oncology

1514

potential problems. If function and independence are trending in a decline, it is reasonable to employ social work proactively to put in place some caregiver/support options before an acute situation arises. All of the problems, or potential problems, outlined in the plan of care may not be addressed to a level that avoids or eliminates a decline in health or independence, but it is critical that the issues be detected and anticipated. A CGA provided by a GOP is useless if a comprehensive plan is not developed and implemented for each individual patient. Lastly, ongoing follow-up care is another useful element instrumental to a GOP. Follow-up and evaluation of interventions proposed to people aged 70 and older led to fewer clinic visits, better Instrumental Activities of Daily Living (IADL), improved social activity, improved depression scale scores, better general well-being, and better Mini Mental State Examination (MMSE) scores when compared with those who did not undergo continued healthcare.8 After an initial CGA, long-term case management showed enhanced scores on depression, dementia, functional, and life-satisfaction screening instruments. Managing ongoing care becomes a reasonably large component of the GOP, and has been shown to reduce overall healthcare costs by 33%.27 Ongoing discussion at weekly team meetings of patients as they progress though the cancer treatment process can help to provide a strategy for healthcare delivery. The following is a case presentation involving a GOP, and shows how interventions can be provided to enhance the quality of life of a patient and ultimately the outcome of cancer treatment. This case, and others presented later in this chapter, were seen in the Senior Adult Oncology Program (SAOP) at the H Lee Moffitt Cancer Center and Research Institute at the University of South Florida. Case presentation 1 • Mrs A is a 78-year-old woman with breast cancer diagnosed in 1990. She underwent a right mastectomy, which revealed a stage II infiltrating ductal carcinoma. Following surgery, Mrs A underwent four cycles of cyclophosphamide and doxorubicin, which she tolerated well. Six months after treatment, her tumor marker began to increase. A bone scan revealed a metastasis in her lower spine and left hip. She underwent treatment for her bone involvement and her hormonal therapy was altered. Mrs A lives alone. Her daughter, who lives fairly close by, is a single parent with a young son. Mrs A was divorced several years ago. Her ex-husband also lives close by; he has health problems, which Mrs A’s daughter tends to regularly. Transportation is not a problem at this time, because Mrs A is able to drive herself. Mrs A states that she is able to do all the activities that she wants to do; however, she has begun to feel less energetic and has pain in her lower back. Mrs A sees several physicians in south Florida as well as her oncologist. Mrs A complained of having ‘so many medicines’ and felt confused over times and dosages of medication. A CGA showed her MMSE score to be 26/30, the Geriatric Depression Scale (GDS) did not screen positive for depression, and her Activities of Daily Living (ADL) showed no limitation; however, her IADL showed problems with performing some tasks around the house. Her medication inventory showed that she was taking 12 medications, several of which were for blood pressure. She had also been taking temazepam for sleep over the last

Interdisciplinary teams in geriatric oncology

1515

several months. A dietary assessment revealed that she was eating mostly soup because she did not feel like cooking or cleaning the kitchen regularly. • Screening for functional limitations, dementia, and depression can reveal potential or actual problems. The MMSE in this case did screen positive for dementia. The MMSE is readministered in 1 month and compared. A complete assessment of medications, and potential drug interactions, will be assessed by the pharmacist and communicated to the primary care facility outside of the cancer center. Functional limitations may require some intervention by discussing the matter with the support person to see if needs could be met by friends and family. Changes in the blood pressure regime were instituted and will be followed while under the care of the SAOP. A multivitamin was initiated, and advice on getting prepared fresh vegetables and other healthy meal preparation short-cuts was discussed. • This case represents a senior who is essentially independent. However, anticipating possible problems such as maintaining her home and being able to live alone may help avoid more stressor situations. By discussing the situation with Mrs A and her support person, initial plans were developed. Changes in medications may have avoided injury resulting from falls or possible worsening dementia. Dietary intervention can also provide support for overall general health required to endure cancer therapy.

Figure 64.1 The ultimate goal of cancer research, prevention, and treatment in older patients is enhanced independence and quality of life. Clinical experience does inform the

Comprehensive Geriatric Oncology

1516

direction of research, treatment, and prevention. Goals of a GOP At the risk of sounding simplistic, a general overall goal of a GOP is to maintain independence to the extent possible, and to enhance quality of life (QoL) (Figure 64.1). A multidisciplinary CGA is central to this goal. Problems that are not yet apparent upon a more focused assessment may be detected by the CGA, thus saving the patient and family the stress of a more immediate encounter. As discussed earlier, a CGA may work best when performed on people who have treatable comorbidities that if untreated will affect QoL or independence.11 This is not to say that a seemingly healthy older person would not benefit at all from this specialized care. People with increased comorbidities may also have more support limitations, independence problems, QoL issues, etc. than someone without any health limitations. Older people with a diagnosis of cancer may be more likely to benefit from a GOP and CGA than those without a malignancy or a history of malignancy that has been resolved. Another goal of a GOP is screening. A GOP can contribute to the success of screening programs through assessment development and management of a patient health plan.28,29 Community outreach is important to the success of screening programs. Performing seminars regularly in senior centers to discuss screening examinations may dispel misconceptions, such as that older people cannot endure chemotherapy, which can act as barriers to participation. Along with the importance of screening, it is essential to provide education as part of the GOP functions. Cancer education is the ‘process of influencing behavior to elicit changes in the knowledge, attitudes, and skills required to maintain and improve health’.30 Although it is commonsense, it is important to provide pamphlets to people who smoke cigarettes, who do not regularly undergo screening examinations, or who do not perform breast self-examinations, so that the information can be considered at a later time. Health education material should be assessed for larger print and overall ease of readability. Glossy small-print brochures packed with information may be difficult for many seniors to read physically. Promoting and performing research is another goal of the GOP. Many seniors are not included in clinical trials. Focusing on protocols especially for seniors may help contribute to optimal cancer therapy outcomes and prolong the meaningful survival of older people with cancer. GOP target population People with comorbid conditions and/or geriatric syndromes may be the most likely to benefit.5 The SAOP at the H Lee Moffitt Cancer Center and Research Institute at the University of South Florida found that 20% of people 70 and over had a diagnosis and at least one deficit in ADL, 26% screened positive for depression, 40% had a least one impairment in IADL, and 25% had some dementia as determined by the MMSE.31 Most of the seniors involved in the SAOP are active, healthy individuals despite a diagnosis of

Interdisciplinary teams in geriatric oncology

1517

cancer and cancer treatment. Many of the deficits detected in this population could have been missed without the use of a GOP. Another approach to defining a target population best served by a GOP is to prescreen. People who are too healthy or people who are too sick will not greatly benefit from a GOP, and it is important to determine what group of people will benefit most. Prescreening is a way of deciding which patients should undergo the GOP and a CGA by performing a brief interview that assesses for issues such as polypharmacy, comorbidities, and functional changes that may lead to greater effectiveness of a GOP.32 The only drawback to prescreening is that many people who seem very healthy or independent may actually have some treatable deficits. Prescreening may lead to cost and time savings for the patient and health facility; therefore, ways to conduct prescreening should be investigated. There are abbreviated components of the CGA, such as the first five questions of the GDS,33 which were found to be as equally effective as the entire 15item instrument. The MMSE has shown been found to be effective in the first several questions.34 An abbreviated CGA performed by a nurse may help to focus care on the groups of elderly that can benefit most from the CGA, and thus enhance the benefits that a CGA can provide. Developing a senior adult oncology program (SAOP) When deciding on what disciplines should make up a GOP, it is important to look at the specific needs of the older cancer patient. Older people are likely to suffer from issues such as polypharmacy, malnutrition, comorbid conditions, and psychosocial concerns.35 The disciplines that are important in addressing these types of conditions are a registered dietitian, a social worker, a pharmacist, a geriatric nurse practitioner, a primary care nurse, and a medical oncologist/geriatrician (who acts as the team leader). As suggested earlier, many institutions commonly compose GOPs to include just a physician, a primary care nurse, and a social worker. With the addition of the other disciplines, a GOP can offer a more comprehensive approach to care. A GOP is an expensive approach to care; however, the service provided to the patient and family is an important element in the treatment of cancer. Older cancer patients have many other health issues than just a diagnosis of cancer. By just offering services directed to cancer diagnosis, much of the person goes untreated. Geriatric teams need to be composed of team members who have some experience assessing and treating older people with cancer. Many of the assessment instruments used (ADL, IADL, and MMSE) are specific to geriatrics and are not used with other age groups. Interviews with older people tend to require more time and patience, and require a more intricate treatment plan because of complex physical and psychosocial problems. Team members must be aware of these facts and possess the specific knowledge and patience that this process requires. Oncologist/geriatrician The medical oncologist/geriatrician is central to the GOP and is necessary to provide cancer care to the senior patient. Often, the oncologist is the person who receives each of

Comprehensive Geriatric Oncology

1518

the disciplines’ assessments and constructs a medical plan, in terms of both cancer treatment and geriatric care. In many cases, the physician is the team leader; however, this does not have to be the case. Development of clinical protocols and other research projects is another essential function. There is not a tremendous amount of published literature, and the oncologist/geriatrician is in a prime position to conduct research projects. The role of educator for medical/healthcare staff and the community is another component. Lectures on aging- and cancer-related issues are helpful to community members who want to know about screening and other healthcare concerns. Nurse practitioner (NP) The role of the nurse practitioner typically includes conducting the physical assessment as well as the CGA. Often, this role is a combination of clinical and organizational/management roles: integrating all of the impressions and interventions of the GOP, formulating a plan, and constructing a comprehensive record generally falls under this role. Coordinating weekly team meetings, orchestrating reports of team members and implementing follow-up plans are other aspects of the NP position. Recommendations are most beneficial if the NP or nurse is able to follow-up on the progress of the patient and support persons. It has been shown that recommendations as a result of a CGA are adhered to 50–70% of the time.36 The plan of care should detail the current health diagnosis and syndromes, such as falls and incontinence, as well as some insight into potential limitations based on current health status. In order for follow-up care to be successful, the NP must operationalize the recommendations of the GOP and continues to assess the patient and family as they return to the clinic. Primary care nurse (PCN) Along with the NP, the PCN is important to the case management and follow-up component of the GOP. Telephone calls, fielding questions, education, and unending support are vital to the positive outcome of medical care. CGA recommendations are most beneficial if the nurse is able to follow-up on the progress of the patient and support persons. Regular contact after the initial GOP visit to evaluate the effects of the recommendations, assess current condition, and report any changes will contribute to the success of the treatment and the satisfaction of the patient and family. The PCN generally has the most contact with the patient, compared to the other team members, and is vital to the operation of the GOP. Dietitian Malnutrition has been shown to be common among people over 70. In terms of seniors admitted to a hospital, nutritional deterioration often occurs during an inpatient stay.37 Nutritional assessments limited not only to diet but also to nutritional supplements and vitamins all combine to provide a complete picture of nutritional health. The dietitian works with other members of the GOP to create interventions that work to maintain or increase general health to anticipate cancer treatment. The dietitian can also be

Interdisciplinary teams in geriatric oncology

1519

instrumental in addressing symptoms such as constipation, nausea, weight loss or gain, and problems with diminished appetite. Pharmacist Issues with polypharmacy and harmful drug interactions are more common in older people than in those under 6538 (see Chapter 41 of this volume39). Assessment of prescription as well as non-prescription medication can help avoid or correct problems that can occur with numerous medications. By asking patients to simply bring in their daily medications (including non-prescription medications) at their initial visit with the GOP, the pharmacist can obtain insight into specific medications and the prescribing physicians. Medication assessment is an important aspect of the GOP, especially when patients are on chemotherapy, which can be toxic. The pharmacist is also helpful in adjusting dosages of chemotherapy in cases where comorbidities, laboratory values, performance status, and frail health may necessitate changes. Education is a large component of the pharmacists’ task, which can be developed for patients and healthcare staff alike. Social worker The social worker has a diverse role, ranging from assessment of financial status and capabilities, to the ways in which patient, family, and support persons are copying. Conducting a social history and assessing support systems and coping status can be a means of instituting proactive interventions. Problems such as lack of a caregiver or reduced financial means are difficult to solve; however, it may be less difficult to address these problems before a crisis ensues. Screening for dementia and depression is another role of the social worker. Obtaining a mental health baseline can be helpful as a patient progresses through cancer care in order to determine when episodic depression and anxiety necessitate pharmacological interventions. Establishing trust and a therapeutic dialogue may contribute to QoL and patient satisfaction. Problems encountered by a GOP While it is the intention of this chapter to report all the advantages of a GOP, disadvantages do exist. Communication tends to be a major problem associated with having numerous disciplines evaluating a patient. Collaboration is not always easy and seamless. The following is a case presentation illustrating poor communication between members. Case presentation 2 • Mrs M was a 77-year-old lady with metastatic breast cancer that was diagnosed in 1988; shortly thereafter she underwent chemotherapy and radiotherapy. In late 1994, Mrs M developed melanoma to her right knee. An excision was performed. In 1995, a recurrence to the left groin was discovered and excised. In 1978, a stroke left Mrs M with right hemoparalysis and inability to speak in complete sentences; she came to

Comprehensive Geriatric Oncology

1520

rely on her husband for total care. Mrs M had been married to her husband for 50 years and they had four children living in the area but did not have much contact with them or with their grandchildren. Initial assessment by the SAOP found (from Mr M) that Mrs M could not communicate, and Mr M responded to the assessment questions on her behalf. Mrs M was very withdrawn and expressionless. Mr M would occasionally express anger and aggressive behavior toward team members individually. When asked on several occasions if he wanted to talk about his feelings, Mr M would become tearful and apologetic. It was noted by the primary care nurse that as Mrs M became weaker and in need of hospitalization, Mr M became more verbally aggressive. Eventually, Mrs M was admitted to hospital for pneumonia. A hospital social worker was not told that Mrs M could not communicate, and began asking her ‘yes’ and ‘no’ questions. It was determined that something was of great stress to her at home. A speech pathologist discovered, through interviews with Mrs M, that Mr M was the source of physical harm and that Mrs M was afraid to return home. When Mr M was confronted about these allegations, he became extremely abusive and began to threaten the social worker and the nursing staff. Officials were notified, and after an investigation while Mrs M was still in the hospital, it was discovered that Mr M had murdered his father for abusing his mother many years ago. After these dramatic events were revealed, Mrs M died quietly in her sleep, in the presence of her children. • A staff conference was conducted following Mrs M’s death to process through the events. After review, it was noted that each team member was aware of Mr M’s aggressive, inappropriate behavior, but did not communicate this information to each other. Following this case, relevant information regarding caregivers is communicated and patients are psychosocially assessed without the presence of the caregiver. This case shows the importance of full communication between team members. This overall situation might still not have been avoided if each team member had reported that Mr M had shown aggressive behavior or had acted inappropriately, but better communication might have prevented the situation from becoming as acute. As a result of this case, it is now standard practice for the SAOP to perform a segment of the psychosocial assessment without the presence of the caregiver or family. As a result of this privacy, patients may be more likely to discuss matters that are of personal concern or issues they feel are likely to upset the family. Appropriate information concerning the family and caregivers should be detailed in the psychosocial report provided by the social worker in order to ensure that adequate interventions are included in the treatment plan. Communication difficulties can also become evident during the initial patient evaluation when each discipline is performing their part of the CGA. A communication sheet, which is a form used by all disciplines to record observations, assessment results, diagnostic results, and recommendation, equips the physician and the rest of the team with a brief summary of relevant information on which to base the comprehensive treatment plan. Table 64.4 provides an example of such a communication sheet. The weekly team meeting will also promote communication and case discussion among team members. In the meeting, patients and families are presented to the entire program for the purposes of treatment planning. Options regarding community services, hospital services, cancer therapies, and other medical interventions are identified. As the

Interdisciplinary teams in geriatric oncology

1521

patient progresses through treatment, the team can follow the progress and update the plan. Sometimes, internal problems such as personality conflicts or role territorialization can impede the attainment of the objectives. The blurring of roles is a construct that should be stressed to all members as they begin to work as a team. A primary care nurse may recommend a

Table 64.4 Example of a communication sheet Pharmacist Medication: Motrin 200mg PRN, digoxin 0.125mg qd for arrhythmia, vitamin A, vitamin C, Benadryl for sinus pain PRN. Not at risk for polypharmacy at this time. Dietitian Weight 125 Ibs, Height 5′3″. Currently maintaining weight with nutritional intake. Ideal body weight is 125 ± 10%, Usual weight 125 Ibs, No difficulties at this time. Social worker Patient lives with her husband of 25 years. She is a retired nurse and has two supportive children that live locally. She has many friends and a wide support system. States that she feel she is coping well with the disease. GDS 0/15, MMSE 30/30. Nurse practitioner History positive for arrhythmia and is currently under treatment by a cardiologist. No allergies, no past surgeries. Physical negative. ADL/IADL is independent. Physician Treatment plan with tamoxifen 10mg bid. Will recommend annual mammogram. Plan to see patient in clinic in 1 month.

particular type of nutritional supplement upon a patient’s request. This sort of blurred interdisciplinary boundary can be a source of dissension between team members. When recommendations are offered by team members other than the specific discipline, report must be communicated to avoid inconsistencies in patient care and as a matter of respect to the other team members. Disadvantages of a GOP Cost savings can be an advantage or disadvantage associated with a GOP. The staff required to provide team services to a single patient/family is significant. The initial visit will usually require 2.5–3 hours to perform the CGA and develop the plan. The value of the CGA is realized in the results of the assessment, such as possible prevention of acute or urgent situations or frequent hospitalizations. The investment is the amount of time and costs required for the initial assessment and the development of the treatment plan. The duration of the initial assessment may represent a burden to the patient and family. The several hours that it requires to complete the CGA may be taxing, especially

Comprehensive Geriatric Oncology

1522

for those who are frail or ill as a result of their malignancy. Abbreviated assessments are currently being developed to help reduce the long time of administration. Case study of a GOP patient This case describes a typical patient seen by the SAOP. This is an initial visit, which generally takes several hours. The patient Mrs A is an 82-year-old women with stage II breast cancer. Her tumor was estrogen/progesterone-receptorpositive, 2 cm in size, and moderately well-differentiated; she was 1/15 lymph-node-positive. The pathology report suggested infiltrating ductal carcinoma with a small component of intraductal carcinoma in situ. She underwent lumpectomy with axillary node dissection. The margins were found to be negative. Mrs A is a very independent women, who lives alone. She was widowed 15 years ago. She has four supportive children, who all live in Indiana. Mrs A currently lives in Florida year around and has a broad support system of friends in her church. She lives in a retirement community and enjoys many of the activities and social gatherings. Mrs A drives and is completely independent; she walks 2 miles a day. Comorbidities Hypertension was diagnosed in 1984 and osteoporosis recently diagnosed in 2000. Medications Mrs A is taking vitamins A and E and a multivitamin preparation. She is taking clonidine 0.1mg orally twice daily for her hypertension and alendronate 10mg daily for her osteoporosis. Past medical history Mrs A fractured an elbow in 1995 when rollerskating. There is a remote history of migraine. Mrs A has had hypertension since 1984, which has been controlled with diet and medication. There is some cardiac arrhythmia; however, assessment revealed no pathology. There is low bone density—Mrs A was diagnosed with osteoporosis in 2000. She is tolerating alendronate very well. Previous surgical history There was an internal reduction of the left elbow in 1995.

Interdisciplinary teams in geriatric oncology

1523

Family medical history Mrs A’s mother had a breast cancer, which was resected 10 years before she died of cardiac problems. CGA The GDS did not screen positive for depression. The MMSE did not screen positive for dementia; however, the score was 26, which can be considered borderline. The MMSE will be readministered during her therapy. Functional assessment did not reveal any limitations. Assessment • Stage II breast cancer. • Hypertension—controlled with clonidine. • Osteoporosis—treated with alendronate. Plan The SAOP oncologist/geriatrician instituted treatment with hormonal therapy: tamoxifen 10mg twice daily. Mrs A is also scheduled to undergo chemotherapy with CMF: cyclophosphamide 100mg/m2 orally on days 1–14, methotrexate 40mg/m2 intravenously on days 1 and 8, and 5-fluorouracil 600mg/m2 on days 1 and 8, with the cycle repeated every 28 days for six cycles. The nurse practitioner suggested that because the patient had not had a hysterectomy, an annual gynecological assessment with transvaginal ultrasound would be useful to detect any potential abnormalities associated with the tamoxifen. The nurse practitioner also recommended that Mrs A’s daughter undergo breast cancer screening. The social worker reported to the SAOP that the patient’s family is living some distance away. The social worker will work with the patient to arrange support while she is undergoing cancer treatment. Mrs A has been advised not to drive while undergoing chemotherapy, and she will arrange some transportation with a neighbor. The MMSE will be readministered during treatment. The dietitian advised Mrs A to discontinue vitamins A and E but to continue taking the multivitamin preparation. Small frequent meals were recommended. Ongoing nutritional assessment will continue as the patient returns for her scheduled appointments. The pharmacist assessed the patient’s current medications, and concurred with the dietitian regarding the discontinuation of vitamins A and E. The use of clonidine and alendronate will be regularly assessed by the team during chemotherapy. The pharmacist will work with the oncologist to prescribe the proper dosages of chemotherapy. The primary care nurse provided Mrs A with written educational materials and answered her questions concerning chemotherapy. Contact phone numbers were provided and a return visit was established.

Comprehensive Geriatric Oncology

1524

A copy of the dictation detailing the SAOP visit was sent to the primary care physician responsible for treatment of the hypertension and osteoporosis. Conclusions As the population of older people increases worldwide, healthcare should be directed specifically to those in their 70s, 80s, 90s, and even above. GOP is a step in a direction new to provide that specialized care. The development of GOP requires discipline from the interdisciplinary team, and from the sponsoring agencies. References 1. Kinsella K. Demographic dimensions of global aging. J Fam Issues 2000; 21:541–58. 2. Franceschi S, La Vecchia C. Cancer epidemiology in the elderly. Crit Rev Oncol Hematol 2001; 39:219–26. 3. Repetto L, Comandini D, Mammoliti S. Life expectancy, comorbidity and quality of life: the treatment equation in the older cancer patients. Crit Rev Oncol Hematol 2001; 37:147–52. 4. Fried L, Storer D, King DE, Lodder F. Diagnosis of illness presentation in the elderly. J Am Geriatr Soc 1991; 39:117–23. 5. Balducci L. Perspectives on quality of life of older patients with cancer. Drugs Aging 1994; 4:313–24. 6. Balducci L, Yates J. General guidelines for the management of older patients with cancer. Oncology 2000; 14:221–7. 7. Overcash J, Chen H, Extermann M et al. Impact on survival and time to disease progression in the older cancer patient. In: Proceedings of the IV International Conference on Geriatric Oncology, 1998:232. 8. Burns R, Nichols LO, Martindale-Adams J, Graney MJ. Interdisciplinary geriatric primary care evaluation and management: two-year outcomes. J Am Geriatr Soc 2000; 48:8–13. 9. Zupko K. An autonomy support model of geriatric team function. Tennessee Med 2000; 93:295– 7. 10. Lee W, Eng C, Fox N, Etienne M. PACE: a model for integrated care of the frail older patients. Program of All-inclusive Care for the Elderly. Geriatrics 1998; 53:62–73. 11. Boult C, Boult LB, Morishita L et al. A randomized clinical trial of outpatient geriatric evaluation and management. J Am Geriatr Soc 2001; 49:351–9. 12. Rubenstein LZ, Goodwin M, Hardley E et al. Working group recommendations: targeting criteria for geriatric evaluation and management research. J Am Geriatr Soc 1991; 39(Suppl): 37S-41S. 13. Winograd CH, Gerety MG, Chung M et al. Screening for frailty: criteria and predictors of outcomes. J Am Geriatr Soc 1991; 39: 778–84. 14. Millisen K, Foreman MD, Abaraham IL et al. A nurse-led interdisciplinary intervention program for delirium in elderly hip-fracture patients. J Am Geriatr Soc 2001; 49:680–1. 15. Bloom S, Peterson B. Non-Hodgkin lymphomas. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:619–41. 16. Balducci L, Silliman RA, Diaz N. Breast cancer in the older woman: an oncologic perspective. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:662–703. 17. Balducci L, Beghe C. Cancer and age in the USA. Crit Rev Oncol Hematol 2001; 37:137–45.

Interdisciplinary teams in geriatric oncology

1525

18. Trimble E, Carter C, Cain L et al. Representation of older patients in cancer treatment trials. Cancer 1994; 74:2208–14. 19. Park-Fuller LM. Narration and narratization of a cancer story: composing and performing a clean breast of it. Text and Performance Quarterly 1995; 15:60–67. 20. Riessman CK. Strategic uses of narrative in the presentation of self and illness: a research note. Soc Sci Med 1990; 30:1195–200. 21. Goodwin J, Hunt W, Samet J. A population-based study of functional status and social support networks of elderly patients newly diagnosed with cancer. Arch Intern Med 1991; 151:366–70. 22. Wortman C, Dunkel-Schetter C. Interpersonal relationships and cancer. J Soc Issues 1979; 35:120–8. 23. Reynolds P, Kaplan G. Social connections and risk for cancer: prospective evidence from the Alameda County study. Behav Med 1990; 16:101–10. 24. Irwin PH, Kramer S. Social support and cancer: sustained emotional support and successful adaptation. J Psychosoc Oncol 1988; 6:53–71. 25. Guidry JJ, Greisinger A, Aday L et al. Barriers to cancer treatment: a review of published research. Oncol Nurs Forum 1996; 23:1393–8. 26. Parr J, Overcash J. New look at multidisciplinary assessment of the older persons in medical settings: different foci in different settings. Annual Meeting of the Gerontological Society of America, Los Angeles, CA 1995. 27. Waszynski CM, Murrakami W, Lewis M. Community care management. Advanced practice nurses as care managers. Care Manager 2000; 2:148–152. 28. Jennings-Dozier K, Mahon S. Introduction: Cancer prevention and early detection—from thought to revolution. Oncol Nurs Forum 2000; 27:33–6. 29. Mahon SM. The role of the nurse in developing cancer screening programs. Oncol Nurs Forum 2000; 27:19–27. 30. Treacy JT, Mayer DK. Perspectives on cancer patient education. Semin Oncol Nurs 2000; 16:47–56. 31. Overcash J. Applying the Comprehensive Geriatric Assessment (CGA) to the older cancer in a senior adult oncology program (SAOP) setting. Annual Meeting of the Gerontological Society of America, Cincinnati, OH, 1997. 32. Maley RC, Hirsch SH, Reuben DB. The performance of simple instruments in detecting geriatric conditions and selecting community-dwelling older people for geriatric assessment. Age Ageing 1997; 26:223–31. 33. Hoyl MT, Allessi CA, Harker JO et al. Development and testing of a five-item version of the Geriatric Depression Scale. J Am Geriatr Soc 1999; 47:873–8. 34. Koenig HG. An abbreviated Mini-Mental State Exam for medically ill older adults. J Am Geriatr Soc 1996; 44:215–16. 35. Overcash J. The case for a geriatric oncology program in a cancer center. In Comprehensive Geriatric Oncology, 1st edn (Balducci L, Lyman GH, Ershler WB, eds). Amsterdam: Harwood, 1998:813–24. 36. Cefalu CA, Kaslow LD, Mims B, Simpson S. Follow-up of comprehensive geriatric assessment in a family medicine residency clinic. J Am Board Fam Pract 1995; 8:337–40. 37. Incalzi RA, Landi F, Cipriani L et al. Nutritional assessment: a primary component of multidimensional geriatric assessment in the acute care setting. J Am Geriatr Soc 1996; 44:166– 74. 38. Corcoran ME. Polypharmacy in the older person with cancer. Cancer 1994; 4:419–28. 39. Corcoran ME. Polypharmacy in the senior adult patient. In: Comprehensive Geriatric Oncology, 2nd edn (Balducci L, Lyman GH, Ershler WB, Extermann M, eds). London: Martin Dunitz, 2004:502–9.

65 Spirituality and medicine Mary Jane Marsh, Russell Meyer, Lodovico Balducci Introduction This final chapter explores the interactions of patient’s and provider’s spirituality with the management of diseases in general and of cancer particularly. The issues of spirituality are not unique to cancer or to aging, but spirituality represents a strong influence in the practice of healthcare1 and deserves a special discussion in a textbook such as this one. Spirituality is the key to shared decision making,2,3 the cornerstone of relationshipcentered care a model of care that best seems to suit modern healthcare. For many years, an artificial distinction between the world of objectivity (clinical data) and that of subjectivity (personal feelings, beliefs, and values) has discouraged any open discussion of spirituality between patients and providers. This trend has been reinforced by the progressively more limited time allotted to ambulatory visits. The fallacy of this approach has been revealed in the increasingly adversarial attitudes of patients toward organized medicine, despite the outstanding achievements of the past two decades.4 This hostility is one more expression of alienation from a human environment where the space for basic needs has progressively shrunken. The race for scientific and technological achievements has become an end in itself, unable or unwilling to accommodate the aspirations that it purported to serve. In this environment, human beings cannot help feeling as foreigners because of the dichotomy between the official language of society and their personal experience. Not surprisingly, this alienation has been felt in healthcare, whose scope includes the most consequential experiences of human life, and not surprisingly, the reversal of the tide has also appeared in this same area. Three movements have restored the centrality of human experience in the practice of healthcare: the assessment of quality of life,5 symptom control,6 and end-of life management.7,8 These movements have found an area of confluence in the need to acknowledge individual consciousness as the final arbiter of all health interventions that must be congruent with the individual ‘gestalt’ of oneself and of the world. In medical ethics, this principle has been codified in the concept of patient autonomy. Patient autonomy implies that under no circumstances should personal freedom be trampled upon in healthcare, because the value of each person is unique and is not lessened by any circumstances. Respect of autonomy invokes a spiritual perspective in human relationships. After defining spirituality, we shall review the instruments available to study spirituality and the interactions of spirituality and healthcare.

Spirituality and medicine

1527

Definition of spirituality The world ‘spirituality’ derives from the Latin spiritus (spirit), which in turn translates the Greek pneuma or ‘wind’. Although it escapes the perception of senses, spirit is yet so real as to direct human will, the way the wind directs the movement of a ship at sea. The most common construct of spirituality is consistent with this view and may be described as a ‘relation with the transcendent’ or as ‘the interpretation of the world that directs our choices and actions’.4 A semantic note is called for at this point. Ancient Greek had two different words to define spirit (pneuma) and psychology (psukhē) implying a difference between these two entities. Despite some obvious overlap between these realms, the distinction is important, because, as we shall see, a spiritual perspective may be fully embraced in the presence of serious psychological dysfunctions. Another important clarification concerns the timehonored opposition between spiritual and material realms. This stark contrast is both contrary to modern thinking and JudeoChristian traditional teaching. One of the best-known contemporary philosophers, the Mexican Octavio Paz, highlights how a spiritual perspective is necessary to the fulfillment of all bodily aspirations, in his book La Llama Doble (‘Double Flame’).9 The unconditional gift of one’s body to another person is the quintessence of love: the body becomes then the necessary instrument of the spirit, which leads to communion of two lives, or, said otherwise, the human body can find fulfillment of its needs only when guided by a spiritual perspective. The Song of Songs, a most holy writing for Jews, Christians, and Moslems, describes in most graphic terms the sexual relation of a man and a woman, with its highs and lows, and is universally interpreted as the longing of God for Humanity and the sensuous response that God expects from humanity. In the Pauline epistles, the love of Christ for the Church is repeatedly compared to the love of a man and a woman. A sixteenthcentury Catholic mystic, Theresa de Avila, reports in her writing a very sensual love for Christ in the Eucharist. These few examples should suffice to indicate that both contemporary thinking and Judeo-Christian tradition converge in recognizing body and spirit as complementary aspects of the unique human person. The spirit dictates the use of the body; the body animates with holy desire the dictates of the spirit. In Judeo-Christian tradition, God should be the final object of human desire. The pursuance of God with a lesser desire than we direct toward other humans or earthly things has been called original sin. Forms of spirituality Three major spiritual directions are recognizable in the contemporary world:10 one is inspired by the three major monotheistic religions (Judaism, Christianity, and Islam), the second is inspired by the major Eastern religions (Hinduism, Buddhism, etc.), and the third is related to the ‘New Age’ movement. We shall try to identify the most distinctive characteristics of each type of spirituality:

Comprehensive Geriatric Oncology

1528

In the monotheistic religions, the essence of spirituality is the sacrifice, understood in its semantic meaning. Sacrifice derives from the Latin sacrum facere, which means to make sacred. Sacred (sacrum in Latin, Hagios in Greek) means ‘reserved to a special use’. Marriage is a type of social ‘sacrifice’ embraced by virtually all cultures. In marriage, the spouses ‘sacrifice’ their sexuality by reserving for each other and no-one else the use of their sexes. In a more general sense, sacrifice means to submit oneself to the will of God. The social implications are that since every person has the potential of being ‘sacrificed’ or ‘dedicated’ to God, each person is sacred and therefore cannot be used outside of God’s design. This illicit use includes all sorts of personal exploitation from slavery to murder, to medical experimentation, to extramarital sex. Sacrifice may be rewarded by the security of God’s love and protection, which in Christianity and Islam takes the form of a lasting vision of God. Is it possible to nurture this type of spirituality without belief in God? The testimony of people able to live their marital vows, to avoid robbing or hurting one’s neighbor without being part of any form of organized religion, suggests that this type of spirituality might charm and entice even non-believers. The mainstay belief of Eastern religions is the permanence of life that cannot be destroyed, but may take different forms (hence the belief in reincarnation). One of these forms is that of a deity, dedicated to fulfill specific needs, such as the conduct of war, the solution of epidemics, famine, or drought—but this deity is just another expression, rather than the Creator, of life. Hence, the sacredness of all humans is not supported by God’s will: the caste system preached by early Hinduism suggested that each human being had a limited value and could be disposed of under specific circumstances. Humans may be able to achieve the deepest spiritual awareness by their own effort, through meditation and mortification of bodily needs: it is not clear whether this awareness implies a vision of the deity or personal eternity. Despite obvious differences from the monotheistic religions, it is important to highlight areas of confluence. The Eastern beliefs in meditation and flesh mortification have inspired Christian asceticism, which has flourished in the monastic movements. In addition, both types of spirituality preach fairness and kindness in human relationships. The New Age movement includes multiple, disparate, and as-yet developing beliefs, and perhaps it is unfair to lump these different experiences under the same banner. The basic belief of the movement is that there are forces in nature well beyond what our senses and our science can perceive, these forces may emanate from any natural element, and the perception of these forces requires an attentiveness that in general calls for the respect of other human beings and of nature. In this sense, the whole world may be sacred—though not in the sense espoused by the monotheistic religions: the sacredness derives from the potential energy of each substance, not from the design of a personal God. In the Judeo-Christian tradition—the most predominant in the Western world—disease is just one of the many expressions of evil, not the work of God. The notion that a person’s disease is meant as personal punishment for his or her sins is refuted in the Book of Job, in which God takes the defense of a just man, accused by his friends of hypothetical sins to account for the loss of his family and his riches and for the repulsive skin disease compelling him to live in the outskirts of the city,11 and is refuted again in the gospel of Luke, by the word of Christ himself. In both the Hebrew and Christian

Spirituality and medicine

1529

scriptures, God acts as a compassionate healer of disease any time humankind gives Him the opportunity to do so. The healing mission is thus rooted in God’s compassion itself. Christianity adds a new dimension to the experience of suffering: it offers the opportunity to make of suffering an asset of the human condition: suffering is part of the human condition, and despite the best medical efforts, terminal diseases and death are a reality from which we cannot escape. If we think of health as an absolute value, then the persons who are dying, the persons suffering from disabling conditions, cannot partake of this value, and thus somehow their life is less worthy than the life of a person in perfect health. If, instead, we are able to see a positive side of suffering, including the ability to become more sensitive to spiritual issues, more tolerant of people around us, to obtain and provide forgiveness, then the experience of suffering may be the source of a new, different and more comprehensive life experience. This view is germane to the view of the major Swiss psychologist, Carl Jung, who highlighted the figure of the so-called ‘wounded healer’. In Jung’s view, perfect health, including perfect psychological health, cannot be a value-neutral, purely objective condition. The concept of health is linked to a person’s ‘gestalt’, which must include an interpretation of the universal experience of suffering. Thus, the healer themself needs to have experienced suffering in order to be able to provide a sense of healing to another person’s sufferings. The myth of the ‘wounded healer’ mirrors the original most ancient concept of Western medicine, as the Greek god of medicine, Asklepios, has experienced himself the wounds of wars. In the Christian faith, this myth finds its fulfillment in the incarnation and passion of Christ. Clearly, a spiritual perspective may foster patientprovider communication, and may favor healing in the presence of terminal illness. In the following sections, we shall explore the influence of spirituality on a number of health outcomes. Study of spirituality A number of studies4 have explored the interactions of health and spirituality in the areas of public health, addictive disorders, disease outcome, and communication. Despite obvious limitations such as the absence of a gold standard of spirituality and the presence of confounding variables, a number of solid conclusions can be reached: • A lifelong spiritual practice is associated with decreased mortality and reduced prevalence of comorbid conditions, durable functional independence, and acceptance of a healthy lifestyle.12 • Spiritual awareness may cure substance addiction, especially alcoholism. • A spiritual perspective has been associated with a more rapid and complete recovery from cardiac surgery14 and rehabilitation from serious illnesses,15 improvement of depressive symptoms,16 and ability to recover from substance abuse.13 • Patients in many circumstances desire to share with care providers, especially nurses, their spiritual needs.17 Including religion and spirituality in a medical visit may make discussion with nurses more congruent with the patient’s situation and may facilitate end-of-life care18 An important question is whether spirituality might have a negative impact on medical outcome. After reviewing more than 1100 studies, Koenig16 concluded that no adverse

Comprehensive Geriatric Oncology

1530

effects were detectable, after the exclusion of the refusal of certain forms of treatment due to religious beliefs (e.g. refused of blood transfusion by Jehovah’s Witnesses). Spirituality and healthcare: practical applications The practical consequences of these findings pertain to all the areas of healthcare, from practice to education to research. However, the scope of these consequences is controversial. One of the goals of this chapter is to state the problems and to open an informal forum on this important issue. As a starting point, let us recognize that a number of healthcare professionals and patients either do not accept or ignore this spiritual dimension of their profession and of their disease. Let us also postulate that spiritual awareness may only germinate in a consciousness that does not feel beleaguered by external constrains and impositions. Any activity trying to impose a spiritual perspective in medicine seemingly would be counterproductive. Whereas we cannot coerce a spiritual perspective on patients and providers, we can alert both of groups to this perspective which we believe to be necessary to ensure congruence and mutual respect. It would be inappropriate to promote any type of religious belief as a form of alternative or adjunctive therapy, but it would be equally inappropriate to ignore, criticize, or is any way belittle the hope of a patient to obtain cure and healing through prayer and faith Research in spirituality and medicine An agenda for future research should include: • A gold standard of spirituality, to be used for the validation of current instruments. Attendance at religious services or the practice of prayer may fail to include deeply spiritual individuals who do not belong to any religious denomination. We propose that future studies use attitudes toward sacrifice to gauge individual spirituality. • Spirituality and recovery from drug abuse, according to the guidelines proposed by Alcoholics Anonymous. • The influence of spirituality and prayer on recovery from a number of diseases. • Validation of alleged miraculous cures needs a new and fresh look from the medical profession. • Influence on outcome of spirituality by different religious affiliations. • Spirituality in patient-provider communication. • Qualitative research for the study of spirituality.

References 1. O’Connor CI. Characteristics of spirituality, assessment, and prayer in holistic nursing. Nurs Clin North Am 2001; 36:33–46. 2. Frosch DL, Kaplan RM. Shared decision making in clinical medicine: past research and new directions. Am J Prev Med 1999; 17:285–94.

Spirituality and medicine

1531

3. Miller DL, Bolla LR. Patient values: the guide to medical decision making. Clin Geriatr Med 1998; 14:813–19. 4. Balducci L, Meyer R. Spirituality and medicine: a proposal. Cancer Control 2001; 8:368–76. 5. Montgomery MR, Gragnolati M, Burke KA et al. Measuring living standards with proxy variables. Demography 2000; 37:155–74. 6. McDonnell FJ, Sloan JW, Hamann SR. Advances in cancer pain management. Curr Pain Headache Rep 2001; 5:265–71. 7. Cowan D. The dying patient. Curr Oncol Rep 2000; 2:331–7. 8. Byock I. Dying Well: The Prospectfor Growth at the End of Life. New York: Riverhead, 1997. 9. Paz, O. La Llama Doble: Amor y Erotismo. SA: Editorial Seix Barral, 1992. 10. Campbell RA. Truth, Authority, and Faiih. Expanding Humanity’s Vision of God: 2000 Winners. Radnor, PA: John Templeton Foundation, 2000:29–31. 11. Patterson S, Balducci L, Meyer R. The Book of Job: a 2,500-year-old current guide to the practice of oncology: the nexus of medicine and spirituality. J Cancer Educ 2002; 17:237–40. 12. Strawbridge WJ, Cohen RD, Shema SJ et al. Frequent attendance of religious services and mortality over 28 years. Am J Public Health 1997; 87:957–61. 13. Kownacki RJ, Shadish WR. Does Alcoholics Anonymous work? The results from a metaanalysis of controlled experiments. Subst Use Misuse 1999; 34:1897–916. 14. Oxman TE, Freeman DH, Manheimer ED. Lack of social participation or religious strength and comfort as risk factors for death after cardiac surgery in the elderly. Psychosom Med 1995; 57:5–15. 15. Idler EL, Kasl LV. Religion among disabled and non-disabled persons II: Attendance at religious services as predictor of the course of disability. J Gerontol B 1997; 52: S306–13. 16. Koenig HG. The Healing Power of Faith: Science Explores Medicines Last Great Frontier. New York: Simon and Schuster, 1999. 17. Post SG, Puchalski CM, Larson DB. Physicians and patient spirituality: professional boundaries, competency, and ethics. Ann Intern Med 2000; 127; 578–83 18. Daaleman TP, VandeCreek L. Placing religion and spirituality in end-of-life care. JAMA 2000; 284:2514–7.

Index 5-bromo-2’-deoxyuridine (BrdUrd), DNA damage 89 7, 12-dimethylbenz[a] anthracene (DMBA), skin cancer 86 absorption, pharmacokinetics 463–4 ABVD, HL 613–14 access to care, screening 378 ACTH see adrenocorticotropic hormone actinic keratosis, skin cancer 784–6 acute lymphocytic leukemia (ALL) 199–200 acute myeloid leukemia (AML) 199–200, 530, 553–60, 808–9 age-related disease biology 556–8 attenuated treatment 554–6 challenges 553 chemotherapy 553–6 clinical trials 557–8 growth factors 557–8 new directions 558–9 outcomes 555 remissions 553–4 treatment recommendations 558 adjuvant therapy bone cancer 646 breast cancer 678–93, 706–7 colorectal cancer 714 pain 816 ADR see adverse drug reactions adrenal corticosteroids, CLL 570–1 adrenocorticotropic hormone (ACTH) 216 advance directives, surgical approaches 403–4 advanced-stage cancer, diagnosis 57 adverse drug reactions (ADRs), polypharmacy 505–6 age-related barriers, secondary prevention, cancer 372–3 age-related cancers 128 age-related changes, DNA repair 80–3 age-related disease biology, AML 556–8 age-related factors, chemotherapy 481 age-related practical considerations, brain cancer 764–5 age/stage relationship 42 aggressive lymphomas 622–3 management 628–34 ‘aggressiveness’, tumor see tumor ‘aggressiveness’ aging apoptosis 138–46 assessment 223–35 assessment in oncology practice 232–3

Index

autonomic function 208–10 biological markers 71 biological principles 147–8 biology 67–74 blood pressure 209 body composition 208 bone marrow function 430–6 and cancer 3–10, 15–21, 399–400 cancer incidence 5–6, 15–16, 127–8 cancer prevalence 5–6 carcinogenesis 354–5 cardiac function 212–13 cellular 69 cellular senescence 132 chemotherapy 138–46 clinical evaluation 225–32 colorectal cancer 715 creatinine clearance 218 dietary restriction 147–8 vs. disease 67 endocrine aspects 215–17 exercise 212–13 extrinsic-stochastic 69–71 gastrointestinal function 213–15 gene expression profiles 95 genetically-determined 69–71 growth factors 102–26 immune function changes 160–3 immunity 72, 164–5 immunological changes 158–70, 803–4 incidence, tumor 148–50 intervertebral disc changes 208 intrinsic-stochastic 69–71 laboratory assessment 231–2, 528 liver physiology 215 markers 71 molecular basis 105–6 molecular biology 80–3 monoclonal gammopathy relationships 196–7 morbid anatomy 183–4 multistage carcinogenesis model 83–8 musculoskeletal function 219–20 nervous system 220–1 non-neoplastic pathology 187–9 nutritional status 237–9 oncogenes 102–26 organismal 69 perceptions 207–22 physiological changes 415–20 physiology 6, 207–22 premature, carcinogenesis 90 renal function 217–19

1533

Index

respiratory system 211–12 risk factor 75–101 screening 18–19, 367–8 skin changes 210–11 spontaneous tumor development 75–6, 90–2 statistics 3–6, 42–4 stress 164–5 structural changes 803–4 symptoms relevance 207–22 taxonomy 227, 527–8, 538 theories 69–71 vs. time 68 tissue microenvironment 129–30 treatment tolerance 207–22 tumor ‘aggressiveness’ 150–5, 180–6 tumor-host interactions 147–57 tumor suppression 127 vital signs 208–10 aging accelerators, carcinogens as 88–92 aging phenotypes, cellular senescence 133 aging reference, chemotherapy 482 Akt, apoptosis 140 albumin, nutrition assessment 331 ALCL see anaplastic large cell lymphoma alkylating agents, CLL 571 ALL see acute lymphocytic leukemia allogeneic HSCT 494–6 CGL 592 allopurinol, CLL 570 alternative therapies cancer prevention 341 cancer treatment 341 nutrition 341 prostate cancer 735 AML see acute myeloid leukemia amputations 836 AMS see atypical myeloproliferative syndrome amyloidosis, heart 188 anaplastic large cell lymphoma (ALCL) 622 androgens CLL 571 prostate cancer 727 anemia 442–52 cardiovascular complications 446 causes 443 chemotherapy 473–4 clinical consequences 445–7 cognition 447 costs 450 defining 442 diagnostic workup 447–50 epidemiology 442–3

1534

Index

fatigue 446 functional dependence 446 iatrogenic complications 447 management 447–50 pathogenesis 443–5 reversal 449 and survival 445–6 anesthetic implications, surgery 415–20 anesthetic management general versus regional anesthesia 422–3 induction agents 421–2 premedication 421 surgery 421–3 angiogenesis MM 646–7 pharmacologic disruption 120–2 anorexia 336, 817–18 anthropometrics, nutrition 330–1 antiangiogenic agents, chemotherapy 481 antioxidants, immune function 166 antisense oligonucleotides brain cancer 761 CGL 595 apoptosis aging 138–46 Akt 140 assays 139 bcl-2 140–1, 143 caspase activation 138–9 caspase regulation 141–2 chemotherapy 142–4 death receptor pathway 138–9 in development 139–42 DNA fragmentation 142 future 144 mitochondrial pathway 138–9 MM 647–8 p53 142–4 PKB 140 pro-survival signals 140 prostate cancer 726 suicide pathways 138–9 tumorigenesis 140–1 zinc chelators 122 appetite regulation, cancer cachexia 241–3, 245 appropriate treatment 59–62 arginine vasopressin (AVP) 217 assessment aging 223–35 aging, in oncology practice 232–3 CGA 225–9, 254, 525–7 functional assessment 231

1535

Index

1536

laboratory assessment 231–2 metastases 840 nutrition 329–31 older patient with cancer 223–35, 395–6 physical performance 229–31 QoL 294–5 rehabilitation 839–40 screening 528 social support 305 symptoms 813–14 assessment forms, nutrition 344–8 attitudinal barriers, screening 381–2 atypical myeloproliferative syndrome (AMS) 596–7 autoimmune complications, CLL 576 autologous HSCT 496–8 MM 643–4 autonomic function, aging 208–10 AVP see arginine vasopressin B-cell chronic lymphocytic leukemia (B-CLL) see chronic lymphocytic leukemia B-cell lymphoma, development 153 B-cell neoplasms, NHL 620 B-CLL see chronic lymphocytic leukemia B lymphocytes, immune function changes 160–1, 436, 437–8 baclofen, hiccup 826 barriers cancer prevention 372–3, 376–86 screening 380–4 basal cell carcinoma, skin cancer 786–8 Bayes’ Theorem, clinical decision analysis 25 bcl-2 apoptosis 140–1, 143 breast cancer 173, 176–7 BCVPP, HL 613–14 bereavement issues, family caregiving 849–50 biochemical parameters, nutrition 331 biologic response modifiers, chemotherapy 479 biologic therapy, management, cancer 394 biological characteristics, breast cancer 171–9 biological markers, aging 71 biological principles, aging 147–8 biology aging 67–74 breast cancer 668–9, 694 cancer 67–74 biomedical gerontology, research 69–72 bladder cancer chemoprevention 360 chemotherapy 743–6 CMV 746 combined therapy 743–6

Index

1537

detection/confirmation rates 48 diagnosis 57–9 evaluation 742–3 histologic grade 182 incidence 38–40, 259 invasive 284, 742–6 MVAC 746 radiotherapy 284, 743–6 staging 742 superficial 742 surgery 409–10 susceptibility 76–80 TCC 742–8 treatment 742, 743–6 VIG 746 blood pressure, aging 209 BNCT see boron neutron capture therapy body composition aging 208 physiological changes 535 body shape, breast cancer 667 bone. see also hematopoiesis; musculoskeletal function bone cancer adjuvant therapy 646 detection/confirmation rates 48 metastases 837 susceptibility 76–80 bone loss, rehabilitation 839 boron neutron capture therapy (BNCT), brain cancer 761 bowel obstruction 827–8 nausea 827 brachytherapy 276 brain cancer 756–7 cervical cancer 283–4 prostate cancer 734 brain cancer 749–70 age-related practical considerations 764–5 antisense oligonucleotides 761 BNCT 761 brachytherapy 756–7 chemotherapy 757–9, 760–1 data quality 50 diagnosis 750–3, 764 differential diagnosis 753 epidemiology 749–50 future 760 gene therapy 761 grading 752–3 hormonal therapy 759 immunomodulators 759–60 immunotherapy 761–2

Index

incidence 259 pathologic diagnosis 752–3 photodynamic therapy 761 QoL 762–4 radiologic diagnosis 751–2 radiotherapy 459, 755–7, 760 retinoids 759 signs 750–1 surgery 754–5 symptoms 750–1 therapy 753–60 treatment 764–5 BrdUrd see 5-bromo-2’-deoxyuridine breast cancer adjuvant therapy 678–93, 706–7 bcl-2 173, 176–7 biological characteristics 171–9 biology 668–9, 694 body shape 667 care of survivors 707–8 chemoprevention 355–7 chemotherapy 355–6, 678–93, 706–7 chemotherapy, agents, doses 692 clinical aspects 673–5 clinical trials 355–6, 669–73, 704–7 current approach 693 cytosarcoma phylloides 674 data quality 50 DCIS 673–5, 673–7 detection/confirmation rates 48 diagnosis 57–9, 667–9 diet 667 DNA ploidy 173 early detection 669–73 early-stage 704–7 endocrine factors 663–7 epidemiology 662, 693 family history 663 geriatric perspective 704–9 histologic grade 182 hormonal agents 690 HRT 663–7 incidence 6–7, 38–40, 259 localized 677–93 lymph node mapping 677–8 management 312–13 medullary carcinoma 674 metastatic disease 707 mortality rates 29–37, 275 mucinous carcinoma 674 oncologic perspective 662–703 outcomes 175–7

1538

Index

1539

p53; 173, 176–7 Paget’ s disease 674 pathologic aspects 673–5 PgR 174 prevention 669–73, 694 QoL 295–6 radiotherapy 276–8, 457–8, 677–80 recurrence 679–80, 681–9 relapse 176–7 RFS 175–7 risk factors 662–7 screening 368–70, 704 stage distribution by age 41 staging 676 surgery 407–8 survival 175–7, 183–4, 277, 680–7 survivors 707–8 tamoxifen 355–6, 677–93, 706–7 treatment 667–9, 694–5 see also mammary gland 5-bromo-2’-deoxyuridine (BrdUrd), DNA damage 89 bronchopneumonia 188 death cause 190 bulk-forming laxatives 821 burden, cancer 52–3 Burkitt lymphoma 623 Burnet’s intrinsic mutagenesis theory 70 busulfan, CGL 585–6 cachexia, cancer see cancer cachexia cancer and aging 3–10, 15–21, 399–400 biology 67–74 and cellular senescence 133–5 death causes 192 incidence see incidence, cancer molecular basis 105 spread 192 cancer burden 52–3 cancer cachexia 236–49, 817–18 appetite regulation 241–3, 245 cytokines 239–41 HPA axis 243–4 leptin 241–3 metabolic disorders 239–44 metabolic state 239 nutrition 325 nutritional status 237–9 therapeutic approaches 244–6 cancer centers, role 45–6 cancer incidence see incidence, cancer

Index

cancer management see management, cancer cancer prevention 365–75 alternative therapies 341 assumptions 365–6 barriers 372–3, 376–86 breast cancer 669–73, 694 colorectal cancer 711 early detection 365–6 principles 365–7 prostate cancer 727 screening 366–8 social support 302 see also chemoprevention; screening cancer-related damage, rehabilitation 831–9 cancer treatment, alternative therapies 341 carcinogen-metabolizing enzymes 80 carcinogenesis aging 354–5 aging, premature 90 chemoprevention 349–50 iron-finger proteins 106–7 lifespan extension 92–6 molecular biology of aging 80–3 pharmacologic disruption 120–2 spontaneous tumor development 75–6 susceptibility 76–80 tumor growth 147–8 zinc-finger proteins 106–7, 117 see also multistage carcinogenesis carcinogens as aging accelerators 88–92 aging effect on susceptibility 86 characteristics 85–7 ribotoxic responses 107–16 cardiac function, aging 212–13 cardiotoxicity, chemotherapy 474–5 cardiovascular system morbid anatomy 187–8 physiological changes 417–18, 535 surgery 424–5 care of survivors, breast cancer 707–8 caregiving CLL 576–7 HSCT 498–9 interventions 848–9 outcomes 512–13 stress process model 844–8 see also family caregiving; social support caspase activation, apoptosis 138–9, 141–2 caspase regulation, apoptosis 141–2 CBL see chronic basophilic leukemia CEL see chronic eosinophilic leukemia

1540

Index

cellular aging 69 cellular response, stress 117, 118–19 cellular senescence aging 132 aging phenotypes 133 and cancer 133–5 causes 130–1 evolutionary antagonistic pleiotropy 133 inducers 131 mutations 133–5 tumor suppression 131–2 celomic epithelial carcinoma of the ovary 771–5 clinical presentation 772–3 etiology 771 management 773–4 prognostic factors 771–2 salvage therapy 774–5 screening 772–3 centers, cancer see cancer centers cerebrovascular diseases, death cause 190 cervical cancer brachytherapy 283–4 diagnosis 57–9 IMRT 284 incidence 7, 259 radiotherapy 283–4 screening 372 susceptibility 76–80 CGA see Comprehensive Geriatric Assessment CGL see chronic granulocytic leukemia chemoprevention 349–64 bladder cancer 360 breast cancer 355–7 carcinogenesis 349–50 clinical trials 353–4 colorectal cancer 358–9 head and neck cancer 359–60 lung cancer 359, 360 mechanisms 350–3 prostate cancer 357–8 sites of action 350 see also cancer prevention chemotherapy 463–88 ABVD 613–14 age-related factors 481 aging 138–46 aging reference 482 algorithm 540 AML 553–6 anemia 473–4 antiangiogenic agents 481 apoptosis 142–4

1541

Index

BCVPP 613–14 biologic response modifiers 479 bladder cancer 743–6 brain cancer 757–9, 760–1 breast cancer 355–6, 678–93, 706–7 cardiotoxicity 474–5 CHOP 529–30, 541–3, 630–4 clinical trials 653–8 colorectal cancer 715 complications 393–4 cytotoxic agents, new 476–7 endometrial carcinoma 780–1 enzymes 469 farnesyltransferase inhibitors 481 hematopoiesis 471 HL 613–14 hormonal therapy 477–9 interferons 479 interleukins 479 management, cancer 392–4, 481 MDR 467–9 monoclonal antibodies 480–1 MOPP 613–14 mucositis 474 myelotoxicity 470–4 nausea 474 nephrotoxicity 475 neurotoxicity 475–6 neutropenic infections 541–3 NHL 627 oral agents 476–7 organ-specific toxicity 470–6 outcomes 836–7 pharmacodynamics 467–70 pharmacokinetics 463–70 polychemotherapy, NHL 630–1 prostate cancer 737 pulmonary toxicity 475 SCLC 653–8 surgery 424 toxicity 470–6 trends 553–6 tumor kinetics 469–70 tumor-specific antineoplastic therapy 479–81 tyrosine kinase inhibitors 481 willingness to take 250–1 chlorambucil, CLL 571–2 CHOP colony-stimulating factors 529–30 neutropenic infections 541–3 NHL 630–4 chronic basophilic leukemia (CBL) 600–1

1542

Index

1543

chronic eosinophilic leukemia (CEL) 598–600 chronic granulocytic leukemia (CGL) 578–96 accelerated myeloproliferative phase 588–9 acute leukemia 589 allogeneic HSCT 592 antisense oligonucleotides 595 busulfan 585–6 defining 578–9 diagnosis of metamorphosis 588 hematologic findings 582–3 HSCT 590–1 hydroxyurea 585 hyperleukocytosis/hyperviscosity 586 hyperuricemia 586–7 interferon-a therapy 592–4 investigational therapies 594–5 laboratory findings 580–2 lymphoid blastic change 589 MDR 591 metamorphosis 588–91 molecular genetics 595 multiple cell lines 591 myeloid blastic change 589–90 natural history 582–4 Philadelphia-chromosome-negative 596 physical signs 580, 582 presentation 579 prognosis 582–4, 583–4 progression 583 prolonging chronic phase 587–8 psychosocial aspects, management 587 radiotherapy 586 refractoriness 591 renal failure 586–7 splenic irradiation 586 stem cells, hematopoietic 591 symptoms 579–80, 582 therapy, new approaches to 592–4 treatment 584–7 treatment, metamorphosis 588–91 tyrosine kinase inhibitors 594–5 chronic leukemias 561–607 acute leukemias 601 comorbidity 562 definitions 561 significance 561–2 see also named leukemias chronic lymphocytic leukemia (CLL) 562–78, 621, 805–6 active treatment 569 adrenal corticosteroids 570–1 alkylating agents 571 allopurinol 570

Index

1544

androgens 571 autoimmune complications 576 chlorambucil 571–2 cladribine 574 classification 562–3 clinical staging 568–9 cyclophosphamide 572–3 cytogenetic findings 565 disease acceleration 566 drug resistance 575–6 epidemiology 563 estrogens 571 evaluation, therapy 572–3 fludarabine 573–5 HSCT 577–8 immunologic complications 567 innovative treatments 577–8 laboratory findings 564–5 monoclonal antibodies 577 multidrug resistance 566 multiple-agent regimens 572 natural history 565–9 new drugs 577 patient management 569–78 pentostatin 574 physical signs 564 prognosis 565–9 progression 566 purine antagonists 573–5 radiotherapy 570 Rai system 568–9 Richter syndrome 566 splenectomy 572 supportive care 576–7 symptoms 563–4 terminology 562–3 transformation to acute leukemia 566–7 transformations 566 chronic myeloid leukemia (CML) 199–200, 578–602 chronic myelomonocytic leukemia (CMML) 597–8 chronic neutrophilic leukemia (CNL) 598 cladribine, CLL 574 clinical decision analysis 11–25 Bayes’ Theorem 25 clinical protocols 255–6 costs 12–13 DEALE 13, 25 decision trees 13–15 essentials 11–15 life-expectancy 12–13 Monte Carlo technique 14 outcome measures 12–13

Index

1545

predictive values 12, 24 prevalence, cancer 12 probabilities 12 QALYs 12, 14–15 screening 18–19 test performance 24 treatment considerations 19–21 clinical implications, age-related changes, emergencies 539–41 clinical protocols 250–8 CGA 254 comorbidity 252–3 cost-effectiveness 256 decision analysis 255–6 endpoints choice 251 external validity 250–1 mathematical studies 254–5 meta-analysis 255 pharmacological studies 254 screening 253–4 clinical trials 8–9 AML 557–8 breast cancer 355–6, 669–73, 704–7 chemoprevention 353–4 chemotherapy 653–8 comorbidity 261–3 consent 264–5 costs 265–7 eligibility criteria 261 enrollment problems 260–1 family decision 268–9 growth factors 557–8 NHL 631–4 patient refusal 267–8 physician decision 263–4 prostate cancer 370–1 remedial strategies 269–70 SCLC 653–8, 659–60 screening 368, 370–1 under-representation 259–74 CLL see chronic lymphocytic leukemia ‘clocks of aging’ 92 CML see chronic myeloid leukemia CMML see chronic myelomonocytic leukemia CMV, bladder cancer 746 CNL see chronic neutrophilic leukemia colony-stimulating factors, CHOP 529–30 colorectal cancer 710–17 adjuvant therapy 714 aging 715 chemoprevention 358–9 chemotherapy 715 classification 713

Index

1546

clinical presentation 712 colon cancer 714 compliance, preoperative treatment 280–1 detection 711–13 detection/confirmation rates 48 diagnosis 57–9, 711–13 diagnostic studies 712–13 epidemiology 710–11 etiology 710–11 hepatic resection 715 histologic grade 182 incidence 7, 38–40, 259, 710 liver cancer 715 management 314–15, 713–15 metastatic disease 715 molecular development 349–50 mortality rates 29–37, 275 NSAIDs 358–9 pathology 713 preoperative treatment 280–1 prevention 711 prognosis 713 QoL 296 radiotherapy 279–81 rectal cancer 714–15 recurrence 715 risk factors 710 screening 370, 711–12 stage distribution by age 42 staging 713 surgery 408, 713–14 surveillance 715 susceptibility 76–80 communication demography 378–80 generation gap 396–7 physician-patient 378–80, 396–7 screening 378–80 community-based barriers, screening 382–3 comorbidity 252–3 assessment 45–6 causes 192 chronic leukemias 562 clinical trials 261–3 emergencies 538–9 GROG 286–7 prevalence 261–3 prognostic evaluation 310–11 radiotherapy 454 compliance, polypharmacy 507 compliance, preoperative treatment, colorectal cancer 280–1 complications, chemotherapy 393–4

Index

1547

Comprehensive Geriatric Assessment (CGA) 225–9, 254, 525–7 emergencies 540–1 GOPs 854–7 prognostic evaluation 311–12 screening 367–8 conformal radiotherapy 275–6 connective tissue cancer, detection/confirmation rates 48 constipation 326, 337–8, 820–3 contractures, rehabilitation 839 corticosteroids 818 dyspnea 820 nausea 824 cost-effectiveness analysis 516–17 clinical protocols 256 diagnosis 510–24 studies 517–21 treatment 510–24 costs 9 anemia 450 cancer 514 clinical decision analysis 12–13 clinical trials 265–7 polypharmacy 506 cough 824–7 counseling, individual 306 see also social support countries, mortality rates by 29–37 creatinine clearance, aging 218 critical care 401 cutaneous angiosarcoma 796–7 cutaneous stomas, surgery 835–6 cyclophosphamide, CLL 572–3 cytogenetic abnormalities, monoclonal gammopathies 199–200 cytokines aging effects 434–6 cancer cachexia 239–41 hematopoiesis 434–6 cytosarcoma phylloides, breast cancer 674 cytotoxic agents, new, chemotherapy 476–7 cytotoxic chemotherapy, management, cancer 392–4 danger signals 62 data collection, QoL 293 data quality, epidemiology research 49–51 DCIS see ductal carcinoma in situ death causes 190–1 programmed cell see apoptosis see also mortality rates death receptor pathway

Index

1548

apoptosis 138–9 MM 648 decision analysis, clinical see clinical decision analysis decision analysis, economic 524 declining exponential approximation for life-expectancy (DEALE) 523–4 clinical decision analysis 13, 25 deep vein thrombosis (DVT) 838–9 dehydroepiandrosterone (DHEA) 216 immune function 165–6 delirium, emergencies 544–6 demography communication 378–80 screening 376–8 see also epidemiology research; population statistics depression 818–19 detection colorectal cancer 711–13 see also early detection detection/confirmation rates, cancer sites 48 DHEA see dehydroepiandrosterone diabetes 216–17 diagnosis advanced-stage cancer 57 brain cancer 750–3, 764 breast cancer 667–9 colorectal cancer 711–13 cost-effectiveness 510–24 delays 62 early-stage cancer 56–7 endometrial carcinoma 779 factors affecting 56–64 local-stage cancers 58–9 prostate cancer 730 unstaged cancers 58–9 diagnostic studies, colorectal cancer 712–13 diarrhea 326, 337, 823 diet, breast cancer 667 dietary restriction, aging 147–8 dietitian, SAOPs 858 diffuse large B-cell lymphoma (DLCL) 622 digestive tract, morbid anatomy 189 7, 12-dimethylbenz[a]anthracene (DMBA), skin cancer 86 disease, vs. aging 67 distribution, pharmacokinetics 464 DLCL see diffuse large B-cell lymphoma DMBA see 7, 12-dimethylbenz[a]anthracene DNA damage 70–1 BrdUrd 89 DNA fragmentation, apoptosis 142 DNA ploidy, breast cancer 173 DNA repair age-related changes 80–3

Index

1549

lymphocytes 162 dopamine antagonists, nausea 824 dopamine-related agents, hiccup 826 dose adjustment, GFR 528–9 Down syndrome 69 drug resistance CLL 575–6 MM 200–1 see also multidrug resistance dry mouth 325–6, 334–5 ductal carcinoma in situ (DCIS), breast cancer 673–7 DVT see deep vein thrombosis dysphagia 326, 338 dyspnea 819–20 corticosteroids 820 morphine 820 early detection breast cancer 669–73 markers 119–20 secondary prevention, cancer 365–6 social support 302 early diagnosis, screening 518–20 early satiety, nutrition 335 early-stage cancer breast cancer 704–7 diagnosis 56–7 economic analyses 513–21 economic outcomes 513–14 effectiveness, vs. efficacy 56 efficacy, vs. effectiveness 56 emergencies 534–50 CGA 540–1 clinical implications, age-related changes 539–41 comorbidity 538–9 construct 534–5 delirium 544–6 functional changes 537–9 medical changes 538–9 neutropenic infections 541–3 physiological changes 535–7 social aging 539 visceral perforation 544 volume depletion 543–4 endocrine aspects aging 215–17 see also hormonal therapy endocrine system, physiological changes 419–20 endocrine tumors, surgery 407 endometrial carcinoma 778–81 chemotherapy 780–1

Index

1550

clinical course 778 diagnosis 779 evaluation 779 hormonal therapy 780 management 779–80 pathology 778 prognostic factors 778 enemas 823 energy, nutrition 331–2 enzymes carcinogen-metabolizing 80 chemotherapy 469 epidemiology anemia 442–3 brain cancer 749–50 breast cancer 662, 693 CLL 563 colorectal cancer 710–11 monoclonal gammopathies 194–6 NHL 619 epidemiology research 47–55 data quality 49–51 future 55 incidence data 48–9 information sources 47–52 mortality data 47–8 survival data 49–52 see also population statistics error catastrophe theory 70 esophageal cancer data quality 50 diagnosis 57–9 radiotherapy 282–3 surgery 406–7 susceptibility 76–80 estrogens, CLL 571 ethical issues 400–1 nutrition 339–40 etiology celomic epithelial carcinoma of the ovary 771 colorectal cancer 710–11 malnutrition 324–6 NHL 620 prostate cancer 725–7 squamous cell carcinoma of the uterine cervix 775 evaluation bladder cancer 742–3 clinical 225–32 endometrial carcinoma 779 HSCT 493–4 older patient with cancer 309–19 evolutionary antagonistic pleiotropy, cellular senescence 133

Index

1551

excretion, pharmacokinetics 465–7 exercise, aging 212–13 extranodal marginal zone B-cell lymphoma of MALT type 621 management 626 extrinsic-stochastic aging 69–71 eye cancer, detection/confirmation rates 48 family caregiving 843–52 bereavement issues 849–50 coping 847 diversity 844 future 850 health outcomes 847–8 implications, healthcare delivery 850 interventions, caregivers 848–9 social support 846–7 stress process model 844–8 see also social support family role, social support 304–5 farnesyltransferase inhibitors, chemotherapy 481 fatigue 816–17 anemia 446 febrile neutropenia 809–11 see also neutropenic infections FL see follicular lymphoma fludarabine, CLL 573–5 follicular lymphoma (FL) 621, 622 management 626–8 frailty 236–49 prognostic evaluation 310 see also assessment free-radical hypothesis 70 functional assessment 231 functional changes, emergencies 537–9 functional impairment, measures 261–3 future apoptosis 144 brain cancer 760 family caregiving 850 QoL 299 research 55 training 390 G-CSFs see granulocyte colony-stimulating factors gallbladder cancer, diagnosis 57–9 gastric cancer data quality 49, 50 detection/confirmation rates 48 diagnosis 57–9 histologic grade 182 incidence 38–40

Index

1552

mortality rates 29–37 surgery 407 susceptibility 76–80 gastrointestinal function aging 213–15 nutrition 326–7 physiological changes 419, 535 gender cancer incidence 5–6 cancer prevalence 5–6 population statistics 42–4 gene expression profiles, aging 95 gene therapy, brain cancer 761 generation gap, communication 396–7 genes, tumor suppressor genes 103–5 genetically-determined aging 69–71 genetically modified mice, spontaneous tumor development 90–2 genitourinary lesions, morbid anatomy 189 genitourinary system, physiological changes 419 geriatric assessment 525–6 geriatric oncology programs (GOPs) 853–61 benefits 855–6 case presentations 856, 859–61 defining 853–4 disadvantages 860 goals 857 problems 859–60 target population 857 see also CGA Geriatric Radiation Oncology Group (GROG) 275–90 geroprotectors effects, hypothetical 96 spontaneous tumor development 93–6 GFR see glomerular filtration rate GH see growth hormone glomerular filtration rate (GFR), dose adjustment 528–9 glossaries 24 geriatric glossarium 224 goals, treatment 395 GOP see geriatric oncology programs grading brain cancer 752–3 prostate cancer 730 graft-versus-myeloma (GVM) effect, MM 644–5 granulocyte colony-stimulating factors (G- CSFs), CHOP 529–30 GROG see Geriatric Radiation Oncology Group growth factors aging 102–26 AML 557–8 clinical trials 557–8 hematopoiesis 471 immune senescence 154–5

Index

1553

molecular biology 103–5 prostate cancer 727 growth hormone (GH) 216 growth modulation, zinc chelators 122 growth, tumor see tumor growth guidelines management, cancer 525–33 nutrition 328–9 GVM effect see graft-versus-myeloma effect gynecologic cancers 771–83 celomic epithelial carcinoma of the ovary 771–5 endometrial carcinoma 778–81 radiotherapy 458 squamous cell carcinoma of the uterine cervix 775–8 surgery 410 see also cervical cancer; ovarian cancer head and neck cancer 718–24 case reports 722–3 chemoprevention 359–60 GROG 286–7 incidence 259 management 719–23 pathogenesis 718–19 radiotherapy 281–2, 286–7, 455–6 recent advances 721–2 surgery 410 viruses 718–19 hematologic malignancies, MPS-1 mRNA 113 hematopoiesis 427–41 bone marrow function, aging effects 430–6 bone marrow function, normal 427–9 bone marrow stroma 434 chemotherapy 471 cytokines 434–6 growth factors 471 immune function changes 436–8 stem cells 427–9 hematopoietic changes, physiological changes 535–7 hematopoietic stem cell transplantation (HSCT) 489–501 allogenic 494–6 autologous 496–8, 643–4 CGL 590–1 CLL 577–8 death causes 492–3 evaluation 493–4 increasing utilization 490 MM 643 non-myeloblative transplants 499 outcomes 494–8 principles 489–90

Index

1554

process 490–3 supportive care 498–9 tolerance 494–8 toxicity 498–9 trends 491 hematopoietic system, susceptibility 76–80 hemoglobin levels maintenance 530 hepatic resection, colorectal cancer 715 HHV-8 see human herpesvirus 8 hiccup 825–7 histology, tumor ‘aggressiveness’ 181–2 Hodgkin lymphoma (HL) 608–18 biology 608–9 chemotherapy 613–14 complications, therapy 614 diagnosis 609–10 epidemiology 608 histology 610–11 immunology 611 incidence 8 lymphadenopathy 609 pathogenetic scheme 608–9 prognosis 614–15 recurrence 614 staging 611–13 staging laparotomy 612–13 treatment 613–14 hormonal agents, breast cancer 690 hormonal therapy brain cancer 759 chemotherapy 477–9 endometrial carcinoma 780 management, cancer 394 see also endocrine aspects hormone replacement therapy (HRT), breast cancer 663–7 HPA axis see hypothalamic-pituitary-adrenal axis HRT see hormone replacement therapy HSCT see hematopoietic stem cell transplantation human herpesvirus 8 (HHV-8), monoclonal gammopathies 199 humoral immune system 158–9 Hutchinson-Gilford syndrome 69 hydration, nutrition 333 hydroxyurea, CGL 585 hyperleukocytosis/hyperviscosity, CGL 586 hyperuricemia, CGL 586–7 hypothalamic-pituitary-adrenal axis (HPA axis), cancer cachexia 243–4 IACR see International Association of Cancer Registries IARC see International Agency for Research on Cancer iatrogenic damage, rehabilitation 832–7 immobility, rehabilitation 838–9

Index

1555

immune decline, age-related mechanisms 165–6 reversal 165–6 immune forces, tumor growth 152 immune function antioxidants 166 changes, age 160–3, 165–6 immune function changes aging effects 436–8 B lymphocytes 160–1, 436, 437–8 lymphocytes 160–3 macrophage function 161–2 NK cells 162 T lymphocytes 160, 436–7 immune senescence growth factors 154–5 lymphomagenesis 149–50 tumor growth 154–5 immune system decreased immunity, age 159–60 humoral 158–9 model 158–9 organization 158–9 immunity aging 72, 164–5 stress 164–5 immunocompetence, nutrition 327 immunologic complications, CLL 567 immunological changes, aging 158–70, 803–4 immunomodulators, brain cancer 759–60 immunoregulatory factors, responses 163–4 immunotherapy brain cancer 761–2 NHL 634 IMRT see intensity-modulated radiotherapy incidence, cancer 38–40 by age 5–6, 15–16 aging rate 127–8 by gender 5–6 sites 6–8, 259 incidence, colorectal cancer 7, 38–40, 259, 710 incidence data, epidemiology research 48–9 incidence, tumor, aging 148–50 indolent lymphomas, NHL 621, 624–8 induction agents, anesthetic management 421–2 infections 401 infectious complications 803–12 information sources, epidemiology research 47–52 informed consent, clinical trials 264–5 innovative treatments, CLL 577–8 intensity-modulated radiotherapy (IMRT), cervical cancer 284 interactions, drug-drug, polypharmacy 506

Index

1556

interdisciplinary teams 853–62 interferon-a therapy, CGL 592–4 interferons chemotherapy 479 NHL 627–8 interleukins aging effects 434–6 chemotherapy 479 immunoregulatory factor 163–4 interleukin-6 197–9, 434–6 monoclonal gammopathies 197–9 International Agency for Research on Cancer (IARC), incidence data 48–9 International Association of Cancer Registries (IACR), incidence data 48–9 International Prognostic Index (IPI), NHL 629 intervertebral disc changes, aging 208 intestinal cancer detection/confirmation rates 48 mortality rates 29–37 see also colorectal cancer; gastric cancer intrinsic-stochastic aging 69–71 invasive bladder cancer 742–6 radiotherapy 284 investigational therapies, CGL 594–5 IPI see International Prognostic Index iron-finger proteins carcinogenesis 106–7 molecular biology 106–7 Kaposi sarcoma-associated herpesvirus (KSHV) see human herpesvirus 8 keratoacanthoma 790–1 kidney histologic structure 189 nephrotoxicity, chemotherapy 475 see also renal function kidney cancer diagnosis 57–9 susceptibility 76–80 knowledge-based barriers, screening 380–1 KSHV see human herpesvirus 8 laboratory assessment, aging 231–2, 528 lactose intolerance 336–7 larynx cancer, detection/confirmation rates 48 latent tumors 191 laxatives 821–3 lean body mass loss, nutrition 326 length-time bias, screening 366 leptin, cancer cachexia 241–3 leukemia incidence 8, 259 see also acute myeloid leukemia; chronic leukemias

Index

1557

life-expectancy 44, 67–8 clinical decision analysis 12–13 comorbidity 45–6, 192, 252–3 DEALE 13, 25 estimate 526–7 statistics 3–6, 16–17 lifespan 67–8 extension, and carcinogenesis 92–6 limb amputations, surgery 836 lip cancer, diagnosis 57–9 liver cancer colorectal cancer 715 data quality 50 hepatic resection 715 surgery 409 susceptibility 76–80 liver, histologic structure 189 liver physiology, aging 215 local-stage cancers, diagnosis 58–9 longevity, tumor development 90–2 LPL see lymphoplasmacytic lymphoma LRP see lung-resistance protein lung see also respiratory system lung cancer chemoprevention 359, 360 data quality 50 detection/confirmation rates 48 diagnosis 57–9 histologic grade 182 incidence 7, 38–40, 259 management 313–14 mortality rates 31–7, 275 NSCLC 278–9 QoL 296–7 radiotherapy 278–9, 456–7 SCLC 279 screening 372 survival 279 susceptibility 76–80 see also small cell lung cancer lung-resistance protein (LRP), multidrug resistance 201 lymph node mapping, breast cancer 677–8 lymph nodes, recurrence 838 lymphadenopathy, HL 609 lymphedema, surgery 835 lymphocytes activation 162–3 DNA repair 162 immune function changes 160–3 membrane fluidity 162–3 membrane signal transduction 162–3

Index

1558

nutrition assessment 331 lymphoma, incidence 259 lymphomagenesis, immune senescence 149–50 lymphoplasmacytic lymphoma (LPL) 621 management 625–6 MCL see mantle cell lymphoma macrophage function, immune function changes 161–2 magnitude of the problem 38–46 malignant melanoma 791–5 malnutrition see nutrition mammary gland susceptibility 76–80 see also breast cancer management, cancer 309–10, 391–8 biologic therapy 394 breast cancer 312–13 celomic epithelial carcinoma of the ovary 773–4 chemotherapy 392–4, 481 colorectal cancer 314–15, 713–15 communication 396–7 cytotoxic chemotherapy 392–4 endometrial carcinoma 779–80 evidence, recommendations 526–8 geriatric assessment 525–6 hormonal therapy 394 lung cancer 313–14 prostate cancer 314 radiotherapy 392 special issues 394–7 squamous cell carcinoma of the uterine cervix 776–8 surgery 391–2 targeted therapy 394 treatment-related recommendations 528–31 manpower 9 mantle cell lymphoma (MCL) 622 management 628 markers aging 71 clinical 330–1 dietary 330 early detection 119–20 MPS-1 ribosomal protein 118–19 MPS-H antigens 119–20 oncogenic processes 119–20 prognosis 119–20 rating 122 mathematical studies, clinical protocols 254–5 maturation, zinc chelators 122 maximum survival 67–8 MDR see multidrug resistance

Index

1559

MDS see myelodysplastic syndromes median survival 67–8 medical caregivers, social support 306 medical changes, emergencies 538–9 medullary carcinoma, breast cancer 674 megestrol acetate 818 melanocytic lesions, MPS-1 ribosomal protein 118–19 melanoma B16 153–4 detection/confirmation rates 48 diagnosis 57–9 growth 153–4 incidence 7, 259 malignant melanoma 791–5 membrane fluidity, lymphocytes 162–3 membrane signal transduction, lymphocytes 162–3 membrane-stabilizing agents, hiccup 826 Merkel cell carcinoma 795–6 meta-analysis, clinical protocols 255 metabolic disorders, cancer cachexia 239–44 metabolic state, cancer cachexia 239 metabolism, pharmacokinetics 464–5 metallopanstimulin-1 ribosomal protein see MPS-1 ribosomal protein metastases assessment 840 bone cancer 837 metastatic disease breast cancer 707 colorectal cancer 715 prostate cancer 735–7 MGUS see monoclonal gammopathy of unknown significance midazolam, hiccup 827 mitochondrial pathway, apoptosis 138–9 MM see multiple myeloma molecular basis aging 105–6 cancer 105 molecular biology aging 80–3 carcinogenesis 80–3 growth factors 103–5 iron-finger proteins 106–7 MM 647–8 MPS-1 ribosomal protein 107–16 tumor suppressor genes 103–5 zinc-finger proteins 106–7 molecular development, colorectal cancer 349–50 molecular genetics, CGL 595 monoclonal antibodies chemotherapy 480–1 CLL 577 monoclonal gammopathies 194–203

Index

1560

clinical conditions, associated 195 cytogenetic abnormalities 199–200 epidemiology 194–6 HHV-8; 199 interleukin-6 197–9 MGUS 194–6 natural history 194–6 relationships, aging 196–7 monoclonal gammopathy of unknown significance (MGUS) 194–6 Monte Carlo technique, clinical decision analysis 14 MOPP, HL 613–14 morphine dyspnea 820 pain 815–16 mortality rates 40, 275, 323 breast cancer 29–37, 275 colorectal cancer 29–37, 275 by countries 29–37 gastric cancer 29–37 intestinal cancer 29–37 lung cancer 31–7, 275 myeloma 32 prostate cancer 31–7, 275 statistics 6, 15–16, 29–37 treatment considerations 20 trends 29–37 worldwide approach 29–37 mouth cancer, detection/confirmation rates 48 MPS-1 mRNA expression 117–18 hematologic malignancies 113 MPS-1 ribosomal protein 107–16 amino acid sequence 114 biological characteristics 115 detection 111 expression 117–18 gene expression features 112 hematologic malignancies 113 levels changes 115–16 markers 118–19 melanocytic lesions 118–19 molecular biology 107–16 nucleotide sequence 114 pharmacologic disruption 120–2 ribotoxic responses 107–16 schematic representation 113 MPS-H antigens, markers 119–20 mucinous carcinoma, breast cancer 674 mucositis chemotherapy 474 nutrition 325 multidrug resistance (MDR)

Index

CGL 591 chemotherapy 467–9 CLL 566 MM 200–1 multiple-agent regimens, CLL 572 multiple myeloma (MM) 196–7, 806–8 adjuvant therapy, bone disease 646 angiogenesis 646–7 apoptosis 647–8 autologous HSCT 643–4 death receptor pathway 648 GVM effect 644–5 high-dose therapy 643 HSCT 643–4 molecular biology 647–8 multidrug resistance 200–1 prognostic factors 642 proteasome inhibitors 648–9 targeted therapy 647–8 thalidomide 646–7 treatment 642–50 multistage carcinogenesis 75–101, 148 model, aging 83–8 muscle atrophy, rehabilitation 839 muscle injury, surgery 835 musculoskeletal function aging 219–20 physiological changes 416–17 mutant mice, spontaneous tumor development 90–2 mutations 128–9 cellular senescence 133–5 MVAC, bladder cancer 746 myelodysplastic syndromes (MDS) 808 myeloid leukemia, detection/confirmation rates 48 myeloma detection/confirmation rates 48 incidence 259 mortality rates 32 myelotoxicity 470–4 myocardial fibrosis 188 National Cancer Institute (NCI) 57–9 National Institute on Aging (NIA), research 45–6 natural killer (NK) cells immune function changes 162 NK-cell neoplasms, NHL 620 nausea 823–4 bowel obstruction 827 chemotherapy 474 nutrition 326, 335–6 NCI see National Cancer Institute

1561

Index

1562

nebulized lidocaine, hiccup 827 nephrotoxicity, chemotherapy 475 nerve injury, surgery 832–5 nervous system aging 220–1 physiological changes 418–19, 537 recurrence 837–8 neuroendocrine theory 71 neurological function, nutrition 327 neurosurgery 411 neurotoxicity, chemotherapy 475–6 neutropenic infections chemotherapy 541–3 emergencies 541–3 febrile neutropenia 809–11 new drugs, CLL 577 NHL see non-Hodgkin lymphoma NIA see National Institute on Aging NK-cell neoplasms, NHL 620 NK cells, immune function changes 162 nodal marginal zone B-cell lymphoma (with or without monocytoid B cells) 621 management 626 non-compliance, polypharmacy 507 non-Hodgkin lymphoma (NHL) 619–41 Ann Arbor staging 623 B-cell neoplasms 620 biology 619–20 chemotherapy 627 classification 620–1 clinical characteristics 620 clinical trials 631–4 epidemiology 619 etiology 620 evaluation 623–4 immunotherapy 634 incidence 8 indolent lymphomas 621, 624–8 interferons 627–8 management 624–34 NK-cell neoplasms 620 radiotherapy 626–7 risk factors 620 staging 623 T-cell neoplasms 620 non-neoplastic pathology, characteristic patterns 190 non-small cell lung cancer (NSCLC) 278–9 non-steroidal anti-inflammatory drugs (NSAIDs) colorectal cancer 358–9 pain 816 NP see nurse practitioner NSAIDs see non-steroidal anti-inflammatory drugs NSCLC see non-small cell lung cancer

Index

nurse practitioner (NP), SAOPs 858 nursing NP 858 PCN 858 nutrition 323–48, 400 alternative therapies 341 anorexia 336 anthropometrics 330–1 assessment 329–31 assessment forms 344–8 biochemical parameters 331 cancer cachexia 325 care plan 333 challenges 324, 326–8 chronic illness 327–8 clinical markers 330–1 constipation 326, 337–8 diarrhea 326, 337 dietary markers 330 dry mouth 325–6, 334–5 dysphagia 326, 338 early satiety 335 energy 331–2 enteral support 339 ethical issues 339–40 follow-up 341 gastrointestinal function 326–7 guidelines 328–9 hydration 333 immunocompetence 327 lactose intolerance 336–7 lean body mass loss 326 malnutrition etiology 324–6 malnutrition prevalence 323–4 malnutrition significance 323–4 mucositis 325 nausea 326, 335–6 neurological function 327 pharmacological approaches 340 physical fitness 340 physical limitations 328 physiological changes 327 pressure ulcers 328 protein 332–3 psychological factors 328 reassessment 341 requirements 331–40 risk 333–8 sensory losses 327 smell changes 324–5, 334 social support 328 support methods 339

1563

Index

taste changes 324–5, 334 TPN 339 tumor effects 324 nutritional status aging 237–9 cancer cachexia 237–9 oncogenes, aging 102–26 oncogenic processes, markers 119–20 oncological rehabilitation see rehabilitation oncologist/geriatrician, SAOPs 858 opioids bowel obstruction 827 cough 825 pain 815–16 organ-specific toxicity, chemotherapy 470–6 organismal aging 69 orthopedics, surgery 411 osmotic laxatives 822 osteoarthritis 219–20 outcome measures, clinical decision analysis 12–13 outcomes AML 555 cancer care 512–13 chemotherapy 836–7 economic 513–14 family caregiving 847–8 HSCT 494–8 improving 62 ovarian cancer celomic epithelial carcinoma of the ovary 771–5 detection/confirmation rates 48 diagnosis 57–9 histologic grade 182 incidence 38–40, 259 stage distribution by age 41–2 susceptibility 76–80 overdetection bias, screening 366–7 overtreatment 61–2 p53; apoptosis 142–4 breast cancer 173, 176–7 Paget’s disease, breast cancer 674 pain 814–16 adjuvant therapy 816 control, non-pharmacologic techniques 814 control, pharmacologic approaches 814–16 NSAIDs 816 opioids 815–16 palliative radiotherapy 287

1564

Index

1565

pancreatic cancer data quality 50 detection/confirmation rates 48 diagnosis 57–9 incidence 7, 38–40, 259 surgery 408–9 susceptibility 76–80 pathological damage, rehabilitation 837–8 pathology colorectal cancer 713 endometrial carcinoma 778 patient attitudes, screening 381 Patient Outcome Research Team (PORT), prostate cancer 729–30 PCN see primary care nurse pelvic malignancies, radiotherapy 458–9 pentostatin, CLL 574 perioperative considerations 415–26 perioperative management 423–5 peripheral T-cell lymphoma 622 peritoneum, susceptibility 76–80 PgR see progesterone receptor pharmacist, SAOPs 858 pharmacokinetics absorption 463–4 chemotherapy 463–70 distribution 464 excretion 465–7 metabolism 464–5 pharmacologic changes 420–1 pharmacologic disruption angiogenesis 120–2 carcinogenesis 120–2 MPS-1 ribosomal protein 120–2 pharmacological approaches, nutrition 340 pharmacological studies, clinical protocols 254 pharynx cancer, detection/confirmation rates 48 Philadelphia-chromosome-negative CGL 596 photodynamic therapy, brain cancer 761 physical fitness, nutrition 340 physical limitations, nutrition 328 physical performance, assessment 229–31 physician attitudes, screening 381–2 physician-patient communication 378–80, 396–7 physicians’ role, social support 305 physiological changes aging 415–20 body composition 535 cardiovascular system 417–18, 535 emergencies 535–7 endocrine system 419–20 gastrointestinal function 419, 535 genitourinary system 419

Index

1566

hematopoietic changes 535–7 musculoskeletal function 416–17 nervous system 418–19, 537 nutrition 327 pulmonary system 418 surgery 415–20 systemic changes 537 physiology, aging 6 PKB see protein kinase B pleura cancer, susceptibility 76–80 pneumonia 804–5 polypharmacy 502–9 ADR 505–6 arenas 504–5 compliance 507 consequences 505–7 costs 506 development 502–4 interactions, drug-drug 506 non-compliance 507 prevention 507–8 population statistics 3–6, 15–18, 29–37, 42–4 see also epidemiology research PORT see Patient Outcome Research Team prealbumin, nutrition assessment 331 precursor B-lymphoblastic leukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia) 623 predictive values, clinical decision analysis 12, 24 premature aging, carcinogenesis 90 premedication, anesthetic management 421 prepucial gland, susceptibility 76–80 pressure sores, rehabilitation 839 pressure ulcers, nutrition 328 prevalence comorbidity 261–3 malnutrition 323–4 prevalence, cancer clinical decision analysis 12 statistics 5–6 prevention, cancer see cancer prevention primary care nurse (PCN), SAOPs 858 probabilities, clinical decision analysis 12 progesterone receptor (PgR), breast cancer 174 prognosis CGL 582–4, 583–4 CLL 565–9 colorectal cancer 713 HL 614–15 markers 119–20 prognostic evaluation cancer management 309–10 CGA 311–12

Index

comorbidity 310–11 frailty 310 older patient with cancer 309–19 prognostic factors celomic epithelial carcinoma of the ovary 771–2 endometrial carcinoma 778 programmed cell death see apoptosis proliferative senescence 127–37 prostaglandins, immunoregulatory factor 163 prostate cancer 277, 725–41 alternative therapies 735 androgens 727 apoptosis 726 brachytherapy 734 chemoprevention 357–8 chemotherapy 737 clinical trials 370–1 combination testing 729 controversy 728–9 cryotherapy 734–5 current recommendations 728 cytogenetic data 726 data quality 50 detection/confirmation rates 48 diagnosis 57–9, 730 etiology 725–7 grading 730 growth factors 727 hereditary 725–6 histologic grade 182 incidence 7, 38–40, 259 laparoscopic radical prostatectomy 733 management 314 metastatic disease 735–7 mortality rates 31–7, 275 oncogenes 726 PORT 729–30 prevention 727 QoL 297–8, 737 radical perineal prostatectomy 733 radical prostatectomy 731–3 radiotherapy 278, 455, 733–4 research 737–8 risk factors 357 screening 370–2, 727–30 stage distribution by age 42 staging 730 surgery 409, 731–3 susceptibility 76–80 treatment 730–7 tumor suppressor genes 726 watchful waiting 730–1

1567

Index

proteasome inhibitors, MM 648–9 protein kinase B (PKB), apoptosis 140 protein, nutrition 332–3 protocols, clinical see clinical protocols psychological factors, nutrition 328 psychosocial adaptation, social support 303–4 psychosocial aspects, management, CGL 587 psychostimulants 817, 819 PTH see serum parathyroid hormone pulmonary system physiological changes 418 surgery 424 pulmonary toxicity, chemotherapy 475 purine antagonists, CLL 573–5 QALYs see quality-adjusted life-years QoL see quality of life quality-adjusted life-years (QALYs) clinical decision analysis 12, 14–15 treatment considerations 19–21 quality of life (QoL) 291–300, 512–13 assessment 294–5 brain cancer 762–4 breast cancer 295–6 colorectal cancer 296 conceptualization 291–3 data collection 293 defining 291–2 future 299 history 291–2 instruments 294 lung cancer 296–7 measurement 293–4 multidimensionality 292–3 prostate cancer 297–8, 737 special aspects 298–9 race and ethnicity, screening 377 radiotherapy 275–90, 453–62 advances 275–6 bladder cancer 284, 743–6 brachytherapy 276 brain cancer 459, 755–7, 760 breast cancer 276–8, 457–8, 677–80 cervical cancer 283–4 CGL 586 CLL 570 colorectal cancer 279–81 comorbidity 454 conformal radiotherapy 275–6 damage, radiotherapy-related 836

1568

Index

data lack 453–4 esophageal cancer 282–3 GROG 275–90 gynecologic cancers 458 head and neck cancer 281–2, 286–7, 455–6 IMRT 284 lung cancer 278–9, 456–7 management 276–84 management, cancer 392 NHL 626–7 NSCLC 278–9 palliative 287 pelvic malignancies 458–9 prostate cancer 278, 455, 733–4 SCLC 658–60 socioeconomic data 454–5 technical conditions 454 toxicity 658–9 rectal cancer diagnosis 57–9 see also colorectal cancer recurrence breast cancer 679–80, 681–9 HL 614 lymph nodes 838 nervous system 837–8 skin cancer 838 rehabilitation 830–42 assessment 839–40 bone loss 839 cancer-related damage 831–9 contractures 839 DVT 838–9 iatrogenic damage 832–7 immobility 838–9 muscle atrophy 839 pathological damage 837–8 pressure sores 839 respiratory problems 838 surgical approaches 403 teams 831 relapse-free survival (RFS), breast cancer 175–7 renal failure, CGL 586–7 renal function aging 217–19 see also kidney research advancement 38–46 biomedical gerontology 69–72 epidemiology 47–55 future 55 implications 44–5

1569

Index

NIA 45–6 prostate cancer 737–8 spirituality 865–6 respiratory problems, rehabilitation 838 respiratory system aging 211–12 morbid anatomy 188 see also lung. retinoids, brain cancer 759 RFS see relapse-free survival ribotoxic responses carcinogens 107–16 MPS-1 ribosomal protein 107–16 stress 116, 117 zinc-finger proteins 117 Richter syndrome, CLL 566 risk factors aging 75–101 breast cancer 662–7 colorectal cancer 710 NHL 620 prostate cancer 357 risk, nutrition 333–8 saline laxatives 822 SAOPs see senior adult oncology programs scar pathology, surgery 832 SCLC see small cell lung cancer screening access to care 378 aging 18–19, 367–8 assessment 528 attitudinal barriers 381–2 barriers 380–4 barriers improvement 383–4 benefits 366–7 breast cancer 368–70, 704 cancer 18–19 celomic epithelial carcinoma of the ovary 772–3 cervical cancer 372 CGA 367–8 clinical protocols 253–4 clinical trials 368, 370–1 colorectal cancer 370, 711–12 communication 378–80 community-based barriers 382–3 community interventions 382–3 current tests 367–8 demography 376–8 early diagnosis 518–20 knowledge-based barriers 380–1

1570

Index

1571

length-time bias 366 lung cancer 372 office interventions 382 overdetection bias 366–7 overtreatment 61–2 physician attitudes 381–2 prostate cancer 370–2, 727–30 race and ethnicity 377 recommendations 22 secondary prevention, cancer 366–8 social support 302 socioeconomic variation 376–8 tests 229–31 urban versus rural 378 see also cancer prevention secondary prevention, cancer see cancer prevention SEER see Surveillance, Epidemiology, and End Results database selective serotonin reuptake inhibitors (SSRIs) 819 senescence, cellular see cellular senescence senescence, proliferative 127–37 senescent phenotype 132–3 senior adult oncology programs (SAOPs) 857–61 sensory losses, nutrition 327 serum parathyroid hormone (PTH) 216 ‘seven danger signals’ 62 signal transduction, lymphocytes 162–3 simultaneous surgical problems 401–2 singultus 825–7 sites for cancer incidence, statistics 6–8, 16 skin cancer 784–99 actinic keratosis 784–6 basal cell carcinoma 786–8 cutaneous angiosarcoma 796–7 keratoacanthoma 790–1 malignant melanoma 791–5 Merkel cell carcinoma 795–6 recurrence 838 squamous cell carcinoma 788–90 surgery 411 susceptibility 76–80 tumorigenesis 784 ultraviolet radiation 784 skin changes, aging 210–11 SLL see small lymphocytic lymphoma small cell lung cancer (SCLC) 279 chemotherapy 653–8 clinical trials 653–8, 659–60 prognostic factor, age as 652–3 radiotherapy 658–60 treatment 651–61 small lymphocytic lymphoma (SLL) 621 management 625

Index

1572

smell changes, nutrition 324–5, 334 social aging, emergencies 539 social network role, social support 304–5 social support 301–8 assessment 305 cancer prevention 302 cancer treatment 303 caution 305 counseling, individual 306 defining 301–2 early detection 302 effects 302 family role 304–5 medical caregivers 306 nutrition 328 physicians’ role 305 psychosocial adaptation 303–4 referral 305–6 screening 302 social network role 304–5 support groups 305–6 social worker, SAOPs 858–9 socioeconomic variation, screening 376–8 soft tissue sarcoma, incidence 259 soft tissues, susceptibility 76–80 spirituality 863–6 defining 863–4 forms 864–5 practical applications 865 research 865–6 study 865 splenectomy, CLL 572 splenic marginal zone B-cell lymphoma (with or without villous lymphocytes) 621 management 626 spontaneous tumor development aging 75–6, 90–2 geroprotectors 93–6 squamous cell carcinoma of the uterine cervix 775–8 etiology 775 management 776–8 staging 775–6 squamous cell carcinoma, skin cancer 788–90 SSRIs see selective serotonin reuptake inhibitors stage distribution by age 41–2 staging bladder cancer 742 breast cancer 676 CLL 568–9 colorectal cancer 713 HL 611–13 NHL 623 prostate cancer 730

Index

1573

squamous cell carcinoma of the uterine cervix 775–6 statistics aging 3–6, 42–4 life-expectancy 3–6, 16–17 mortality rates 6, 15–16, 29–37 population 3–6, 15–18 prevalence, cancer 5–6 sites for cancer incidence 6–8, 16 survival 15–16 stem cells, hematopoietic 427–9 aging effects 431–4 CGL 591 integrity 432–4 pluripotent 431–2 precursors 432 progenitor cell cycle kinetics 432 stimulant laxatives 822–3 stomach cancer see gastric cancer stool softener laxatives 822 stress aging 164–5 cellular response 117, 118–19 immunity 164–5 ribotoxic responses 116, 117 stress process model, family caregiving 844–8 structural changes, aging 803–4 support groups, social support 305–6 support methods, nutrition 339 supportive care cancer treatment 520–1 CLL 576–7 HSCT 498–9 medical caregivers 306 surgery advances 406–14 anatomic changes 423 anesthetic implications 415–20 anesthetic management 421–3 brain cancer 754–5 breast cancer 407–8 cardiovascular system 424–5 chemotherapy 424 colorectal cancer 408, 713–14 cutaneous stomas 835–6 damage, surgery-related 832–6 endocrine tumors 407 esophageal cancer 406–7 gastric cancer 407 gynecologic cancers 410 head and neck cancer 410 limb amputations 836 liver cancer 409

Index

1574

lymphedema 835 management, cancer 391–2 muscle injury 835 nerve injury 832–5 neurosurgery 411 orthopedics 411 perioperative considerations 415–26 perioperative management 423–5 pharmacologic changes 420–1 physiological changes 415–20 prostate cancer 409, 731–3 pulmonary system 424 scar pathology 832 skin cancer 411 thoracic tumors 410 surgical approaches 399–405 advance directives 403–4 emergencies 402 minimally invasive surgery 402–3 rehabilitation 403 simultaneous surgical problems 401–2 wound healing 403 Surveillance, Epidemiology, and End Results (SEER) database 57–9 survival breast cancer 175–7, 183–4, 277, 680–7 epidemiology research 49–52 lung cancer 279 statistics 15–16 survival, host, tumor ‘aggressiveness’ 182–4 survivors, breast cancer 707–8 symptoms assessment 813–14 management 813–29 symptoms relevance, aging 207–22 systemic changes, physiological changes 537 T-cell activation 162–3 T-cell neoplasms, NHL 620 T lymphocytes, immune function changes 160, 436–7 tamoxifen, breast cancer 355–6, 677–93, 706–7 targeted therapy management, cancer 394 MM 647–8 taste changes, nutrition 324–5, 334 taxonomy, aging 227, 527–8, 538 TCC see transitional cell carcinoma teams GOPs 853–7 interdisciplinary 853–62 PORT 729–30 rehabilitation 831

Index

1575

SAOPs 857–61 test performance, clinical decision analysis 24 testicular cancer, susceptibility 76–80 thalidomide, MM 646–7 theories, aging 92 therapeutic approaches, cancer cachexia 244–6 therapy see treatment thoracic tumors, surgery 410 thyroid cancer detection/confirmation rates 48 diagnosis 57–9 susceptibility 76–80 thyroid-stimulating hormone (TSH) 216 time, vs. aging 68 tissue microenvironment, aging 129–30 tongue cancer, susceptibility 76–80 total parenteral nutrition (TPN) 339 toxicity chemotherapy 470–6 radiotherapy 658–9 TPN see total parenteral nutrition training future 390 geriatrics 389–90 oncology 389–90 transferrin, nutrition assessment 331 transitional cell carcinoma (TCC), bladder cancer 742–8 transplantation see hematopoietic stem cell transplantation treatment 8, 53–5 appropriate 59–62 bladder cancer 742, 743–6 brain cancer 764–5 breast cancer 667–9, 694–5 clinical decision analysis 19–21 cost-effectiveness 510–24 difficulties 62 factors affecting 56–64 goals 395 mortality rates 20 overtreatment 61–2 place 53–5 prostate cancer 730–7 QALYs 19–21 treatment-related recommendations, management, cancer 528–31 treatment tolerance, aging 207–22 trends chemotherapy 553–6 HSCT 491 mortality rates 29–37 trials see clinical trials tricyclic antidepressants 819 TSH see thyroid-stimulating hormone

Index

1576

tuberculosis 805 tumor ‘aggressiveness’ aging 150–5, 180–6 histology 181–2 historical perspective 180–6 survival, host 182–4 tumor development, longevity 90–2 tumor growth 147–57 carcinogenesis 147–8 immune forces 152 immune senescence 154–5 reduced 151–5 tumor-host interactions, aging 147–57 tumor incidence, aging 148–50 tumor kinetics, chemotherapy 469–70 tumor-specific antineoplastic therapy, chemotherapy 479–81 tumor suppression aging 127 cellular senescence 131–2 tumor suppressor genes molecular biology 103–5 prostate cancer 726 tumorigenesis apoptosis 140–1 requirements for malignant 128 spontaneous 75–6, 90–2 tumors latent 191 malignant, extreme ages 191–2 undiagnosed 191 tyrosine kinase inhibitors CGL 594–5 chemotherapy 481 undiagnosed tumors 191 unstaged cancers, diagnosis 58–9 urban versus rural, screening 378 uterine cancer detection/confirmation rates 48 diagnosis 57–9 susceptibility 76–80 valproic acid, hiccup 826–7 vessel wall, susceptibility 76–80 vestibular disturbances, nausea 824 VIG, bladder cancer 746 viral pneumonia 805 viruses, head and neck cancer 718–19 visceral perforation, emergencies 544 vital signs, aging 208–10 volume depletion, emergencies 543–4

Index

vomiting see nausea vulnerability 227–8 Werner syndrome 69 wound healing, surgical approaches 403 xerostomia 325–6 zinc chelators apoptosis 122 growth modulation 122 maturation 122 zinc-finger proteins carcinogenesis 106–7, 117 molecular biology 106–7 molecular model 114 MPS-1 ribosomal protein 107–16 ribotoxic responses 117 zymbal gland, susceptibility 76–80

1577